Received: 25 July 2019
Revised: 9 November 2019
Accepted: 13 November 2019
DOI: 10.1111/1541-4337.12516
COMPREHENSIVE REVIEWS IN FOOD SCIENCE AND FOOD SAFETY
Sesquiterpenes in grapes and wines: Occurrence, biosynthesis,
functionality, and influence of winemaking processes
Zizhan Li
Kate Howell
School of Agriculture and Food, Faculty of
Veterinary and Agricultural Sciences,
University of Melbourne, Parkville, Victoria,
Australia
Correspondence
Pangzhen Zhang, School of Agriculture and
Food, Faculty of Veterinary and Agricultural
Sciences, University of Melbourne, Parkville,
Vic 3010, Australia.
Email: pangzhen.zhang@unimelb.edu.au
Funding information
University of Melbourne
Zhongxiang Fang
Pangzhen Zhang
Abstract
Grapes are an important global horticultural product, and are mainly used for winemaking. Typically, grapes and wines are rich in various phytochemicals, including
phenolics, terpenes, pyrazines, and benzenoids, with different compounds responsible
for different nutritional and sensory properties. Among these compounds, sesquiterpenes, a subcategory of the terpenes, are attracting increasing interest as they affect
aroma and have potential health benefits. The characteristics of sesquiterpenes in
grapes and wines in terms of classification, biosynthesis pathway, and active functions
have not been extensively reviewed. This paper summarizes 97 different sesquiterpenes reported in grapes and wines and reviews their biosynthesis pathways and relevant bio-regulation mechanisms. This review further discusses the functionalities
of these sesquiterpenes including their aroma contribution to grapes and wines and
potential health benefits, as well as how winemaking processes affect sesquiterpene
concentrations.
KEYWORDS
biosynthesis, functionality, grape, sesquiterpene, winemaking
1
I N T RO D U C T I O N
Grape berries are composed of hundreds of different compounds, in which the volatile organic compounds (VOCs) significantly affect the aroma of grapes and wines (D’Onofrio,
Matarese, & Cuzzola, 2017). Among these aromatic compounds, terpenes represent a major category. Terpenes are a
group of plant secondary metabolites with strong pollinatorattractive characteristics that can protect plant from the invasion of foreign matters including microorganisms and insects
(Bicas, Dionisio, & Pastore, 2009). Terpenes can be structurally decomposed into isoprene (C5 H8 ) residues and classified as monoterpenes (10 carbons), sesquiterpenes (15 carbons), diterpenes (20 carbons), triterpenes (30 carbons), and
tetraterpenes or carotenes (40 carbons). The chemical structure of terpenes is highly diverse, with an estimation of over
40,000 different compounds (Yu & Utsumi, 2009).
Most identified terpenes contributing to specific grape and
wine flavor and aroma are classified as the monoterpenes subCompr Rev Food Sci Food Saf. 2020;19:247–281.
class. This subclass has been extensively studied for their significant influences on the aroma of grapes and wine, and considered as important quality traits of wine products (Black,
Parker, Siebert, Capone, & Francis, 2015). Various wine sensory characteristics, such as floral, fruity, and citrus flavors
are attributed to monoterpenes, linalool, nerol, and citronellol (Mateo & Jimenez, 2000). Monoterpenes originated from
grapes have been attracted more research interest compared to
other origins (Duhamel et al., 2018), and this subclass of compounds has been extensively reviewed on its structural identification, aroma and sensory characteristics, and biosynthesis
(Black et al., 2015; Mateo & Jimenez, 2000). Additionally,
the degradation products of carotenoids, C13-norisoprenoids
are also important odorants contributing to numerous aroma
in grapes and wines, such as honey-like (generated by
𝛽-damascenone) or raspberry-like (generated by 𝛽-ionone)
note (Baumes, Wirth, Bureau, Gunata, & Razungles, 2002).
Among the large terpene chemical family, sesquiterpenes
are a subclass abundant in plant essential oils and utilized
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247
SESQUITERPENES IN GRAPES AND WINES…
248
FIGURE 1
The structures of parent carbon skeletons of all sesquiterpenes identified in grapes and wine
in the perfumery industry (D’Onofrio, Boss, & Cox, 2006).
Aroma-active sesquiterpenes are known to exist in numerous
plant species, such as carrot and ginseng (Ahn et al., 2015;
Kjeldsen, Christensen, & Edelenbos, 2003). Some scientists
suggested that the sesquiterpene content in a grape variety is
responsible for the organoleptic and nutraceutical characteristics of grape products (D’Onofrio et al., 2017). For example,
rotundone, an oxygenated bicyclic sesquiterpene, was identified from grape and wine and responsible for “black pepper”
character in Shiraz wine (Wood et al., 2008). This sesquiterpene could be formed by aerial oxidation and biosynthesis
from its precursor named 𝛼-guaiene (Huang, Burrett, Sefton,
& Taylor, 2014; Takase et al., 2016). Other sesquiterpenes,
prominently 𝛼-ylangene, 𝛽-caryophyllene, 𝛼-caryophyllene,
and germacrene D, and oxygenated sesquiterpenes, including farnesol and nerolidol, have been identified as the main
sesquiterpenes constituents in grapes and wines (Luo et al.,
2019; May & Wüst, 2012; Zhang et al., 2016a). However,
research on sesquiterpene in grapes and wines is limited
compared to other terpenes subclasses such as monoterpenes
and isoprenoids. Important aspects including the classification of sesquiterpenes in grapes and wines, biosynthesis and
regulation mechanisms, aroma/flavor importance, potential
health benefits, and how winemaking processes can influence the sesquiterpene content in wine products, have not yet
been extensively reviewed. This review categorizes sesquiterpenes and their derivatives in grapes and wines, and elucidates their biosynthesis pathways and regulation mechanisms.
Importantly, the functionality of the sesquiterpenes, including their aromatic attributes and potential health benefits, and
the effects of winemaking on sesquiterpene composition are
summarized.
SESQUITERPENES IN GRAPES AND WINES…
249
1
2
3
Farnesane
Skeleton
4
5
FIGURE 2
6
Structure of acyclic sesquiterpenes in grape and wine
Bisabolane Skeleton
7
8
9
Germacrane Skeleton
13
FIGURE 3
10
Humulane Skeleton
14
15
11
12
Elemane Skeleton
16
17
Structures of monocyclic sesquiterpenes in grape and wines
2 CLASSIFICATION OF
SESQUITERP E N E S I N G R A P E S
AND WINES
Terpenes are widely distributed in plants, insects, microorganisms, animals, and halobios. Sesquiterpenes belong to the
terpene structural family with 15 carbon atoms and three isoprene units. Over 200 carbon skeletons have been identified
in this class of compounds from different organisms (Cane,
1990). Based on the number of carbon rings in their chemical structure, sesquiterpenes are typically classified as acyclic,
monocyclic, bicyclic, tricyclic, and tetracyclic (Figures 2 to
SESQUITERPENES IN GRAPES AND WINES…
250
18
19
20
21
22
23
Eudesmane Skeleton
24
27
28
33
34
25
29
26
30
35
31
36
32
37
38
Cadalane Skeleton
39
40
45
41
46
42
47
43
48
44
49
50
Guaiane Skeleton
51
Acorane Skeleton
52
53
Bicyclogermacrane Skeleton
57
54
Caryophyllane Skeleton
58
FIGURE 4
60
Bergamotane Skeleton
64
65
56
Chamigrane Skeleton
59
Eremophilane Skeleton
63
55
66
61
62
β-santalane Skeleton
67
Structure of bicyclic sesquiterpenes in grapes and wines
5; Cincotta, Verzera, Tripodi, & Condurso, 2015). Additionally, they can also be grouped according to the number of carbons in the rings, where most rings contain five, six, seven,
and even up to 11 carbons. Several sesquiterpenes are clas-
sified based on different oxygen-containing groups, which is
relevant to their physical and chemical properties and physiological activities, such as sesquiterpene alcohol, sesquiterpene
aldehyde, and sesquiterpene lactone (Da Costa, Terfloth, &
SESQUITERPENES IN GRAPES AND WINES…
251
Tricyclic sesquiterpenes:
Aromadendrane Skeleton
68
69
70
71
72
Copane Skeleton
75
Clovane Skeleton
76
83
Longifolane Skeleton
89
77
78
Cedrane Skeleton
79
80
Cubebane Skeleton
84
85
86
92
91
81
Thujopsane Skeleton
87
Panasinsane Skeleton α-santalane Skeleton
90
74
Aristolane Skeleton
Bourbonene Skeleton
82
73
93
88
Patchoulane Skeleton
94
95
Tetracyclic sesquiterpenes:
Cyclosativane Skeleton
96
FIGURE 5
Structure of tricyclic and tetracyclic sesquiterpenes in grape and wine
Gasteiger, 2005). To the best of our knowledge, 97 sesquiterpenes have been identified in grapes, wines, and pomaces and
are shown in Figures 2 to 5. They are classified by the number
of carbon rings and sub-classified by the parent carbon skeletons on which their chemical structures are based (Figure 1).
2.1
97
Acyclic sesquiterpenes
Within the identified sesquiterpenes, the acyclic group has
the smallest number of members, with only six acyclic
sesquiterpenes identified in grapes and wines and all containing a farnesane skeleton (Figure 2). The presence of (Z,
E)-𝛼-farnesene (1) and its isomer (E, E)-𝛼-farnesene (2) in
grapevines (V. vinifera L. cv. Marselan) has been confirmed,
although their concentrations may vary depending on the varieties and grapevine phenological stages (Chalal et al., 2015).
𝛽-Farnesene (3) was reported in Syrah, Nero d’Avola, and
Frappato wines in trace amount (Cincotta et al., 2015), which
are associated with the floral properties of wines. The presence of 2,3-dihydrofarnesol (4), farnesol (5), and nerolidol (6)
SESQUITERPENES IN GRAPES AND WINES…
252
in several types of wine such as Grillo and Cataratto was also
confirmed (Scacco et al., 2012). The production of compound
(5) and its isomer (6), as well as (4), is due to the instability
of the diphosphate group during the biosynthesis of (1), (2),
(3), and E-nerolidol in grapes (Petronilho, Coimbra, & Rocha,
2014).
2.2
Monocyclic sesquiterpenes
There are 11 monocyclic sesquiterpenes that have been identified in grapes and wines (Figure 2). 𝛼-Bisabolene (7) and
𝛽-bisabolene (8) have bisabolane skeleton, in which compound (7) was identified in Malbec (0.19 𝜇g/L) and in trace
amount in Petit Verdot and Sagrantino wine (Cincotta et al.,
2015; Perestrelo, Barros, Rocha, & Câmara, 2011), while
compound (8) was present in Shiraz grapes and Nero d’Avola
wines at low concentrations (Robinson, Boss, Heymann,
Solomon, & Trengove, 2011). Germacrenes are a subclass of
sesquiterpenes with germacrane skeleton, which can be further classified into germacrene A, germacrene B (13), germacrene C, and germacrene D (14), and they are precursors of
numerous sesquiterpenes hydrocarbons (Zhang et al., 2016c).
Among these four compounds, (14) is a major susquiterpene
in Vitis vinifera cv. Lemberger grapes and wine (May, Lange,
& Wust, 2013; Perestrelo et al., 2011). Compound (13) has
been identified in Baga grapes (Vitis Vinifera L. cv Baga) after
28 days of ripening. 𝛾-Elemene (16) and its isomer 𝛿-elemene
(17) were also identified in Baga grapes with the elemane
skeleton. However, these two compounds were observed in
grapes at a relatively late stage almost 35 days after ripening (Coelho, Rocha, Delgadillo, & Coimbra, 2006; Perestrelo
et al., 2011).
𝛼-Caryophyllene (15), also known as humulene, together
with 𝛼-curcumene (9), were identified from V. vinifera L. cv.
Marselan in response to sulfated laminarin treatment (Chalal et al., 2015). Compound (15) was also reported to be only
present in the grape skin, but not in the pulp of Bual and Bastardo grapes (Perestrelo et al., 2011). 𝛽-Sesquiphellandrene
(10) and 𝛼-bisabolol (12) were identified in Cabernet Sauvignon wine (Robinson et al., 2011), while lanceol (11), an
sesquiterpene alcohol, was identified in Merlot wine (Welke,
Manfroi, Zanus, Lazarotto, & Zini, 2012). Similar to compounds (7) and (8), compounds (9) to (12) also have the bisabolane skeleton (Breitmaier, 2006).
2.3
Bicyclic sesquiterpenes
Bicyclic sesquiterpenes represent the largest group of
sesquiterpenes in grapes and wines, which can be further classified into 11 subcategories based on the carbon skeleton, with
eudesmane, cadalane, and guaiane skeletosn being the most
prevalent ones (Figure 4).
