Current Medicinal Chemistry, 2007, 14, 1653-1671
The Road to Advanced Glycation End Products: A Mechanistic Perspective
1653
‡
S.-J. Cho, G. Roman# , F. Yeboah♣ and Y. Konishi*
National Research Council Canada, Biotechnology Research Institute, 6100 Royalmount Ave., Montréal, QC, H4P 2R2,
Canada
Abstract: Protein glycation is a slow natural process involving the chemical modification of the reactive amino and guanidine
functions in amino acids by sugars and carbohydrates-derived reactive carbonyls. Its deleterious consequences are obvious in the
case of long-lived proteins in aged people and are exacerbated by the high blood concentration of sugars in diabetic patients. The
non-enzymatic glycation of proteins occurs through a wide range of concurrent processes comprising condensation,
rearrangement, fragmentation, and oxidation reactions. Using a few well established intermediates such as Schiff base, Amadori
product and reactive α-dicarbonyls as milestones and the results of in vitro glycation investigations, an overall detailed
mechanistic analysis of protein glycation is presented for the first time. The pathways leading to several advanced glycation end
products (AGEs) such as (carboxymethyl)lysine, pentosidine, and glucosepane are outlined, whereas other AGEs useful as
potential biomarkers of glycation are only briefly mentioned. The current stage of the development of glycation inhibitors has
been reviewed with an emphasis on their mechanism of action.
Keywords: Proteins, carbohydrates, glycation, diabetes, aging.
INTRODUCTION
The chemical reaction between amino containing
compounds (proteins and amino acids) and the carbonyl group
of reducing sugars that leads to browning and the development
of flavor in foods systems, was first described by Louis Camille
Maillard in 1912. Although the French chemist postulated that
the reaction could have important implications in human health,
particularly in diabetes, research efforts on the topic in the early
years following the discovery of Maillard reaction were focused
primarily on understanding its chemistry, and exploiting the
knowledge thereof to improve the sensory attributes of foods,
such as color, flavor, taste, and the overall appeal. In addition to
its beneficial aspects in enhancing the sensory properties of
foods, the Maillard reaction also results in the loss of the
nutritional quality of food proteins and the formation of
deleterious reaction products with genotoxic, mutagenic, and
carcinogenic properties [1-4]. In recent years, the formation of
potentially toxic compounds in foods via the Maillard reaction
has engendered a flurry of research activity that is aimed at
elucidating the mechanism(s) by which these compounds are
formed, and to device food processing methods that can
minimize their formation [2, 5-7]. Recent research efforts on the
potential health consequences of Maillard reaction in food
systems suggests that melanoidins produced in foods during
thermal processing may suppress allergic reaction [8], exhibit
antioxidant properties [9] and desmutagenic activity [10].
Further studies are needed to distinguish between the harmful
and beneficial effects of these compounds [11]. Orally absorbed
diet-derived AGEs have been shown to be taken up into the
bloodstream and add to the body pool of endogenously formed
AGEs, as they are only partially eliminated in the urine [12], and
increased dietary AGE intake has been reported to contribute
significantly to the elevated levels of AGEs in patients with
renal failure [13].
The importance of the Maillard reaction is not only relevant
to foods and food systems. Since the discovery of the evidence
that the Maillard reaction also occurs in vivo [14], its relevance
*Address correspondence to this author at the National Research Council Canada,
Biotechnology Research Institute, 6100 Royalmount Ave., Montréal, QC, H4P
2R2, Canada; Tel: (514)-496-6339; Fax (514)-496-5243;
E-mail: yasuo.konishi@cnrc-nrc.gc.ca
# Current address: Department of Chemistry, Queen's University, Kingston, ON,
K7L 3N6, Canada
♣Current address: Ecopia BioSciences Inc., 7290 Frederick-Banting, Saint-Laurent,
QC, H4S 2A1, Canada
‡NRC Publication No. 47556
0929-8673/07 $50.00+.00
to human health has gained increasing attention. The Maillard
reaction in vivo is generally termed glycation, and the glycation
reaction between reducing sugars or their derivatives and
amino-containing biomolecules, such as body proteins (plasma,
tissue and membrane proteins), DNA, and lipids has been
implicated in the development of several age- and diabetesrelated micro- and macro-vascular pathologies that underlie
nephropathy, neuropathy, retinopathy, and sclerosis [15-18].