2.3.1 Sesquiterpenes with eudesmane
skeleton
There are nine bicyclic sesquiterpenes (18 to 26) in grapes and
wines that have the eudesmane parent skeleton (Oliveira, Ferreira, Nunez, Rodriguez, & Emerenciano, 2000). 𝛼- (18) and
𝛽-Selinene (19) and 𝛾-eudesmol (20) were reported in Merlot, Petit Verdot, and Sagrantino wines, respectively (Cincotta
et al., 2015; Schreier, Drawert, & Junker, 1976). 𝛾-Selinene
(21), 𝛿-selinene (22), 7-epi-𝛼-selinene (23), selina-3,7-diene
(24), and selina-4,6-diene (25) are isomers of compounds (18)
and (19). Both (21) and (22) have been identified in V. vinifera
L. cv. Baga, Bual, and Bastardo grapes (Coelho et al., 2006;
Perestrelo et al., 2011), while (23) was identified in Shiraz
wine (Zhang et al., 2016c). Compounds (24) and (25) were
also reported in the exocarp of Shiraz grape in trace amount
(May et al., 2013; Parker, Pollnitz, Cozzolino, Francis, &
Herderich, 2007). Eudesm-7(11)-en-4-ol (26) is a sesquiterpene alcohol with the eudesmane skeleton, and has only been
reported in grape pomaces of Nerello Mascalese but not in
other cultivars (Ruberto, Renda, Amico, & Tringali, 2008).
2.3.2
Sesquiterpenes with cadalane skeleton
The sesquiterpenes with cadalane skeleton is the largest group
of sesquiterpenes identified in grapes and wines with 24 compound being reported (ApSimon, 2009). 𝛼-Cadinene (27),
𝛽-cadinene (28), 𝛾-cadinene (29), 𝛿-cadinene (30), 𝜔cadinene (31), and 𝛼-amorphene (32) are isomers. Among
these, compounds (27) to (30) and (32) were identified in
Baga grape at middle to late maturation stages (Coelho
et al., 2006). Compounds (28) to (30) were also identified
in distillates obtained from pomaces of Albarinõ, Treixadura,
Godello, Loureira, Dona Branca, and Torronte´s grapes
(Lopez-Gallego, Agger, Abate-Pella, Distefano, & SchmidtDannert, 2010; May et al., 2013), while (31) was only reported
in Shiraz grape (Zhang et al., 2016c). Three sesquiterpene
alcohols, 𝛼-cadinol (33), epi-𝛼-cadinol (34), and 𝛿-cadinol
(35) have been reported in grape pomaces and berry skin distillates. Compound (33) was identified from the distillates of
Istrian Malvasia, Chardonnay, Muscat Blanc, Rose Muscat of
Porec, and Teran grapes (Lukic et al., 2010), while (34) and
(35) were detected in the stalks of Frappato, Nerello Mascalese, Nero d’Avola, and Cabernet Sauvignon grapevines
(Ruberto et al., 2008). 𝛼-Muurolene (36) and 𝛾-muurolene
(37) are major sesquiterpenes reported in Cabernet Sauvignon
and Riesling grapes (Kalua & Boss, 2009, 2010). According to Cincotta et al. (2015), compound (36) was also identified in wine and grape of Shiraz, Merlot, and Nero d’Avola.
However, muurola-4 (14), 5-diene (38) was only reported in
stalks of Nerello Mascalese and Cabernet Sauvignon grapes
(Ruberto et al., 2008). Bicyclosesquiphellandrene (40) and
epi-bicyclosesquiphellandren (41) are both stereoisomers of
(38). Compound (40) was identified in Shiraz grape (Parker
SESQUITERPENES IN GRAPES AND WINES…
et al., 2007), while (41) has been reported in Baga grape at
very late stage of ripening (Coelho et al., 2006). The alcohol type, t-muurolol (39) was reported in Storgozia grapes, a
Bulgarian grapevine variety (Todorova, Batovska, Parushev,
Djakova, & Popov, 2010).
Cadalene (42) and 𝛼-calacorene (43) were previously identified in Baga grape and wine (Keyzers & Boss, 2009; Rocha,
Coelho, Vinholes, & Coimbra, 2006). Compound (43) was
also detected in berry distillates and pomaces of various grape
varieties, such as Istrian Malvasia, Chardonnay, and Muscat
Blanc (Lukic et al., 2010). 𝛽-Calacorene (44) is the stereoisomer of (43), and previously reported in Shiraz grape (Parker
et al., 2007) and the exocarp of a neutral variety named Lemberger (May et al., 2013). Calamenene (45) and epizonarene
(47) have been reported in the grape of six different varieties,
including Yellow Muscat, Gewürztraminer, Riesling, Lemberger, Cabernet Sauvignon, and Shiraz (May & Wüst, 2012).
Compound (45) was also reported in the skin distillates of
Teran grapes with low concentration (0.13±0.11 mg/L) and
in other grape varieties of Muscat Blanc and Cabernet Sauvignon with even lower contents (Lukic et al., 2010). Calamene
(46) has only been reported in Australian Cabernet Sauvignon wine, but not grapes (Robinson et al., 2011). Zonarene
(48) is a stereoisomer of (47), and reported in Shiraz grape
(Parker et al., 2007). Cubenol (49) and epi-cubenol (50) are
two alcohol-type sesquiterpenes with the cadalane skeleton.
Compound (49) was only reported as a novel constituent in
Cabernet Sauvignon wine, and has not been detected in other
V. vinifera L. varieties (Robinson et al., 2011), while (50) has
been reported in Shiraz grape only (Zhang et al., 2016c).
2.3.3
Sesquiterpenes with guaiane skeleton
Bicyclic sesquiterpenes with guaiane skeleton have two fused
rings with five and seven carbons, respectively (Figure 4). 𝛼Guaiene (51), 3,7-guaiadiene (52), guaia-6,9-diene (53), and
𝛾-gurjunene (54) are representative sesquiterpenes in this subcategory and they are isomers with similar structures. Compound (51) has been considered as critical sesquiterpene with
aromatic importance, as recent researches indicated that it
is the precursor of rotundone (55) (Takase et al., 2016), a
sesquiterpene ketone contributes to the peppery character in
Shiraz grape and wine (Wood et al., 2008). The presence of
(51) in grape was confirmed 40 years ago (Schreier et al.,
1976), and has been detected in Shiraz grape at low concentrations (Zhang et al., 2016c). Compound (52) was reported
in ripened Vitis vinifera L. cv. Baga grapes (Coelho et al.,
2006), while (53) was identified in different grape varieties
including Yellow Muscat, Gewürztraminer, Riesling, Lemberger, Cabernet Sauvignon, and Shiraz (Coelho et al., 2006;
May & Wüst, 2012). So far, (54) has only been reported
in Shiraz wine with concentration about 1.4 𝜇g/L (Cincotta
et al., 2015). Compound guaiazulene (56) also has the gua-
253
iane skeleton, and has been reported in the skin of Bual and
Bastardo grapes (Perestrelo et al., 2011) and sparkling wine
made from Fernão-Pires and Baga grape (Coelho, Coimbra,
Nogueira, & Rocha, 2009).
2.3.4
Other bicyclic sesquiterpenes
𝛼-Alaskene (57) has the acorane skeleton (Brock, Huss,
Tudzynski, & Dickschat, 2013), and has been reported in
Cabernet Sauvignon wines in Australia (Robinson et al.,
2011). Bicyclogermacrene (58) is structurally similar to germacrene with a classic bicyclogermacrane skeleton, and has
been reported as a trace constituent in the skin of Bual and
Bastardo grapes (Perestrelo et al., 2011). 𝛽-Caryophyllene
(59) is the stereoisomer of (15) derived from a typical
caryophyllane skeleton (Tang, Gao, & Zhang, 2015). It has
been reported in numerous studies in different grape varieties, such as Shiraz and Cabernet Sauvignon grapes (Hampel,
Mosandl, & Wust, 2005; Kalua & Boss, 2009). 𝛼-Chamigrene
(60) and 𝛽-chamigrene (61) are two stereoisomers consisted
of a chamigrane skeleton (Kimura, Kamada, & Tsujimoto,
1999). These two compounds have been recognized in table
wines but not in any grape varieties (Coelho et al., 2009;
Rocha et al., 2006), therefore, may possibly come from oak.
isocalamenene (62) could be derived from (45) through isomerization (Chang & Wu, 1999), and it has been identified in Shiraz grapes as a major sesquiterpene (Parker et al.,
2007). 𝛼-Bergamotene (66) was reported in Chardonnay grape
berry skin distillates and further identified as a constituent
in young leaves of grapes at relatively low concentration
(0.08 ± 0.06 mg/L of distillates; Lukic et al., 2010; Matarese,
Scalabrelli, & D’Onofrio, 2013). Both valencene (63) and
𝛽-vetivenene (64) have the eremophilane skeleton, which
may be generated from eudesmane skeleton by the migration of methyl group from C-10 to C-5 (Lucker, Bowen, &
Bohlmann, 2004). Compound (63) is a volatile compound
identified in Baga grape, and in Shiraz and Petit Verdot wines
(Cincotta et al., 2015; Coelho et al., 2006). Compound (64)
was reported in some Cabernet Sauvignon wine originated
from West Australia (Robinson et al., 2011). The same study
also reported the presence of an oxide-type sesquiterpene
named Cabreuva oxide D (65), which has not been reported
in any other studies. 𝛽-Santalol (67) is a sesquiterpene alcohol
with a 𝛽-santalane skeleton (Breitmaier, 2006), and has been
detected in Brazilian Merlot wine (Welke et al., 2012).
2.4
Tricyclic and tetracyclic sesquiterpenes
Among tricyclic sesquiterpenes in grapes and wines,
aromadendrane is the common carbon skeleton that is
structurally similar to guaiane precursor (Figure 5). The
aromadendrane is a 6,11-cycloguaiane with an additional
cyclopropyl ring formed by cyclization (Cincotta et al., 2015).
Aromadendrene (68), allo-aromadendrene (69), 𝛼-gurjunene
254
(70), 𝛽-gurjunene (71), isoledene (72), viridiflorol (73), and
epiglobulol (74) are reported in grapes and wines with the
aromadendrane skeleton. Compound (68) was identified in
Baga grape (Coelho et al., 2006). Another study also detected
the presence of (68) and its isomer (69) in Bual and Bastardo
grape (Perestrelo et al., 2011). Compound (70) was identified
in Cabernet Sauvignon grape during the pre-veraison stage
(Kalua & Boss, 2010), and also reported in Shiraz, Nero
d’Avola, Frappato, and Petit Verdot wines (Cincotta et al.,
2015). The later study also reported the presence of (73), a
sesquiterpene alcohol, in Nero d’Avola wine. Compounds
(71) and (72) were both identified from the skin of Bual and
Bastardo grapes (Perestrelo et al., 2011), whereas (74) was
reported as in Shiraz grape (Zhang et al., 2016c).
𝛼-Copaene (75), 𝛽-copaene(76), 𝛼-ylangene (77), and
𝛽-ylangene (78) are four stereoisomers with the copane parent
skeleton (Figure 5), which is supposed to be derived from the
cadalane skeleton (Bhat, Nagasampagi, & Sivakumar, 2005).
Compound (75) has been identified from numerous grape
varieties, including Cabernet Sauvignon, Gewürztraminer,
Riesling, Yellow Muscat, and Shiraz grapes (Kalua & Boss,
2009, 2010; May & Wüst, 2012; Schreier et al., 1976). However, compound (76) was only reported in Australian Shiraz grapes (Parker et al., 2007). Similar to (75), (77) was
extensively reported in different studies as one of the major
sesquiterpene compounds in grapes (Coelho et al., 2006;
Forde, Cox, Williams, & Boss, 2011), while (78) and aristolene (79) were reported in the distillates of five grape varieties under dichloromethane extraction (Lukic et al., 2010).
Compound (79) and calarene (80) are sesquiterpenes with an
aristolane skeleton (Olennikov, Dudareva, Osipenko, & Penzina, 2009), in which (80) was firstly identified in Shiraz grape
skin (Vernin et al., 1988). 𝛼-Cedrene (81) (cedrane skeleton)
is a tricyclic sesquiterpene that has been reported in Cabernet Sauvignon and Petit Verdot wine (Cincotta et al., 2015;
Verzera et al., 2016). Clovene (82) is derived from the clovane
skeleton and was reported at low concentration (0.55 ± 0.09
𝜇g/kg of berry weight) during Shiraz grape ripening (Zhang
et al., 2016c).
𝛼-Bourbonene (83) and 𝛽-bourbonene (84) are two
stereoisomers with the bourbonane skeleton (Figure 5). Compound (83) was identified in marc distillates of four different grape including Istrian malyasia, Chardonnay, Rose
Muscat of Porec, and Teran (Lukic et al., 2010), while (84)
was extensively reported in a number variety of grapes and
wines and considered as a common sesquiterpene in Shiraz
and grape (Ruberto et al., 2008; Schreier et al., 1976). 𝛼Cubebene (85), 𝛽-cubebene (86), and cubebol (87) are tricyclic sesquiterpenes with cubebane skeleton, where (85) and
(86) were both identified in the skin of Bual and Bastardo
grapes (Perestrelo et al., 2011). Compound (85) was also
reported in Cabernet Sauvignon grape (Kalua & Boss, 2009,
2010). Compound (87) is a sesquiterpene alcohol detected
SESQUITERPENES IN GRAPES AND WINES…
in Gewürztraminer grape (May et al., 2013). Sesquichamene
(88), also known as (Z)-thujopsene, has a classic thujopsane
skeleton, and previously reported in Brazilian Merlot (Welke
et al., 2012). The study also documented a sesquiterpene alcohol 𝛼-santalol (93), which is the stereoisomer of (67) with
the 𝛼-santalane skeleton (Matsuo & Mimaki, 2012), and the
patchoulane skeleton-derived 𝛽-patchoulene (94) in this grape
variety (Breitmaier, 2006). Cyperene (95) is also derived from
the patchoulane skeleton (Ahn et al., 2015) and was identified
from Bulgarian grape (Todorova et al., 2010).
Longifolene (89) is a volatile sesquiterpene emitted by V.
vinifera L. cv. Marselan grapevine cuttings with a longifolane
skeleton (Chalal et al., 2015), while its stereoisomer 4,5,9,10dehydro-isolongifolene (90) and 𝛼-panasinsen (92) (panasinsane parent skeleton) were only reported in Cabernet Sauvignon wine in Western Australia, but has not been reported
in any grape varieties (Robinson et al., 2011), and therefore may come from winemaking process. Cycloisolongifolene (91) was reported in sparkling wine made from Baga
and Fernao-Pires grape varieties. It has been suggested that
(90) could be derived from (89) through rearrangement and
isomerization catalyzed at acidic condition (Yadav, Nayak, &
Dev, 1980). Nonetheless, the accurate skeleton of (90) and
(91) has not been mentioned in any literature.
Regarding to tetracyclic sesquiterpenes, the increasing
carbon rings result in complicated identification and analysis
of these compounds. Therefore, the tetracyclic sesquiterpenes
have not been extensively studied, with limited tetracyclic
sesquiterpenes reported in grapes and wines (Figure 5).
Cyclosativene (96) with a cyclosativane skeleton (ApSimon,
2009) was reported in ripe Baga grape (Coelho et al., 2006)
and Australia shiraz grape (Parker et al., 2007). Longicyclene
(97) was only reported as a volatile compound emitted by
Marselan grapevine cutting (Chalal et al., 2015), and it has
been considered as the interconversion compound of (89)
(Hanson, 2007). However, the accurate parent skeleton of
(97) has not been reviewed from any literature.
3 BIO SYNTH ES IS O F
S ES Q UITERP ENES IN G RAP ES
AND WINES
In recent decades, sesquiterpenes have been continuously
challenging chemists and food scientists who focus on their
synthesis and origin. It has been suggested that terpene compounds could include over 200 diverse carbon skeletons from
different species (Cane, 1990), and all sesquiterpenes share
a common intermediate precursor farnesyl diphosphate (FPP)
(Ruzicka & Stoll, 1922). FPP is condensed from two isomeric
five-carbon precursors, IPP and DMAPP and catalyzed by
farnesyl diphosphate synthase (FPPS) as shown in Figure 6
(Zhang et al., 2016c). IPP and DMAPP could be generated
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MVA Pathway
255
MEP Pathway
be chemically synthesized as a major product when (59) is
treated in concentrated sulfuric acid in diethyl ether at 0 to
20 ◦ C for over 30 min (Collado, Hanson, & Macias-Sanchez,
1998).
3.2
IPP
2hIPP
Farnesyl Carbocation
FPP
FIGURE 6
Biosynthesis of fanesyl carbocation from isopentenyl
diphosphate (IPP) and dimethylallyl diphosphate (DMAPP) via
2-C-methyl-D-erythritol-4-phosphate (MEP) and mevalonate (MVA)
pathway
via the MEP pathway in the plastid and the MVA pathway
in the cytosol of plants (Ikram, Zhan, Pan, King, & Simonsen, 2015). Typically, the MVA pathway was considered to
provide the most IPP and DMAPP for the biosynthesis of
sesquiterpenes (Bohlmann & Keeling, 2008). However, precursors from both two pathways could be incorporated into
sesquiterpenes biosynthesis (May et al., 2013). FPP could
then undergo isomerization and cyclization, which provide
possibilities for generating diversified sesquiterpene structures. Sesquiterpenes identified in grapes are derived from
FPP via farnesyl carbocation and the downstream pathway can
be grouped into four major categories with some categories
further classified into subcategories (Figure 7).
3.1
Acyclic cyclization pathway
DMAPP
(E, E)-Humulyl carbocation pathway
The farnesyl carbocation can undergo cyclization at the
C10-C11 double bond, leading to the generation of (E, E)humulyl carbocation (Davis & Croteau, 2000; Mander &
Liu, 2010). This biosynthesis pathway is shown in Figure 8
and is mainly responsible for the production of compounds
(15), (59), (82), and (92). According to Zhang et al. (2016c),
(15) and (59) were most abundant at the early stage of Shiraz grape berry development. The biosynthesis of these two
compounds is controlled by three terpenoid synthase genes
(VvTPS), VvGwECar, VvPNECar, and VvPNaHum (Martin
et al., 2010). Compound (58) is regulated by VvPNEb2epiCar
(Davis & Croteau, 2000). Although the genes responsible for
the biosynthesis of (82) and (92) in grape have not been identified, it has been confirmed that (82) could be formed by
cyclization of farnesyl carbocation catalyzed by AcoTPS15
gene in pineapple (Chen et al., 2017). Compound (92) could
The acyclic cyclization pathway starts with farnesyl carbocation and is responsible for the biosynthesis of (1) to (5)
(Figure 9; Durairaj et al., 2019). Different from other pathways, the parent farnesyl cation does not undergo a cyclization process in this pathway and is mainly responsible for
the productions of several acyclic sesquiterpenes from farnesene family. VvCSaFar is the only reported terpene synthase gene in Vitis vinifera responsible for the biosynthesis
of (2), while VvPNbCur could barely lead to the production
of (1) and (3) (Martin et al., 2010). Compounds (4) and (5)
are two sesquiterpene alcohols derived from farnesene. TPS2
gene isolated from Phyllostachys edulis was confirmed to contribute to the biosynthesis of (5) (Cheng et al., 2007), while
(4) is likely to be derived from this pathway due to the similar
chemical structure to (5). However, the accurate biosynthesis
enzyme in grapevine has not been identified yet.
3.3
(E, E)-Germacradienyl cation pathway
The (E, E)-germacradienyl cation pathway starts with (E, E)germacradienyl cation, which is derived from the farnesyl carbocation through C10-C1 cyclization (Durairaj et al., 2019).
This pathway is significantly branched and could be classified into five main subpathways named germacrene A, germacrene B, germacrene C, germacrene D, and bicyclogermacrene pathways (Figures 10–12).
3.3.1
Germacrene A pathway
Germacrene A derived from (E, E)-germacradienyl cation is
the outset of germacrene A pathway (Davis & Croteau, 2000)
(Figure 10). Sesquiterpenes synthesized through this pathway include compounds (18) (20) (21) (51) (55) (63), and
(95). TPS VvGwGerA (Gw38F3) is predominantly responsible for the production of germacrene A (52%) and (18)
(24%) in grapes (Martin et al., 2010). Compound (63) was
confirmed as a major compound generated by valencene synthase (VvVal) in grapevine berry and flower (Lucker et al.,
2004). The TvGuaS enzyme encoded by VvTPS24 allele is
mainly responsible for the biosynthesis of (51). Additionally, VvTPS24 could code the VvPNSelnt enzyme, which also
contributes to the biosynthesis of (51) at a small percentage
(3.5%) (Martin et al., 2010). However, this enzyme is mainly
responsible for the biosynthesis of (22) and (23). Compound
(51) could be converted into (55) by simple aerial oxidation,
which is a critical chemical synthesis pathway responsible
for the peppery aroma in cool climate region Shiraz (Huang
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256
FIGURE 7
Biosynthesis pathways of sesquiterpenes identified in grapes and wines. Black arrow line illustrates the proposed biosynthesis
pathway summarized from the literatures. The red arrow lines represent unconfirmed biosynthesis pathways which will be elucidated in the
following sections. The brown dashed arrow lines illustrate the potential chemical synthesis of selected sesquiterpenes
FIGURE 9
Biosynthesis of selected sesquiterpenes derived from
the acyclic cyclization pathway. The red arrow line represents the
predicted biosynthesis pathway of compound (4)
FIGURE 8
Biosynthesis of selected sesquiterpenes derived from
the (E, E)-humulyl carbocation pathway. The red arrow line represents
the predicted biosynthesis pathway of compound (92) based on
chemical synthesis as the exact biosynthesis pathway has not been
confirmed yet
et al., 2014). A cytochrome P450 CYP71BE5 enzyme, which
is highly related to VvSTO2 gene, is the biosynthesis enzyme
responsible for this oxidation reaction in grapevine (Takase
et al., 2016). Compound (51) could also lead to the production
of (95) via rearrangement and cyclization in a different pathway of producing (55) (Sonwa & Konig, 2001). VvPNSeInt
was identified as the enzyme responsible for the biosynthesis of (21) from germacrene A as a minor reaction product
(Martin et al., 2010). Compound (19) has been proved to be
highly associated with germacrene A; however, the enzymes
responsible for producing this compound in grape have not
been confirmed.
SESQUITERPENES IN GRAPES AND WINES…
257
FIGURE 10
Biosynthesis of selected sesquiterpenes derived from the germacrene A pathway (in yellow dashed box), germacrene B pathway
(in green dashed box), and germacrene C pathway (in blue dashed box), all of which are under the (E, E)-germacradienyl cation pathway. The red
arrow line represents the predicted biosynthesis pathway of compound (19). The brown dashed arrow lines illustrate the potential chemical synthesis
of selected sesquiterpenes in these sub-pathways
3.3.2
Germacrene B pathway
Similar to the germacrene A pathway, the germacrene B
pathway initiated from germacrene B (13) derived from (E,
E)-germacradienyl cation. This pathway is mainly responsible for the biosynthesis of (16), (24), and (26) (Davis &
Croteau, 2000) (Figure 10). VvPNGerD was identified as a
functional gene in charge of the biosynthesis of (13) in grapes
(Martin et al., 2010). Regarding to downstream compounds,
(16) and (26) could be chemically synthesized from germacrene B by undergoing the Cope rearrangement at above
120 ◦ C and sulfuric acid induced rearrangement, respectively
(Adio, 2009). However, the biosynthesis mechanism of both
compounds in grapes have not been confirmed. Selina-3,7
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258
(11)-diene synthase was confirmed to catalyze the biosynthesis of (24) in actinomycetes, but not yet in grape (Rabe, Citron,
& Dickschat, 2013).
3.3.3
Germacrene C pathway
Germacrene C is the common precursor of the germacrene
C pathway derived from the (E, E)-germacradienyl cation
(Figure 10). Different from germacrene A and B, the biosynthesis pathway of germacrene C includes an additional hydrogen shift step (Davis & Croteau, 2000). Compounds (53) and
(22) are two major products of this pathway and share similar production pattern. Previous study indicated that (23) and
(63) could also be derived from the germacrene C pathway
(Lucker et al., 2004). VitisM4670 cDNA expression could
result in the production of VvVal and VvTPS enzymes responsible for the biosynthesis of (23) and (63) (Lucker et al., 2004).
Nonetheless, these two sesquiterpenes could also be generated
from germacrene A or C pathway, since VvPNSelnt enzyme
could catalyze the production of (23) together with (22) and
(51) (Zhang et al., 2016c). Compound (17) can be chemically
synthesized from germacrene C by undergoing Cope rearrangement at 100 ◦ C in solution. Compound (25) can also
be produced when germacrene C is under acidic conditions
with silica gel at room temperature (Adio, 2009). Regarding to the biosynthetic pathway, 𝛿-elemene synthase coded by
RlemTPS4 gene has been identified to be responsible for the
production of (17) in Citrus jambhiri (rough lemon; Uji et al.,
2015), while the biosynthesis of (25) is mainly associated with
germacrene D pathway (Zhang et al., 2016c). The genes and
enzymes responsible for the biosynthesis of these two compounds in grapevine have not been identified.