Although the molecular basis underlying glycation-induced
pathogenesis is not well established, it is generally accepted
that: 1) glycation leads to the formation and accumulation of
AGEs; 2) AGE-modified matrix proteins behave abnormally with
respect to other matrix components and cell surface receptors
such as integrins; 3) the interaction between AGE-modified
plasma proteins and AGE-specific receptors on macrophages and
mesangial cells induces receptor-mediated production of
reactive oxygen species, which in turn leads to increased
oxidative stress in biological systems [4, 5].
Much of what is known about the nature of the Maillard
reaction or glycation is derived from in vitro studies involving
amino acids and simple reducing sugars under high temperature
conditions. In recent years, however, several in vitro
investigations on the glycation of proteins under physiological
conditions have been carried out [19-23] to help elucidate
relevant pathways and mechanisms of the glycation reaction in
vivo.
The aim of this review is to present a detailed mechanistic
profile of the glycation pathways that lead to the formation of
the main identified AGEs, with the view to pinpoint possible
pathways that can be targeted for the development of antiglycation agents with potential therapeutic value.
THE CHEMISTRY OF GLYCATION
Based on the progress of the glycation process, three broad
reaction stages are distinguishable, namely the initial stage, the
intermediate stage, and the late stage. The initial stage of the
reactions involves the initiation of glycation through aminocarbonyl interaction leading to early glycation products which
contain an intact sugar moiety. The intermediate stage
comprises the chemical transformations of the early glycation
products, and the late stage of glycation is characterized by the
formation of AGEs. In this paper, an attempt has been made to
further divide the complex process of glycation into 7 major
stages labeled (i) to (vii), with the view to allow a more
systematic and detailed description of the chemistry and
© 2007 Bentham Science Publishers Ltd.
1654
Current Medicinal Chemistry, 2007, Vol. 14, No. 15
Cho et al.
mechanism(s) of the reaction. The first stage (i) refers to the
condensation of a terminal amino group of a protein and the
carbonyl group of the acyclic form of a reducing carbohydrate to
form a Schiff base, which then undergoes Amadori
rearrangement to form an Amadori product. Stage (ii ) deals with
non-oxidative and oxidative cleavage reactions of Amadori
products, leading to several identifiable AGEs. Stage (iii)
involves Schiff base degradation through the Namiki pathway
to produce glyoxal and glyoxal-protein adducts, the latter being
subsequently converted into two specific AGEs, Nε(carboxymethyl)lysine (CML) and pentosidine, by a route that
circumvents Amadori rearrangement. Stage (iv ) reactions feature
autoxidative glycosylation, which describes the formation of
glyoxal and a novel carbohydrate having a carbon chain one
atom shorter than the initial sugar. Stage (v) reactions describe
the formation of pentosidine from the Schiff base derived from
arabinose generated in stage (iv ). Stage (vi ) deals with the
formation of several α-dicarbonyls through the autoxidation of
glucose. The production of α-dicarbonyls triggers stage (vii),
which describes the formation of a large array of AGEs different
from CML and pentosidine and mainly including proteinprotein crosslinks. The overall illustration of these stages
occurring during protein glycation is summarized in Scheme
(1).