3.3.4
Germacrene D pathway
The germacrene D pathway starts from compound germacrene D (14), which is also derived from (E, E)germacradienyl cation. The biosynthesis pathway of (14)
shares the same intermediate cation as germacrene C. Typically, (14) in grape is regulated by VvGwGerD and VvPNGerD genes, though it could also be a minor product of
VvGwECar and VvPNECar gene regulation (Bülow & König,
2000; Davis & Croteau, 2000). This pathway is considered
as one of the most important pathways responsible for the
biosynthesis of numerous sesquiterpenes in grape and could
be further classified into three sub-pathways: cadinenyl cation
pathway, muurolenyl cation pathway, and amophenyl cation
pathway as illustrated in Figure 11 (Bülow & König, 2000)
The cadinenyl cation sub-pathway starts from cadinenyl
cation and is mainly responsible for the biosynthesis of (27)
and (29) (Zhang et al., 2016c). In grape, VvGwgCad gene is
mainly responsible for producing (29) (Martin et al., 2010).
The rearrangement and cyclization of cadinenyl cation can
result in the biosynthesis of (28), (30), and (31), which are
the structural isomers of (27) and (29) (Bülow & König,
2000). VvPNCuCad has been confirmed as the functional
gene responsible for producing (30) in grape as a major product together with (29) as a minor product (Martin et al., 2010).
Compound (27) has also been recognized as the primary rearrangement product from cadinenyl cation (Bülow & König,
2000). However, the gene responsible for biosynthesis of (27)
has not been identified. Although Bülow and König (2000)
illustrated that (31) might be synthesized from (27) via (28),
the production pattern of (31) seemed to be different from
that of (27) and (29) during berry development (Zhang et al.,
2016c). Therefore, there is a possibility that (31) could be
formed via an alternative pathway. Compounds (35), (36),
and (37) can be biosynthesized via the cadinenyl cation pathway with the action of 𝛿-cadinol synthase (BvCS) in Boreostereum vibrans of Basidiomycota (Zhou et al., 2016). In
grape, VvShirazTPS26 and VvShirazTPS07 synthases have
been reported responsible for the biosynthesis of (36) and
(37), respectively (Dueholm, Drew, Sweetman, & Simonsen,
2019). Nonetheless, (36) and (37) may mainly be formed from
another pathway discussed below (Zhang et al., 2016c).
Muurolenyl cation is also generated from (14) (Bülow
& König, 2000), and further lead to the muurolenyl cation
pathway, which is responsible for the biosynthesis of 20
identified sesquiterpenes in grape (Davis & Croteau, 2000).
This is the primary biosynthesis pathway of (36) and (37),
together with other products, including (30), (40), and (75)
(Bülow & König, 2000; Davis & Croteau, 2000). VvPNCuCAD (CAN76781) is responsible for biosynthesis of (30) and
(75) in grapevines (Martin et al., 2010). Compound (30) is
primarily biosynthesized via this sub-pathway, and it is an
essential intermediate for the biosynthesis of numerous downstream sesquiterpenes. Compounds (38), (41), (43), (44), (47),
and (48) are oxidation products derived from (30) (Bülow &
König, 2000), and (47) and (48) could be further converted
into (45), which may also be produced from (38). However,
the conversion from (38) to (45) was not identified at any
developmental stages in Shiraz grape (Zhang et al., 2016c).
Compound (39) has a similar basic skeleton as (38), and it
is likely derived from the same pathway, however not confirmed in any study. Compound (42) was supposed to be
derived from (43) and (45) in this pathway (Dutta et al., 2017).
However, limited genes and enzymes have been identified in
grapes responsible for the biosynthesis of sesquiterpenes in
this sub-pathway (Bülow & König, 2000), which requires further investigation.
The amophenyl cation pathway is capable of producing
(32), (47), (48), and (77). Previous study reported that in vivo
expression of VvivMA-TPS28 gene contributed to 14% of
(32) biosynthesis in grapevine flower (Smit, Vivier, & Young,
2019). Very recently, VvShirazTPS07 gene has been characterized, which is responsible for the biosynthesis of (77)
and (78) as major products in Shiraz grape (Dueholm et al.,
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259
FIGURE 11
Biosynthesis of selected sesquiterpenes derived from germacrene D pathway. This pathway can be divided into cadinenyl cation
sub-pathway (in yellow dashed box), muurolenyl cation sub-pathway (in green dashed box), and amorphenyl cation sub-pathway (in pink dashed
box). The red arrow line represents the predicted biosynthesis pathway of compounds (35) and (39) in grapes and wines. The brown dashed arrow
lines illustrate the potential chemical synthesis and rearrangement of selected sesquiterpenes in the sub-pathways
2019). Additionally, the conversion of (47) and (48) might
also occur in this pathway similar to that in the muurolenyl
cation pathway catalyzed by Lewis acid (Bülow & König,
2000). Nonetheless, the VvTPS gene responsible for this conversion is still elusive (Zhang et al., 2016c).
Furthermore, germacrene D pathway is also capable of
the biosynthesis of (22), (25), (76), and (84), but not through
any sub-pathways described above (Bülow & König, 2000).
Controversially, (22) was typically considered as a product
of the germacrene C pathway, however, the exact mechanism
remains elusive (Zhang et al., 2016c). Chemically, (76) and
(84) can be synthesized from (14), and this conversion is
regarded as a pigment-sensitized photocyclization (Brown,
1968). The acid-catalyzed conversion between (83) and (84)
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260
has also been reported (Bülow & König, 2000). Biologically, 𝛽-copaene synthase (cop 4) was isolated from fungus
Coprinus cinereus and mainly responsible for the production
of (76) (Agger, Lopez-Gallego, & Schmidt-Dannert, 2009).
Compound (25) was identified as a minor product catalyzed
by the gamma-humulene synthase (ag5) in Pinus grandis.
Nonetheless, the genes responsible for the biosynthesis
of these sesquiterpenes in grape have not been identified.
Importantly, the VvTPS gene controlling the cadinenyl and
amophenyl cation pathway is most likely different from that
regulating muurolenyl pathway as the patterns of sesquiterpenes evolution during berry development were diverged
(Zhang et al., 2016c).
3.3.5
Bicyclogermacrene pathway
Although the gene responsible for the biosynthesis of (58)
in grape has not been identified, the precursor of (58) has
been confirmed to be (E, E)-germacradienyl cation in other
plants (Figure 12; Attia, Kim, & Ro, 2012; Booth, Page,
& Bohlmann, 2017). Compounds (68)-(72) are downstream
products of (58) in grapevine (Davis & Croteau, 2000;
Paknikar & Fondekar, 2018). VvPNCuCAD (CAN76781)
was confirmed to encode the terpene synthase responsible
for the biosynthesis of (70) as a minor product in grape,
whereas (68) and (69) were minor products generated by
VvShirazTPS26 (Dueholm et al., 2019). Compound (72) was
confirmed to be catalyzed by EC12-ILS (isoledene synthase),
which was functionally characterized and derived from endophytic xylariaceae (Wu et al., 2016). With the same skeleton
to (72), (73) and (74) were suggested to be derived from this
pathway based on studies in other plants (Brown, 2010; Wu
et al., 2016). TPS CO27-31178 gene was identified from four
endophytic xylariaceae, and has been confirmed to catalyze
(73) (Wu et al., 2016). The biosynthesis pathway of (79) and
(80) was proposed to be derived from (58) via hydrogen rearrangement (Le Bideau, Kousara, Chen, Wei, & Dumas, 2017).
However, the genes and synthases responsible for the biosynthesis of (73), (74), (79), and (80) in grapes remain to be further investigated. Compound (54) was regarded as a minor
sesquiterpene catalyzed by TPS-Y1. Since (54) is the structural isomer of (70) and (71), it is hypothesized that (54) is
generated via this pathway. However, the accurate mechanism
needs to be confirmed.
3.3.6 Other pathways derived from (E,
E)-germacradienyl cation
Apart from the metabolites described above, compounds (20),
(33), (35), (52), (56), (73), and (94) are also suggested to
be derived directly from the (E, E)-germacradienyl cation
(Figure 12). However, most of their biosynthesis pathways
have only been confirmed in other plants rather than grapes.
VvShirazTPS26 has been suggested as a multiple-product
synthase responsible for the formation of (33) and (35) from
FPP in grape (Dueholm et al., 2019). Eudesmol synthase
(PhEDS) was suggested to be the enzyme responsible for
the biosynthesis of (20) as a minor product in ginger (Blerot
et al., 2018), however, not investigated in grapevine. TPS
CO27-31178 was identified as the gene responsible for the
formation of (73) in endophytic xylariaceae (Wu et al., 2016).
PatTps117 as a patchoulol synthase was found responsible for
the biosynthesis of 14 sesquiterpenes, including (94) from (E,
E)-germacradienyl cation in Pogostemon cablin (Deguerry
et al., 2006). Both (52) and (56) are of guaiane skeleton,
and most compounds with this skeleton are derived directly
from (E, E)-germacradienyl cation (Durairaj et al., 2019).
Therefore, (52) and (56) are proposed to be synthesized
from (E, E)-germacradienyl cation, although this requires further research. Eudesmols are biosynthesized from the germacradienyl cation. Compound (26) is an isomer of 𝛼- and
𝛽-eudesmol, which have been confirmed to be catalyzed by
eudesmol synthase in ginger (Yu et al., 2008). The same study
suggested (26) to be catalyzed by the same enzyme from the
eudesmol cation. Compound (64) is considered as the product of Wagner–Meerwein rearrangement of the germacradienyl cation (Abelson et al., 2012). However, the enzymes
and genes responsible for this reaction have yet been identified. The biosynthesis pathway of (46) needs further investigation. Since its skeleton is very similar to most sesquiterpenes derived from the germacrene D pathway, it is hypothesized that (46) might also be derived from this biosynthesis
pathway.
3.4
The nerolidyl cation pathway
Instead of undergoing cyclization to form (E, E)-humulyn
and (E, E)-germacradienyl carbocation, the farnesyl cation
could also isomerize to form a nerolidyl cation as an important precursor responsible for the biosynthesis of several
sesquiterpenes (Durairaj et al., 2019). This pathway also
overlaps with the germacrene D pathway as the main precursors and sesquiterpenes including compound (14) and
muurolenyl cation in germacrene D pathway may also be
produced via nerolidol diphosphate (Davis & Croteau, 2000;
Zhang et al., 2016c). The muurolenyl cation pathway was suggested to be generated from nerolidol cation rather than germacrene D pathway at 4 weeks post-flowering since other
major sesquiterpenes of the muurolenyl cation pathway were
not detected at the same time period (Davis & Croteau,
2000; Zhang et al., 2016c). However, there are still numerous sesquiterpenes unique to the nerolidyl cation pathway as
shown in Figures 7 and 13.
Typically, the nerolidyl cation pathway could be further
classified into three sub-pathways based on different cations
precursors derived from the original nerolidyl cation. C1attack on the C10-C11 double bond could result in C1-C10
SESQUITERPENES IN GRAPES AND WINES…
261
FIGURE 12
Biosynthesis of selected sesquiterpenes derived from the bicyclogermacrene pathway (in yellow dashed box) or directly from (E,
E)-germacradienyl cation (in black dashed box). The red arrow lines in the bicyclogermacrene pathway represent the predicted biosynthesis pathways
of compounds (73) and (74) in grape and wine, whereas sesquiterpenes in black box except for compound (33) are only confirmed to be derived
directly from (E, E)-germacradienyl cation in other plants rather than grapes
closure of the nerolidyl cation and subsequently the formation of (Z, E)-germacradienyl carbocation as one of the three
precursors (Durairaj et al., 2019). Similarly, C11-C1 closure
of the nerolidyl cation can result in the formation of another
precursor, the (Z, E)-humulyn cation (Durairaj et al., 2019),
whereas bisabolyl cation acts as the precursor of the third
sub-pathway, and is produced from the nerolidyl cation with
cyclization at the C6-C7 double bond. These biosynthesis
pathways are shown in Figure 13.
3.4.1
(Z, E)-Germacradienyl cation pathway
In the (Z, E)-germacradienyl cation pathway, compounds (76)
and (77) were detected at late stages of berry development
(Davis & Croteau, 2000; Zhang et al., 2016c). Additionally, this sub-pathway is also responsible for the biosynthesis
of their isomers of (75) and (78) (Davis & Croteau, 2000),
which might be catalyzed by the same enzymes responsible for the biosynthesis of (76) and (77) as illustrated above.