The Maillard reaction requires the existence of a primary
amino group in the structure of an organic compound (a protein
in the specific case of the in vivo glycation) to be reacted with
the carbonyl group of a reducing sugar. Several simple ω-amino
acids have been shown to react swiftly with glucose to produce
in a direct manner the expected Amadori products [24]. The
initiation of the glycation process depends primarily on the
nucleophilicity of the amino group. In the case of proteins,
glycation takes place preferentially at a ω-amino group of the
amino acids sequenced in the protein, and at the α-amino group
of the amino-terminal residue of the proteins. Although the ε-
amino group of lysine bears primary importance with respect to
its reactivity in the formation of Amadori products and AGEs,
the relevance of hydroxylysine residues in the collagens should
not be underestimated [25]. Furthermore, a recent paper has
disclosed the formation of ornithine residues from arginine on
the protein backbone in substantial quantities during aging of
collagen and lens crystallins, which subsequently contributes
to the formation of AGEs through glycation and glycoxidation
with age [26]. Although a recent paper reports an equal
distribution of the glycation sites in a certain protein [27],
proofs for the existence of preferential sites of glycation in a
protein have been recurrently reported [28-33].
All reducing carbohydrates can potentially be involved in
the Maillard reaction, and pentoses such as arabinose or ribose,
as well as hexoses such as glucose, fructose, or galactose, and
even disaccharides as lactose or maltose have been encountered
in studies related to protein glycation. The physiologically
relevant D-glucose is one of the least reactive of the common
sugars in protein glycation, a reason possibly leading to its
evolutionary selection as the main free sugar in vivo [34]. On the
other hand, D-ribose is the sugar counterpart in most of the in
vitro studies of protein glycation. In spite of the fact that its
levels in humans are not elevated, D-ribose is preferred for in
vitro experiments because it is known to be more reactive in the
Maillard reaction than D-glucose, probably due to a higher
fraction of the more reactive acyclic form [35-37].
Formation of Schiff Base and its Amadori Rearrangement
(Stage i)
The glycation reaction starts with the nucleophilic attack of
the nitrogen atom of a primary amino group of a lysine residue
at the carbonyl group of a reducing sugar such as glucose (1) to
form the hemiaminal (2), which spontaneously dehydrates to
give the Schiff base (3), as depicted in Scheme (2). Generally, the
glucose
Lys-NH2
(i)
(vi)
(iii)
glyoxal-Lys adduct
Schiff base
(i)
(ii), (iv)
α-dicarbonyls
1,2-enaminol
(iv)
(i)
(iii)
Amadori product
ara binose
(vii)
(ii)
(v)
CML, pentosidine
Scheme 1.
-dicarbonyl-de rived
AGEs
Reaction Mechanisms in the Formation of AGEs
Current Medicinal Chemistry, 2007 Vol. 14, No. 15
formation of Schiff base is reversible, and both addition and
elimination reaction rates are maximized at slightly acidic pH.
With aromatic aldehydes, the equilibrium is shifted in favor of
Schiff base formation, but aliphatic aldehydes that possess a
hydrogen atom on the carbon adjacent to the carbonyl group do
not generally yield Schiff bases [38]. In the case of reducing
sugars, the intermediate Schiff base can undergo rapid
cyclization to form the N-substituted glycosylamine (4) [39],
which is unstable in aqueous medium and can either undergo
hydrolysis to yield the starting substrates, or undergoes
Amadori rearrangement to produce the relatively stable 1amino-1-deoxy-D-fructose (7), also known as Amadori product.
Amadori rearrangement normally involves an acid-catalyzed
ring opening of glycosylamine (4) to give the iminium ion (5).
The iminium ion then undergoes deprotonation to form the
enaminol (6), which upon tautomerism produces the Amadori
product (7). Amadori rearrangement can also be catalyzed by
transition metal ions, via the same mechanism as protons. The
empty d orbitals of transition metal ions readily accept a pair of
electrons to form transition-state complexes with compounds
containing electron-donating groups [40]. Consequently,
examples of Lewis acid-catalyzed Amadori rearrangement have
also been reported [41-43], in which the transition metal ions
are more efficient than protons, as they are usually polyvalent
and can form multiple bonds to the substrate. With regards to
the cyclic glycosylamine (4), metal ions such as Fe 2+ , Fe 3+ , or
Cu 2+ accelerate the formation of the reactive acyclic iminium
ion (5), thus increasing the reaction rate of the Amadori
rearrangement.