Compounds (85) and (86) were derived from an intermediate cadinyl cation generated by the (Z, E)-germacradienyl
cation, followed by hydrogen shift, ring closure, and deprotonation (Davis & Croteau, 2000). The biosynthesis pathway
of (87) is almost the same to that of (85) and (86), except
for one additional step at the end of the pathway, that is,
the quenching of the ensuing carbocation with H2 O (LopezGallego et al., 2010). VvPNCuCad was reported to be the
functional gene encoding cubebol and 𝛿-cadinene synthases,
which are responsible for generating (85) and (87) as major
compounds (20.5% and 14%, respectively) and (86) with trace
amount (3%; Dueholm et al., 2019). This study also characterized a new synthase named VvShirazTPSY2, which is a
cubebene synthase responsible for the biosynthesis of (85)
and (86). The biosynthesis of (96) shares the same intermediate cadinyl cation but subsequently cyclized in a different
mechanism with uncharacterized enzyme in grapes (Davis &
Croteau, 2000). Both (49) and (50) were also derived from an
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262
F I G U R E 1 3 Biosynthesis of selected sesquiterpenes derived from the (Z, E)-germacradienyl cation pathway (in yellow dashed box), (Z,
E)-humulyn cation pathway (in green dashed box), and bisabolyl cation pathway (in blue dashed box), all of which are under the nerolidyl cation
pathway. The red arrow line represents the predicted biosynthesis pathways of compounds (34) and (91). The brown dashed arrow lines illustrate the
potential chemical synthesis of compound (90)
intermediate typically generated in (Z, E)-germacradienyl
cation pathway (Zhang et al., 2016c). Additionally, the
biosynthesis of (34) has been identified in maize (Zea mays)
from this pathway, and ZmTPS7 was characterized as the
functional synthase responsible for catalyzing this compound
(Ren et al., 2016). However, the functional enzyme responsible for the biosynthesis of (34) in grapes remains unclear.
3.4.2
and (97) have been identified in grapes. These two compounds
were proposed as olefins catalyzed by 𝛾-humulene synthase
after hydrogen shift and ring closure (Davis & Croteau, 2000).
However, the functional genes responsible for their biosynthesis in grapevine have not been extensively studied. Nevertheless, acid-catalyzed rearrangement reaction of (89) is reported
to generate (90) and (91) chemically (Zhang, Rinkel, Goldfuss, Dickschat, & Tiefenbacher, 2018).
(Z, E)-Humulyn cation pathway
The (Z, E)-humulyn cation sub-pathway is responsible for
the biosynthesis of several sesquiterpenes (Davis & Croteau,
2000; Little & Croteau, 2002), while only compounds (89)
3.4.3
Bisabolyl cation pathway
The bisabolyl cation pathway is one of the most important terpene pathways in grapes and in charge of the
SESQUITERPENES IN GRAPES AND WINES…
biosynthesis of over 20 sesquiterpenes (Hong & Tantillo,
2014). VvGwaBer was identified as the functional gene
responsible for the biosynthesis of (66) as a major product, whereas VvPNbCur was associated with encoding
𝛽-curcumene synthase responsible for the biosynthesis of (12)
in grapes as a minor product (14%; Martin et al., 2010). The
biosynthesis of (8) has been suggested to be related to gene
VvPNaZin (CAO16257), which encodes a zingiberene synthase in grapevine (Martin et al., 2010). Compound (11) has
been confirmed to be oxidized from (8) (Jones et al., 2011).
Additionally, as the structural isomer of (8), (7) was illustrated to be catalyzed by 𝛼-bisabolene synthase in Abies grandis and Picea abies and has been suggested to be catalyzed
by similar enzyme in grape (Zhu et al., 2014). Compounds
(60) and (61) are structural isomers derived from this pathway.
Although At5g44630 gene was suggested to be responsible for
the biosynthesis of (61) in Arabidopsis (Arabidopsis thaliana;
Wu et al., 2005), the accurate synthase in grape remains elusive. The biosynthesis of both (67) and (93) can be achieved
by diverse Wangner–Meerwein rearrangements catalyzed by
TPS genes followed by oxidation at C12 via a cytochrome
P450 (Jones et al., 2011). SaSSy, SauSSy, and SspiSSy are
three enzymes responsible for the catalysis of (67) and (93) in
Sandalwood (Jones et al., 2011). VvPNaZin gene is responsible for producing 𝛼-zingiberene synthase, which could catalyze the production of 𝛼-zingiberene as a major product and
the generation of (10) as a minor product in grapevine (Martin
et al., 2010). This pathway is also responsible for the biosynthesis of (9), (57), (62), (81), and (88) with limited studies
focusing the specific enzymes catalyzing their production in
grapevine (Hong & Tantillo, 2014).
Apart from the three sub-pathways above, compound (6)
can also be directly derived from the nerolidyl cation and
VvGwaBer was suggested to be the functional gene catalyzing it as a minor product in grapevine (Martin et al., 2010).
Compound (65) was reported to be generated from (6) through
oxidation in Cabreuva oil, while the synthase responsible for
catalysis remains uncertain (Maurer, Hauser, & Ohloff, 1986).
4 A RO M A CO N T R I B U T I O N A N D
HEALTH BENEFITS OF
SESQUITERP E N E S I N G R A P E S
AND WINES
Most sesquiterpenes have been identified as volatile organic
compounds (VOC) that are secondary metabolites produced
by herbivore-induced terpene synthesis in plants (Chalal et al.,
2015). Though the volatility of sesquiterpenes is weaker compared to monoterpenes, which might be due to higher molecular weight, sesquiterpenes could still act as repellants of herbivore insects or attractants to their enemies (Chalal et al.,
263
2015). In grapes and wines, the odor and flavor of different
terpenes have been characterized by scientists, with some of
them being recognized as significant contributors responsible for specific aromatic characteristics. Generally, sesquiterpenes are suggested to provide balsamic, spicy, and woody
notes (Slaghenaufi & Ugliano, 2018). While the aromatic
contribution being an essential function of sesquiterpene,
potential health benefits of different sesquiterpenes, including anti-inflammatory, antimicrobial, and anticancer properties, have also been reported (Perestrelo, Luís Silva, Pereira, &
Câmara, 2014). There have been increasing researches about
their health-promoting effects (Cincotta et al., 2015; Duhamel
et al., 2018). In recent decades, epidemiological research and
clinical trials have illustrated the linkage between a decreased
risk of chronic diseases, including cancer and cardiovascular disease, and increased consumption of food with higher
amount of plant-based phytochemicals including sesquiterpenes (Szajdek & Borowska, 2008; Thoppil & Bishayee,
2011). Among the food rich in phytochemicals, grapes have
always been one of the most widely consumed fruit globally.
The following section summarizes the aroma contribution and
health benefits of the 97 sesquiterpenes previously identified
in grapes and wines (Table 1).
4.1
Acyclic sesquiterpenes
Farnesene is an acyclic sesquiterpene, which showed significant anti-microbial effect against bacteria and fungi,
with a concentration-dependent in vitro cytotoxic effect on
cultured human blood cells, whereas no mutagenic influences
on human lymphocyte cultures at the studied dose were
observed (Celik, Togar, Turkez, & Taspinar, 2014). Among
different isomers of farnesene, compound (2) was suggested
to be responsible for the characteristic green apple odor with
an LOD (limit of detection) concentration of 0.05𝜇g/L in red
wine, while (1) and (3) were described as woody odor perception (Cincotta et al., 2015; Huelin & Murray, 1966; Seo &
Baek, 2005). Regarding to (4), the biological effect of this floral odor compound is poorly understood, and it was reported
as a flavoring agent with no safety concern at existing levels
of intake (Harada, Matsuda, & Yamamoto, 1998; Joint &
Additives, 2006). Similar to farnesene, the farnesol (5) with a
proposed sweet and floral odor at threshold of 1 mg/L in wine
(Zea, Moyano, Moreno, Cortes, & Medina, 2001) has been
confirmed to reduce tumorigenesis based on in vivo studies
using different animal models (Joo & Jetten, 2010). The
reason for its antitumor property was probably due to farnesolinduced apoptosis. Compound (6) was characterized to possess a woody and floral odor perception with an estimated perception threshold of 0.7 mg/L in Shiraz wine (Condurso et al.,
2016; Shimoda, Shigematsu, Shiratsuchi, & Osajima, 1995).
Meanwhile, the pharmacological and health effects of (6)
have been extensively reviewed, with major benefits including
SESQUITERPENES IN GRAPES AND WINES…
264
TABLE 1
Aroma profile and biological effects of sesquiterpenes identified in grapes and wines
Sesquiterpene
Aroma profile
Biological effects
Reference
Woody
Antibacterial, antifungal, free
radical-scavenging, and
anticarcinogenic activity, with a
concentration-dependent cytotoxic
effect
Chehregani, Mohsenzadeh, Mirazi,
Hajisadeghian, and Baghali (2010);
Al-Maskri et al. (2011); Afoulous et al.
(2013)
(E, E)-𝛼-farnesene (2)
Green apple odor
Same as effects of (1)
Same as references of (1)
𝛽-farnesene (3)
Woody
Same as effects of (1)
Same as references of (1)
2,3-dihydrofarnesol (4)
Floral fragrance odor
Flavoring agent
Joint and Additives (2006)
Farnesol (5)
Sweet floral
Chemopreventative, antitumor, and
antibacteria properties, with
controversial allergic effects
Joo and Jetten (2010); Kromidas, Perrier,
Flanagan, Rivero, and Bonnet (2006)
Nerolidol (6)
Woody and floral
Antiparasitic, antioxidant,
anti-inflammatory, and anticancer
characteristics
Chan et al., 2016
Subclass: Acyclic Sesquiterpenes
(Z, E)-𝛼-farnesene (1)
Subclass: Monocyclic Sesquiterpene
𝛼-bisabolol (12)
Floral and woody
Anti-irritant, anti-inflammatory, and
antimicrobial effects
Kamatou and Viljoen (2010)
𝛼-bisabolene (7)
Balsamic and floral odor
Predicted to be anticancer
Yeo et al. (2016)
𝛽-bisabolene (8)
Spice and balsamic
Antifungal, antibacterial, antioxidant, and
antitumor properties
Li et al. (2012); Kimura et al. (2012)
𝛼-curcumene (9)
Woody odor
Cytotoxic, antifungal, and antibiotic
properties
da Silva et al. (2015)
𝛽-sesquiphellandrene
(10)
Woody and almond odor
Not confirmed
Lanceol (11)
Sweet creamy woody
characteristics
Selectively antibacterial characteristics
Ochi et al. (2005)
Sesquiterpene
Aroma profile
Biological effects
Reference of supposed effects
Germacrene B (13)
Woody, earthy and spice
Anti-inflammatory, antimicrobial, and
antioxidant effects
Xiong et al. (2013); Zellagui, Gherraf,
and Rhouati (2012)
Germacrene D (14)
Sweet and woody odor
Similar to germacrene B
Xiong et al. (2013)
𝛼-Caryophyllene (15)
woody
Antimicrobial and antioxidant properties
Magwa et al. (2006)
𝛿-elemene (17)
Woody and spicy odor
Selectively anticancer property
Cheng et al. (2007)
𝛾-elemene (16)
Similar to 𝛿-elemene
Anticancer, analgesic antibacterial,
anti-inflammatory, and antifungi effects
Sivakumar and Jeganathan (2018)
Subclass: Bicyclic Sesquiterpenes with Eudesmane Skeleton
𝛼-selinene (18)
Weak spicy and
balsamic
Antimalarial and antiplasmodial
characteristics
Rukunga and Simons (2006)
𝛽-selinene (19)
Weak spicy
Antimalarial and antiplasmodial
characteristics
Rukunga and Simons (2006)
𝛾-eudesmol (20)
Rose and citrus odor
Cytotoxic, antiproliferation and anticancer
effects
Britto et al. (2012)
𝛾-selinene (21)
Woody
Not confirmed
𝛿-selinene (22)
Not confirmed
Not confirmed
7-epi-𝛼-selinene (23)
Not confirmed
Not confirmed
Selina-3,7-diene (24)
Not confirmed
Not confirmed
Selina-4,6-diene (25)
Not confirmed
Not confirmed
Eudesm-7(11)-en-4-ol
(26)
Not confirmed
Predicted to be anti-microbial
Tzakou et al. (2007)
(Continues)
SESQUITERPENES IN GRAPES AND WINES…
TABLE 1
265
(Continued)
Sesquiterpene
Aroma profile
Biological effects
Reference of supposed effects
Subclass: Bicyclic Sesquiterpenes with Cadalane Skeleton
𝛿-cadinene (30)
Woody and medicinal
Anti-proliferative and anti-cancer effects
Hui et al. (2015)
𝛼-cadinene (27)
Woody with potential
thyme odor
Predicted to be antimicrobial, antioxidant
and anti-inflammatory
Kundu et al. (2013); Xiong et al. (2013)
𝛽-cadinene (28)
Woody with potential
thyme odor
Same as effects of (27)
Same as references of (27)
𝛾-cadinene (29)
Woody with potential
thyme odor
Same as effects of (27)
Same as references of (27)
Kundu et al. (2013); Xiong et al. (2013)
𝜔-cadinene (31)
Not confirmed
Similar to (27)
𝛼-amorphene (32)
Not confirmed
Not confirmed
𝛼-cadinol (33)
Woody odor
Antifungal and hepatoprotective effects
Ho et al. (2011); Tung et al. (2011)
epi-𝛼-cadinol (34)
Astringent and sweet
odor
Antifungal and hepatoprotective effects
Ho et al. (2011); Tung et al. (2011)
𝛿-cadinol (35)
Not confirmed
Not identified
𝛼-muurolene (36)
Woody, herbal and
floral odor
Predicted to be antimicrobial, antioxidant
Zuccolotto et al. (2019)
𝛾-muurolene (37)
Woody and herbal odor
Similar to 𝛼-muurolene
Zuccolotto et al. (2019)
muurola-4(14), 5-diene
(38)
Not confirmed
Not confirmed
t-muurolol (39)
Not confirmed
Minty and woody odor
Bicyclosesquiphellandrene
(40)
Not confirmed
Not confirmed
Epi-bicyclosesquiphellandrene (41)
Ashy and fruity odor
Not confirmed
Cadalene (42)
Not confirmed
Antitumor and antioxidative properties
Kim et al. (2004)
𝛼-calacorene (43)
Woody odor
Antibacterial and antioxidant effects
Kfoury et al. (2018)
Sesquiterpene
Aroma profile
Biological effects
Reference of supposed effects
𝛽-calacorene (44)
Not confimed
Predicted to be antimutagenic and
free-radical scavenging
Albuquerque et al. (2018)
Calamenene (45)
Herbal, spicy and savory
aroma
Antioxidant and antimicrobial effects
Azevedo et al. (2013); Dorman et al.
(2000)
Calamene (46)
Herbaceous and spicy
odor
Predicted to be anti-viral
Bonny et al. (2018)
Zonarene (48)
Not confirmed
Not confirmed
Epi-zonarene (47)
Not confirmed
Not confirmed
Cubenol (49)
Clean and fresh aroma
Antifungal and antimicrobial properties
Kordali et al. (2005); Takao et al. (2012);
Zhang et al. (2008)
Epi-cubenol (50)
Sweet and spicy odor
Antifungal and antimicrobial properties
Takao et al. (2012); Zhang et al. (2008)
Subclass: Bicyclic Sesquiterpenes with Guaiane Skeleton
𝛼-guaiene (51)
Sweet, woody, balsamic
and peppery odor
Anti-inflammatory effects
3,7-Guaiadiene (52)
Not confirmed
Not confirmed
Guaia-6,9-diene (53)
Not confiremd
Not confirmed
Guaiazulene (56)
Not confirmed
Anti-allergic, anti-inflammatory,
anti-ulcer, and antioxidant effects
𝛾-gurjunene (54)
Musty odor
Not identified
Rotundone (55)
Spicy and peppery odor
Flavoring agent and potential
anti-herbivory function
Eldeen et al. (2016)
Kourounakis et al. (1997); Yanagisawa
et al. (1990)
Chadwick et al. (2013)
(Continues)
SESQUITERPENES IN GRAPES AND WINES…
266
TABLE 1
(Continued)
Sesquiterpene
Aroma profile
Biological effects
Reference of supposed effects
Subclass: Other Bicyclic Sesquiterpenes
𝛼-alaskene (57)
Not confirmed
Predicted to be antimicrobial and
anti-inflammatory
Brait et al. (2015); Hamdan, Mohamed,
Abdulla, Mohamed, and El-Shazly
(2013)
Bicyclogermacrene (58)
Sweet and herbaceous
Cytotoxic and potential antitumor effects
Grecco et al. (2015)
𝛽-caryophyllene (59)
Woody and spicy odor
Antibacterial, antifungal,
anti-proliferation, and anticancer effects
Chen et al. (2011); Dahham et al. (2015)
Sesquiterpenes
Aroma profile
Biological effects
Reference of supposed effects
𝛼-chamigrene (60)
Not confirmed
Cytotoxic against Hela cells
Anderson et al. (2018)
𝛽-chamigrene (61)
Woody
Antiviral property and predicted to be
anticancer
Adams et al. (1991); Ashmawya et al.
(2018)
Isocalamenene (62)
Not confirmed
Not confirmed
Valencene (63)
Citrus, green, woody
Antioxidant and cytotoxic against Hela
cells
Liu et al. (2012)
𝛽-Vetivenene (64)
Not confirmed
Antioxidant and responsible for specific
odor of vetiver essential oil
Chahal et al. (2015)
Cabreuva oxide D (65)
Weak woody-ambergris
and fruity odor
Not identified
𝛼-bergamotene (66)
Woody and tea-like
aroma
Predicted to be antidiabetic, analgesic,
antibacterial, and antifungal
Devendran and Sivamani (2015)
𝛽-santalol (67)
Sweet and woody odor
Antibacterial, antiviral, sedative, and
potential anticancer effects
Okugawa et al. (1995); (Paulpandi et al.,
2012)
Subclass: Tricyclic Sesquiterpenes
Aromadendrene (68)
Sweet and dry odor
Antioxidant and antimicrobial effects
El-Ghorab et al. (2007); Mulyaningsih,
Sporer, Zimmermann, Reichling, and
Wink (2010)
Allo-aromadendrene
(69)
Woody odor
Antioxidant
Yu et al. (2014)
𝛼-gurjunene (70)
Balsamic and woody
odor
Not identified
𝛽-gurjunene (71)
Woody odor
Not identified
Isoledene (72)
Woody odor
Cytotoxic and effective against colorectal
cancer
Asif et al. (2016)
Sesquiterpenes
Aroma profile
Biological effects
Reference of supposed effects
Viridiflorol (73)
Floral odor
Anti-inflammatory, antioxidant, and
antibacterial effects
Trevizan et al. (2016)
Epiglobulol (74)
Not confirmed
Antioxidant, antimicrobial, and
anti-inflammatory effects
Mohammed et al. (2016)
𝛼-copaene (75)
Woody and spicy odor
Anticancer, anti-genotoxic, and
antioxidant properties
Hasan Turkez et al. (2014)
𝛽-copaene (76)
Woody odor
Not confirmed
𝛼-ylangene (77)
Black pepper odor
Anticancer, analgesic antibacterial,
anti-inflammatory, and antifungi effects
𝛽-ylangene (78)
Not confirmed
Sivakumar and Jeganathan (2018)
Aristolene (79)
Floral and sweet odor
Antimicrobial
Rahamoz-Haghighi et al. (2014)
Calarene (80)
Not confimed
Sedative, analgesic, anti-convulsant, and
larvicide functions
Chen et al. (2013); Govindarajan et al.
(2016)
𝛼-cedrene (81)
Woody, sweet and fresh
odor
Trypanocidal, antileukemic, antimicrobes,
and anti-obesity properties
Kim et al. (2015)
(Continues)
SESQUITERPENES IN GRAPES AND WINES…
TABLE 1
267
(Continued)
Sesquiterpene
Aroma profile
Biological effects
Clovene (82)
Mild spicy odor
Not confirmed
Reference of supposed effects
𝛼-bourbonene (83)
Not confirmed
Not confirmed
𝛽-bourbonene (84)
Woody and spicy odor
Anticancer property
Wang et al. (2018)
𝛼-cubebene (85)
Citrus, herbal, oily and
woody odor
Predeicted to be antioxidant and
antibacterial
Naidoo et al. (2009)
𝛽-cubebene (86)
Decayed, dusty, yeasty
and rubber-like odor
Not confirmed
Cubebol (87)
Spicy and minty
Used as dietary supplement and flavoring
ingredient
Mischko et al. (2018)
Sesquiterpenes
Aroma profile
Biological effects
Reference of supposed effects
Sesquichamene (88)
Woody odor
Antimicrobial, anti-inflammatory,
diuretic, and anti-spasmodic
characteristics
Jeong et al. (2014)
Longifolene (89)
Strong woody odor
Partially effective against bacteria
Gordien et al. (2009)
4,5,9,10-dehydroisolongifolene
(90)
Not confirmed
Significant antioxidant property
Hamady et al. (2017)
Cycloisolongifolene
(91)
Not confirmed
Antimicrobial effect
Nawi et al. (2014)
𝛼-santalol (93)
Sweet and woody odor
Anticancer, anti-inflammatory,
anti-hyperglycemic, and antifungal
effects
Bommareddy et al. (2019); Santha and
Dwivedi (2013)
𝛼-panasinsene (92)
Not confirmed
Predicted to be antidiabetic
Mahmoud et al. (2016)
𝛽-patchoulene (94)
Not confirmed
anti-inflammatory and antioxidant
characteristics
Chen et al. (2017)
Cyperene (95)
Spicy and herbal odor
Predicted to be anti-inflammatory and
anti-microbial
Sitarek et al. (2017)
Turkez et al. (2015)
Subclass: Tetracyclic Sesquiterpenes
Cyclosativene (96)
Not confirmed
Anti-inflammatory and antifungal effect
Longicyclene (97)
Vanilinic odor
Not confirmed
anti-parasites, antioxidant, anti-inflammation, and anticancer
(Chan, Tan, Chan, Lee, & Goh, 2016; Wang, Wang, & Chen,
2008). It has been considered as a potential novel therapeutic
drug for future commercial exploitation (Chan et al., 2016).
4.2
Monocyclic sesquiterpenes
With spice and balsamic odor perception, 𝛽-bisabolene (8)
was found to be antifungal, antibacterial, and antioxidant,
with additional cytotoxic property against human breast cancer cells (Rusdi, Goh, & Baharum, 2016; Yeo et al., 2016).
The same study further illustrated that (8) could potentially
lead to an approximately 40% reduction of transplanted 4T1
mammary tumors in vivo. Nonetheless, (7) and (12), which
are sesquiterpene alcohol and the structural isomer of (8),
were not identified to exhibit anticancer characteristics. Since
another structural isomer of (7), 𝛾-bisabolene, was confirmed
to possess pro-apoptotic property in oral carcinoma cells (Jou
et al., 2015), scientists suggested that (7), which has a similar aromatic profile as (8), may be anticarcinogenic (Yeo
et al., 2016). Compound (12) is characterized with slightly
floral and woody odor perception, which might possess antiirritant, anti-inflammatory, and antimicrobial effects (Kamatou & Viljoen, 2010). The aroma profile of (9) and (10)
are generally described as woody, while (10) possess an
extra almond scent (Guillén & Manzanos, 1997; Mayuonikirshinbaum, Tietel, Porat, & Ulrich, 2012). The cytotoxic,
antimicrobial, antifungal, and antibiotic characteristics of (9)
have been confirmed, and a synergism effect of (9) with other
antibiotics has been observed (da Silva et al., 2015). However,
the epidemiological studies of (10) have not been extensively
investigated.
Compound (11) has been previously isolated from Santalum album, together with a bicyclic sesquiterpene (67), and
both showed antibacterial properties against different strains
of Helicobacter pylori (Ochi et al., 2005). While the aroma
SESQUITERPENES IN GRAPES AND WINES…
268
of (11) was described as sweet and creamy, (67) was suggested to be mainly responsible for sweet and woody characteristics of sandalwood essential oil (Bhat, Balasundaran,
& Balagopalan, 2006; Buchbauer, Stappen, Pretterklieber, &
Wolschann, 2004). Regarding to germacrenes, (13) and (14)
have similar spice and woody odor, and both were previously identified to be effective antioxidants with other health
effects such as anti-inflammatory and antimicrobial (Cincotta
et al., 2015; Miyazawa, Okamura, Okuno, & Morii, 1999;
Xiong et al., 2013). The essential oil extracted from the root
of Leonurus sibiricus contained (14) and another bicyclic
sesquiterpene (59) as major constituents (Sitarek et al., 2017).
Although (59) itself was previously reported effective against
selected bacteria and to reduce the proliferation of colorectal cancer cells based on in vitro antitumor-promoting assays
(Dahham et al., 2015), a synergistic effect of (14) and (59)
could strength the health benefits of the oil in the antibacteria and anti-inflammation effects. As the structural isomer of (59), (15) also present anti-microbial and antioxidant effects (Magwa, Gundidza, Gweru, & Humphrey, 2006).
Both (15) and (59) were reported to have woody and potential spicy odor in wines (Pereira, Tiernan, Sargent, Klee, &
Huber, 2013).
Elemenes are natural sesquiterpenes present in essential oil in the form of a mixture of 𝛽-elemene, (16), and
(17). Numerous in vitro studies have confirmed the broadspectrum of anti-proliferative effects of 𝛽-elemene against
different types of cancer, such as leukemia, colon, and
lung carcinoma cells (Li et al., 2005; Zhu et al., 2011).