Non-Oxidative and Oxidative Degradation of Amadori
Products (Stage ii)
Amadori products are fairly stable, but with time and under
appropriate conditions they can either decompose to form AGEs
or undergo a reverse reaction to the starting substrates (sugars
and the free amines) [21]. The degradation of Amadori products
may occur both under non-oxidative and oxidative conditions.
At pH 7.4 and 37°C, the reversal of Amadori product to the
starting substrates accounts for more than 90% of its
degradation under non-oxidative conditions [21]. In the pH
range of 4-7, the transformation of the sugar moiety of Amadori
products into α-dicarbonyl compounds, including 1HC
O
HO
CH
NH
1655
deoxyglucose (1-DG) (9), 3-deoxyglucosone (3-DG) (10 ), and 1amino-1,4-dideoxy-2,3-oxo-glucosone (11 ) is a major
degradative pathway [44]. As shown in Scheme (3), the enediol
(8) derived from Amadori product (7) undergoes a lysine residue
elimination to give 1-DG, whereas 3-DG is a result of the lysine
moiety removal from the enaminol (6) [45]. Further degradation
of 3-DG via a retro-aldol reaction generates methylglyoxal (12 )
and glyceraldehyde (13 ) [46]. Presumably, the acid-catalyzed
dehydration of enediol (8) leads to 1-amino-1,4-dideoxy-2,3oxo-glucosone (11 ), whose formation in vivo is still uncertain,
as this compound has not been isolated and characterized. One
of the major consequences of protein-bound dicarbonyl
moieties is the formation of inter- and intra-protein cross-links,
a process responsible for many age and diabetes related health
complications. To the best of our knowledge, no cross-linked
AGEs derived from 1-DG have yet been reported. 3-DG has long
been considered as the major α-dicarbonyl intermediate derived
from the non-oxidative degradation of Amadori products. 3-DG
rapidly reacts with protein amino groups to form AGEs such as
CML (14 ) or representative cross-links, such as imidazolone
(15 ), pyrraline (16 ), and pentosidine (17 ) presented in Fig. (1)
[47]. However, in a recent study, Biemel et al. have showed that
the hitherto unknown 1-amino-1,4-dideoxy-5,6-oxo-glucosone
(19 ) is the major α-dicarbonyl intermediate generated when
glucose was incubated with Boc-lysine, as shown in Scheme (4)
[48]. Starting from Amadori product (7), the migration of the
2,3-enediol function in enediol (8) to the 5,6 position as a result
of successive β-elimination reactions and the final dehydration
at C4 of the 1-amino-5,6-enediol (18 ) leads to 1-amino-1,4dideoxy-5,6-oxo-glucosone (19 ), which is the key intermediate
in the formation of glucosepane (21 ). Glucosepane is an acid
labile lysine-glucose-arginine crosslink that has identified in in
vitro bovine serum albumin (BSA)-glucose incubation mixtures
[49], in human serum albumin and lens proteins [50], and in
senescent human cellular matrix [51]. The intramolecular
condensation between the amino group and the terminal
aldehyde function in 1-amino-1,4-dideoxy-5,6-oxo-glucosone
(19 ) affords the seven-membered ring compound (20 ), which
yields the bicyclic heterocycle upon further condensation with
arginine and ring closure [52]. This mechanism is not well
established, as it is only based on the identification of (19 ) from
which all four diastereoisomers of glucosepane (21 ) could result
in model incubation mixtures [48]. Because the stage at which
Lys
HC
N
Lys
OH
H
C
OH
H
C
OH
HO
C
H
HO
C
H
H
C
OH
H
C
H
C
OH
H
C
Lys-NH2
H
C
OH
HO
C
H
OH
H
C
OH
OH
H
C
OH
–H2 O
CH2 OH
CH2 OH
CH2 OH
1
2
3
O
HO
HO
NHLys
OH
4
H+ or Mn+
H2 C
C
NH
HO
C
H
H
C
OH
H
C
L ys
O
OH
HC
NH
C
OH
HO
C
H
H
C
OH
H
C
OH
Lys
–H+
HC
NH
H
C
OH
HO
C
H
H
C
OH
H
C
OH
CH2 OH
CH2 OH
CH2OH
7
6
5
Scheme 2.