As structural isomers of 𝛽-elemene, (17) was demonstrated
to possess apoptosis-inducing property on Hela cells in
vitro and therefore the potential reduction of anaplastic
thyroid carcinoma cells (Wang et al., 2006), while (16)
was reported to have anticancer, analgesic, antibacterial,
anti-inflammatory, and anti-fungi properties (Sivakumar &
Jeganathan, 2018). Both (16) and (17) were suggested to be
woody and spicy in wines (Iwasa, Iwasaki, Ono, & Miyazawa,
2014).
4.3
Bicyclic sesquiterpenes
Although sesquiterpenes belonging to the Sclinene family
have been widely reported in different plants, there are limited studies investigating their biological effects. The potential antimalarial and antiplasmodial characteristics of (18) and
(19) has been described by Rukunga and Simons (2006); however, unconfirmed health benefits and aroma characteristics
for (21), (22), (23), (24), and (25) (Miyazawa et al., 2016).
Both (18) and (19) are weakly spicy, while (18) is suggested
to be more balsamic (Jirovetz et al., 2006). Importantly, the
therapeutic benefits of (20) (with waxy, rose, and citrus odor)
in alleviating the proliferation and decreasing the number of
tumor cells in liver via caspase-mediated apoptosis have been
elucidated in both in vitro and in vivo studies (Bomfim et al.,
2013; Britto et al., 2012). As the structural isomer of (20),
(26) has been suggested to possess antimicrobial property
(Tzakou, Pizzimenti, Pizzimenti, Sdrafkakis, & Galati, 2007),
although requires further confirmation.
Cadinene is a group of sesquiterpenes with isomeric hydrocarbons including compounds (27) to (31). The essential
oil containing cadinene as a major constituent were found
effective against oxidant, bacteria, and inflammation, and
sesquiterpenes from this group were subsequently suggested
responsible for these health benefits (Kundu et al., 2013;
Xiong et al., 2013). However, very limited studies have
demonstrated the health effects of an individual cadinene,
with (30) as the only one confirmed to be antiproliferative
and apoptotic against human ovary cancer cells (Cincotta
et al., 2015; Hui, Zhao, & Zhao, 2015). Regarding to aromatic importance, (27), (28), and (29) all contribute to woody
odor with potential thyme flavor, whereas (30) has been
recorded as medicinal and woody. (Gutierrez, Bourke, Lonchamp, & Barry-Ryan, 2009). Regarding to alcohol derivatives of cadinene (33) to (35), (33) was reported to possess
strong woody aroma and anti-mite property (Sohrabi, Pazgoohan, Seresht, & Amin, 2017), whereas (34) was considered as astringent and sweet sesquiterpene (Song, Sawamura,
Ito, Kawashimo, & Ukeda, 2000). Both (33) and (34) were
reported as active constituents against seven fungi strains
including Aspergillus clavatus, A. niger, Chaetomium globosum, Cladosporium cladosporioides, Myrothecium verrucaria, Penicillium citrinum, and Trichoderma viride (Ho,
Liao, Wang, & Su, 2011). The hepatoprotective property of
these two sesquiterpenes against LPS/D-GalN-induced liver
damage was also confirmed in mice (Tung et al., 2011). Moreover, the muscle-relaxing and cholera-inhibitory characteristics of (34) were reported (Claeson, Andersson, & Samuelsson, 1991). Nonetheless, the health effect and aroma attribute
of (35) is poorly understood.
Similar to the cadinene family, (36) to (39) were also widely
reported as main constituents in different types of essential oils extracted from various plants (Hadad et al., 2007;
Vijayakumar et al., 2012; Zuccolotto et al., 2019). Both (36)
and (37) have a woody and spicy odor (Cincotta et al., 2015;
Gutierrez et al., 2009). Although several kinds of essential oil
rich in (36) to (39) have been confirmed to have antioxidant
and antimicrobial effects (Cheng, Lin, Chu, Chang, & Wang,
2009; Gudžić, Djokovic, Vajs, Palić, & Stojanovic, 2002),
whether these compounds contribute to any health effects
in vitro and in vivo require further investigation. Though
the exact aroma attributes of (32) have not been confirmed,
(40) and (41) are considered as minty and woody, and fruity,
respectively (Asikin et al., 2018). Nonetheless, the health benefits of all these three sesquiterpenes remain uncertain.
Compound (42) is ubiquitous in numerous plants with antioxidative and anticancer activities (Kim et al., 2004). Due to
SESQUITERPENES IN GRAPES AND WINES…
the limitation water solubility, scientists suggested that the
glycosylated modified derivative of (42) could reduce tumor
more significantly in vivo (Jornada et al., 2015). Compound
(43) is a woody sesquiterpene with strong antibacterial and
antioxidant properties (Kfoury et al., 2018), while the aroma
profile and biological effects of its structural isomer (44) are
poorly understood. Despite of this, some scientists suggested
that (44) might possess anti-mutagenic and free-radical scavenging abilities (Albuquerque, Patil, & Máthé, 2018). Herbal,
savory and spicy (45) has been confirmed to be antioxidant
in vitro with antimicrobial properties in plants, such as sage
and guava (Azevedo et al., 2013; Dorman, Surai, & Deans,
2000; Moon, Cliff, & Li-Chan, 2006). Compound (46) is
an herbaceous and spicy odor sesquiterpene. Although the
antiviral property of manuka oil rich in (46) against Herpes
simplex virus type 1 and 2 (HSV-1, HSV-2) has been validated in vitro on RC-37 cells, its biological effects need to
be further validated in vivo (Cheong, Liu, Zhou, Curran, &
Yu, 2012; Reichling, Koch, Stahl-Biskup, Sojka, & Schnitzler, 2005). Studies on the biological effects and odor perception of (47) and (48) are also limited.
Compound (50) has been confirmed to restrain the activity of T. rubrum DNA polymerase in vitro, and this sweet
and spicy compound has been suggested to be antifungal and
might be utilized in the treatment of tinea disease (Maga,
1987; Takao et al., 2012). Compound (49) is the structural
isomer of (50) with a clean and fresh aroma (Shi et al.,
2014), and both were suggested to be effective in inhibiting different plant-originated fungi (Kordali, Cakir, Mavi,
Kilic, & Yildirim, 2005; Zhang et al., 2008). Compound
(51) has been suggested to possess in vitro inhibitory properties against cyclooxygenase, 5-lipoxygenase, and acetylcholinesterase enzymes, together with anti-inflammatory and
other therapeutic effects (Eldeen et al., 2016). The aroma perception of (51) was described as woody, balsamic, sweet, and
peppery (Pripdeevech, Khummueng, & Park, 2011). Compound (52), (53), and (54) are structural isomers of (51). However, their functions have not been confirmed, while only
(54) has been confirmed to provide musty odor (Condurso
et al., 2016). Compound (56) has been widely accepted to be
anti-allergic, anti-inflammatory, and anti-ulcer (Yanagisawa,
Kosakai, Tomiyama, Yasunami, & Takase, 1990). Its ability in
inhibiting lipid peroxidation and scavenging hydroxyl radicals
was also confirmed (Kourounakis, Rekka, & Kourounakis,
1997)
Compound (55) was primarily extracted from Cyperus
rotundus, and it has been confirmed to be responsible for the
spicy aroma and peppery characteristics of Australian Shiraz
wine (Wood et al., 2008). The odor threshold was only 16 ng/L
in red wine, which might be one of the lowest threshold values
among natural compounds (Huang et al., 2014). It is currently
considered as the only sesquiterpene in grapes and wines with
favorable aroma attributes (Zhang et al., 2015a). The poten-
269
tial anti-herbivory function of (55) in plants was also proposed
(Chadwick, Trewin, Gawthrop, & Wagstaff, 2013); however,
no upregulation of this compound was observed in grapevine
with herbivore treatment (Zhang et al., 2016b). With significant anti-inflammatory property observed in the essential oil
of Piper vicosanum leaves, scientists proposed that this health
effect might be associated with (57) (Brait et al., 2015). Compound (58) was previously reported to be cytotoxic and exhibited strong effects against the murine melanoma (B16F10Nex2) and a varieties of human tumors cell lines (U87, HeLa,
HCT, MCF7, and Siha) in vitro (da Silva et al., 2013; Grecco
et al., 2015; Song et al., 2000). The aroma perception of (58)
was sweet and herb-like. Similar to (58), (60) also exhibited
moderate cytotoxic effect in HeLa cell (Anderson, Girola,
Figueiredo, Londero, & Lago, 2018). As the structural isomer of (60), (61) was reported as an antiviral agent previously (Adams, Lepinefrenette, & Spero, 1991). Although
other biological effects of this woody odor sesquiterpene are
poorly studied, some scientists suggested that it might possess
anti-cancer and anti-inflammatory properties similar to (60)
(Ashmawya, Gad, Ashoura, El-Ahmadya, & Singab, 2018;
Ouzouni, Koller, Badeka, & Riganakos, 2009).
Purified (63) from sweet orange oil has a citrus and woody
odor (Condurso et al., 2016), and it exhibits antioxidant activity and shows cytotoxic effect against Hela cell (Liu, Chen,
Liu, Zhou, & Wang, 2012). Compound (64) extracted from
vetiver essential oil is responsible for the characteristic vetiver
odor, and also exhibits strong antioxidant capacity (Chahal,
Bhardwaj, Kaushal, & Sandhu, 2015; Kirici, Inan, Turk, &
Giray, 2011). Compound (65) has a weak woody-ambergris
and fruity odor (Maurer et al., 1986). Nonetheless, the biological effects of both (62) and (65) were not identified. The
aroma of (66) is described as woody and tea-like (Gutierrez
et al., 2009). Though limited epidemiological studies on (66)
have been carried out, the pharmacological significance of
(66) was suggested to be antidiabetic, analgesic, antibacterial,
and antifungal (Devendran & Sivamani, 2015). Regarding to
the health benefits of (67), apart from the antibacterial property mentioned above, other benefits including reputed sedative characteristic in mice, antiviral property against influenza
A/HK (H3N2) virus and potential anticancer activity have
also been reported (Okugawa, Ueda, Matsumoto, Kawanishi,
& Kato, 1995; Paulpandi et al., 2012).
4.4
Tricyclic and tetracyclic sesquiterpenes
In this group of sesquiterpenes, compound (68) was reported
to have sweet and dry odor, with antioxidant activity (ElGhorab, El-Massry, & Shibamoto, 2007; Song et al., 2000).
Furthermore, a study confirmed the antimicrobial property of
Eucalyptus globulus and (68) was reported as the most active
constituent (Mulyaningsih, Sporer, Reichling, & Wink, 2011).
Compound (69) could provide a woody odor. Previous study
270
reported its strong antioxidant activity, where low concentration of (69) in the leaves of Cinnamomum osmophloeum
could have significant effect against juglone-induced oxidative stress (Yu et al., 2014). Although the aroma attributes
of (70) (balsamic and woody odor) and (71) (woody odor)
have been characterized, the health benefits of these two structural isomers are not well studied (Amelia et al., 2017; Condurso et al., 2016). Compound (72) has a woody odor (Niponsak, Laohakunjit, & Kerdchoechuen, 2011), and its cytotoxic
effect on colorectal cancer cell lines through reactive oxygen species (ROS)-mediated apoptosis has been confirmed in
vitro (Asif et al., 2016). Similar to (72), (73) also provides a
floral odor. Moderate effectiveness of (73) against Mycobacterium tuberculosis was also reported, indicating its potential antibacterial effect (Gomes, Mata, & Rodrigues, 2005;
Trevizan et al., 2016). Additionally, previous research suggested that (73) was responsible for the antioxidant and antiinflammatory effects against carrageenan-induced pleurisy
(Trevizan et al., 2016). Compound (74) could effectively
inhibit the growth of microorganisms, including Listeria
monocytogenes and Staphylococcus aureus (Kim et al., 2004),
and exhibit strong antioxidant and anti-inflammatory activities (Mohammed, Omran, & Hussein, 2016).
Both (75) and (76) have a spicy and woody odor (Cheong
et al., 2012; Fernandes et al., 2019). Compound (75) was
reported to display cytotoxic characteristics on N2a-NB
cell line without genotoxic effect (Turkez, Togar, Tatar,
Geyıkoglu, & Hacımuftuoglu, 2014), and therefore, might be
developed as an anticancer agent. The antioxidant effect of
(75) has also been reported (Turkez et al., 2014), although
not for (76). Compound (77) was reported to display black
pepper odor (Thamnopoulos et al., 2018), while its biological
functions were highly similar to that of (16). Compounds (79)
and (80) possess same chemical skeleton, whereas (79) (floral
and sweet odor) has been identified as an antimicrobial constituent in Acorus calamus essential oil (Rahamoz-Haghighi,
Asadi, Riahi-Madvar, & Baghizadeh, 2014), while (80) was
reported to possess sedative, analgesic, and anti-convulsant
functions (Chen, Han, & Sun, 2013). A recent study also suggested (80) as a larvicide, which was effective in inhibiting
malaria and dengue mosquito (Govindarajan, Rajeswary, &
Benelli, 2016). Compound (81) displays woody and sweet
odor (Cincotta et al., 2015), and it has been reported to exhibit
numerous biological functions, including inhibition of trypan
(IC50 4.07 mg/ml), leukemia (IC50 22.20 mg/ml), and several
microbes. In vivo trial in rats demonstrated its potential antiobesity activity (Kim et al., 2015). Compound (82) has a mild
spicy odor, while its biological effects are poorly understood
(Jirovetz et al., 2006).
Compound (84) has been widely reported in grape and
wine with a spicy and woody odor (Jirovetz, Buchbauer, Shahabi, Shafi, & Jose, 2003). Recently, it was reported to induce
the apoptosis of prostate cancer cells (Wang, Liu, Yu, & Jin,
SESQUITERPENES IN GRAPES AND WINES…
2018). However, the biological functions of its isomer (83)
were poorly understood. The aroma of (85) was described as
citrus and woody. Previous research suggested that Cymbopogon nardus essential oil has free radicals scavenging capacity and likely due to the presence of (85) (Naidoo, Thangaraj,
Odhav, & Baijnath, 2009). As the structural isomer of (85),
(86) contributes to a dusty, yeasty, and rubbery odor (Asikin
et al., 2018; Moon et al., 2006). However, its biological functions on health benefits have not been confirmed. The odor
of (87) was described as spicy and minty with an outstanding cooling and refreshing effects (Velazco, Wuensche, &
Deladoey, 2001), and therefore, it has been mainly utilized
as a flavoring ingredient (Mischko, Hirte, Fuchs, Mehlmer,
& Bruck, 2018). Compound (88) is the active component in
the hiba essential oil responsible for its significant antimicrobial properties (Matsuura, Yamaguchi, Zaike, Yanagihara,
& Ichinose, 2014). Other potential effects of (88) including
anti-inflammatory, diuretic, and anti-spasmodic effects have
also been reported (Jeong, Kwon, Kong, Kim, & Lee, 2014).
Compound (89) was described to have a strong woody odor
(Jirovetz et al., 2003). It was demonstrated to be effective
against Gram-positive bacteria and exhibit antimycobacterial
property (Gordien, Gray, Franzblau, & Seidel, 2009). Derived
from (89), (90) has not been extensively investigated and was
only reported as a potent antioxidant (Hamady et al., 2017).
Though the accurate odor of (91) and (92) have not been
confirmed, previous research has shown that (91) contributed
to the antimicrobial ability of Curcuma aeruginosa rhizome
(Nawi, Simoh, Zainal, & Rahman, 2014), while (92) might
potentially contribute to the antidiabetic effect (Mahmoud
et al., 2016). Compound (93) could typically be extracted
from sandalwood oil, and possess the same woody odor as
(67) (Buchbauer et al., 2004). The cancer preventive characteristics of (93) have been widely confirmed in different cancer models (Bommareddy et al., 2019; Santha &
Dwivedi, 2013). Further, it was also demonstrated to have
anti-inflammatory, anti-hyperglycemic, and antifungal properties (Bommareddy et al., 2019; Misra & Dey, 2013). Compound (94) was previously identified from a traditional Chinese medicine named Pogostemon cablin (Blanco) Benth,
which typically exhibits anti-inflammatory property (Chen
et al., 2017). A recent study has demonstrated the significant anti-inflammatory and antioxidant characteristics of (94)
in vivo using a non-infective murine model (Chen et al.,
2017). Spicy and herbaceous (95) possess strong antiulcerogenic property. It is a key component of the essential oil of
Cyperus rotundus and C. articulates, and has been suggested
as the active constitute contributing to the anti-inflammatory
and antimicrobial properties of oil (Skała et al., 2016). However, the aroma characteristics of (91) to (94) have not been
reported.
Regarding to tetracyclic sesquiterpenes, (96) was demonstrated to exhibit significant anti-inflammatory and antifungal
SESQUITERPENES IN GRAPES AND WINES…
effect (Turkez, Togar, Di Stefano, Taspinar, & Sozio, 2015).
However, the odor perception of (96) has not been confirmed.
Compound (97) was reported with a vanilinic odor however
without any confirmed biological function (Ouzouni et al.,
2009).
5 EFFECTS OF WINEMAKING ON
SESQUITERP E N E S I N W I N E
The ability to alter the composition of sesquiterpenes in wine
by winemaking techniques would allow winemakers to make
wine with particular attributes. We know that the biosynthesis
of sesquiterpenes is located in the grape berry exocarp (skin),
while the relevant biosynthesis activity in berry mesocarp
(flesh) is undetectable (May et al., 2013). Although different
studies have demonstrated that the concentration of the aromatically important sesquiterpene, rotundone, in grapes could
be influenced by various parameters, such as grape cultivars,
grape maturity, and growing conditions (Marais, 1983; Scarlett, Bramley, & Siebert, 2014; Zhang et al., 2015a; Zhang
et al., 2015b), the factors influencing other sesquiterpenes
are unknown. Terpenes have been suggested to exist in grape
berry tissues in both free and glycosidically bound forms
(Carrau, Boido, & Dellacassa, 2008; Gholami et al., 1995;
Schwab & Wüst, 2015), and during the winemaking process,
these compounds could either be directly transferred into
wine or undergo chemical reactions, specifically enzymatic
hydrolysis of the glycosidically bound terpenes to release
free terpenes (Black et al., 2015). All sesquiterpenes in both
grapes and wines summarized in the current study are in free
form (Schwab & Wüst, 2015). Therefore, it can be suggested
that the sesquiterpenes profile of wine is mainly influenced by
the physical extraction of sesquiterpenes from grape, rather
than any chemical reactions leading to the production of
free sesquiterpenes from any precursor forms. The following
section focuses on how different fermentation parameters
and winemaking techniques influence the physical extraction
process of sesquiterpenes from grape to wine, and therefore, the final concentrations of different sesquiterpenes in
wines.
As sesquiterpenes are located in the grape skin, various winemaking operations could influence sesquiterpenes
extraction and concentration, such as pressing, maceration,
involvement of non-grape material, enzymes, and yeast (Sacchi, Bisson, & Adams, 2005). During the pressing process, the
concentration of terpene alcohols in pressed juice was found
two to four times higher than free-run juice (Marais, 1983),
likely due to their main presence in exocarp. Indeed, Versini
(1981) indicated that pressing could remarkably increase the
concentration of aromatic terpenes up to 10 times in the must
and wine. Additionally, increased maceration time and tem-
271
perature could considerably facilitate the release of sesquiterpene into wine, and Caputi et al. (2011) concluded that prolonged skin contact during fermentation could lead to rich
peppery characteristics in wine with higher rotundone extraction. Black et al. (2015) further suggested that additions
of stems and leaves during fermentation contributed to the
enriched rotundone content in wine. Geffroy, Siebert, Silvano,
and Herderich (2017) reported a decreased rotundone concentration by applying increased maceration time and temperature, which was likely due to the absorption of rotundone by
gross wine lees (tartrate and yeast biomass) settled after pressing. Additionally, ethanol concentration in wine could influence the extraction of alcohol-soluble sesquiterpenes (Marais,
1983), and ethanol fortification during winemaking could
enhance the rotundone extraction rate from grape into wine
(Zhang, Luo, & Howell, 2017).
Enzyme treatment during winemaking can enhance terpene concentrations (Marais, 1983). However, Geffroy et al.
(2017) reported that pectolytic enzymes did not influence the
concentration of rotundone in wine, even though pectinases
were excepted to facilitate the extraction of hydrophobic compounds from the exocarp (Sacchi et al., 2005). Individual
sesquiterpenes may respond differently to enzyme addition
during winemaking, and further researches should be conducted to evaluate the influences of enzyme addition on wine
sesquiterpenes. Interestingly, yeast species used for fermentation has also been related to the concentrations of sesquiterpenes in wines. Saccharomyces uvarum has been reported to
effectively lower rotundone in wine up to 20% (Geffroy et al.,
2017). Specific yeasts have also been suggested responsible
for generating terpenes. Fagan, Kepner, and Webb (1981)
documented the production of cis- and trans-nerolidol, and
trans-farnesol by Saccharomyces fermentati, while S. cerevisiae was suggested to synthesis farnesol at a concentration
of approximately 2 𝜇g/L (Carrau et al., 2008)
In order to understand the effects of specific winemaking
techniques on the concentration of rotundone in wines, Geffroy et al. (2017) compared three commonly used winemaking techniques, thermovinification, carbonic maceration, and
rosé vinification. Results showed that both thermovinification
and rosé vinification significantly reduced the concentrations
of rotundone by 20% and 13%, respectively, which is likely
due to the preferment removal of grape exocarp used in these
two treatments. For thermovinification, the extractability of
rotundone was identified to be negatively correlated to extraction temperature (Geffroy et al., 2017). This suggests that the
suitability of the winemaking techniques to specific sesquiterpenes can be highly relevant to the thermal stability of the
compound and the overall skin contact time (Geffroy et al.,
2017; Siebert, Wood, Elsey, & Pollnitz, 2008). Further, carbonic maceration resulted in a 23% reduction of rotundone
in the final wine, and the extraction of compounds using carbonic maceration could be highly related to grape cultivars as
SESQUITERPENES IN GRAPES AND WINES…
272
well as implementation conditions such as processing temperature and yeast addition (Geffroy et al., 2017).
Winemaking processes may influence the sesquiterpene
profile in wines but other research is limited. Rotundone has
been recognized as the sole aromatically important sesquiterpene to wine, and winemaking factors influencing its concentrations have been tested. Nonetheless, almost all other
sesquiterpenes summarized in this review have not been
investigated for their response to winemaking process, due
to their aromatic significance in grape and wine are not well
established.
6
CONC LU SI ON S
Sesquiterpenes are phytochemicals present in grapevine,
grape berry, wine, and pomace. This review considers their
presence and impact in grapes and wine and extensively summarizes 97 sesquiterpenes and classifies them based on their
chemical structures. The biosynthesis pathways of the identified sesquiterpenes have been comprehensively summarized,
which provides novel insights and information to understand
sesquiterpene production in grapes and wines, and manipulation of their production using genetic engineering techniques.
The functional genes and enzymes responsible for the biosynthesis of sesquiterpenes are limited and require further investigation. For odor perception, sesquiterpenes were suggested
to mainly present balsamic, spicy, and woody notes. Though
the aroma profile of wine sesquiterpenes could vary significantly, rotundone is still been considered as the only sesquiterpene with favorable aroma attribute to wine. The contributions
of other sesquiterpenes to wine aroma profile are potentially
important and require further research. Additionally, limited
studies have investigated the aromatic threshold of these compounds in wines, and the effects of winemaking on sesquiterpenes have not been extensively studied. The potential health
benefits of selected sesquiterpenes indicate the significance of
these compounds pharmaceutically. Previous epidemiologic
experiments mainly focused on the biological effects of essential oil rich in sesquiterpenes instead of single compounds. For
comprehensive understanding of sesquiterpenes in grapes and
wines, further studies should be focusing on the identification of novel sesquiterpenes, confirmation of their biosynthesis pathway and regulation mechanism, influence of winemaking on the extraction of sesquiterpenes from grape to wine,
then elucidation of their aroma importance and importantly,
the health benefits of individual sesquiterpenes.
ACKNOW LEDGMENTS
This research was supported by the wine group of the Faculty
of Veterinary and Agricultural Sciences, University of Melbourne.
CONFLICTS O F INTEREST
The authors declare no conflicts of interest.
AUT HO R CON TR IB UT IO NS
Zizhan Li conducted the literature research, drafted the first
version, edited, and proofread the manuscript. Zhongxiang
Fang and Kate Howell contributed to the editing and proofreading of the manuscript and provided critical feedback for
revision. Pangzhen Zhang was project leader, made a substantial contribution in the manuscript concept and design, and
contributed to the overall reviewing, editing, and approval of
the final submission.
ORC I D
https://orcid.org/0000-0001-6498-0472
Kate Howell
https://orcid.org/0000-0002-9902-3426
Zhongxiang Fang
https://orcid.org/0000-0002-9794-2269
Pangzhen Zhang
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How to cite this article:
Li Z, Howell K,
Fang Z, Zhang P. Sesquiterpenes in grapes
and wines: occurrence, biosynthesis, functionality, and influence of winemaking processes.
Compr Rev Food Sci Food Saf. 2020;19:247–281.
https://doi.org/10.1111/1541-4337.12516