Lys
OH
H
O
HO
HO
NHLys
OH
1656
Current Medicinal Chemistry, 2007, Vol. 14, No. 15
Cho et al.
H2C
NH
C
OH
C
OH
H
C+
H
C
Lys
H2C
- H+
OH
Lys
H2C
NH
O
C
O
C
OH
C
O
H
C
H
C
CH2 OH
NH
C
Lys
CH2
OH
H
C
CH2 OH
OH
CH2 OH
11
+ H+
H2 C
NH
C
H2 C
NH
C
OH
O
HO
C
H
H
C
OH
H
Lys
C
2,3-e noliza tion
H
OH
+ H2 O
H
C
OH
C
OH
C
L ys
H
- H2 N
Lys
H
OH
CH2 OH
CH2 OH
7
8
CH3
CH2
H
OH
C
O
C
O
C
O
C
OH
C
OH
HC
OH
C
C
H
OH
CH2OH
CH2 OH
9
1,2-enolization
HC
NH
C
OH
HO
C
H
H
C
OH
H
C
OH
Lys
+ H+
- H2 O
HC
NH
C
OH
C
H
H
C
OH
H
C
OH
CH 2OH
Lys
+ H2 O
- H2N
- H+
O
HC
O
C
O
CH3
12
retro-aldol
H
C
OH
H
C
OH
CH2 OH
O
C
CH2
Lys
HC
HC
H
C
CH2 OH
6
O
OH
CH2 OH
10
13
Scheme 3.
the guanidine function is introduced in the reaction it is still
unclear, the same authors proposed another hypothetical course
of reaction, in which the closure of the five-membered ring
occurs first [49]. The aldimine (22 ) could be derived from
Amadori product (7) by water elimination from its enaminol
tautomer (6). The reaction of (22 ) with the guanidine function of
an arginine side chain affords the deoxyglucosone-derived
imidazoline cross-link DOGDIC (23 ), which upon dehydration
and prototropic rearrangement leads to glucosepane (21 ), as
presented in Scheme (5). The rationale for this pathway relies on
the similarity of this sequence to that proposed for the
formation of imidazolinone derivatives [53, 54] and on the
isolation of DOGDIC distereoisomers from a model incubation
mixture [52]. However, the absence of glucosepane (21 ) in the 3COOH
O
NH
NH
H2 C
(CH2 )4
H2 N
CO OH
The oxidative cleavage of Amadori product has been
proposed as a major pathway for CML formation [55, 56]. CML
is one of the central AGEs and it is used as a biomarker for
CO OH
N
CH2
deoxyosone incubation mixtures, including those with BSA,
definitely rules out DOGDIC (23 ) as a precursor for glucosepane
and invalidates this pathway [52]. Despite its structural
homology with pentosidine (17 ), glucosepane (21 ) is unique
amongst AGEs because it is primarily formed under nonoxidative conditions. As for 1-amino-1,4-dideoxy-2,3-oxoglucosone (11 ), although its formation has not been confirmed
experimentally, this α-dicarbonyl compound is considered as a
primary intermediate in the formation of CML (14 ) in vivo
through the oxidative cleavage of the C2-C3 carbon-carbon
bond of 1-amino-1,4-dideoxy-2,3-oxo-glucosone.
N
(CH2 )3
N
NH 2
HOH2 C
14
CHO
N
N
H
(H2 C) 3
(CH2 )4
CHO H
HOOC
CHO H
H2N
COOH
CH2 OH
Fig. (1).
HN
15
16
N
(CH2) 4
NH2
H2N
17
COOH
Reaction Mechanisms in the Formation of AGEs
H2 C
NH
Current Medicinal Chemistry, 2007 Vol. 14, No. 15
Lys
H2 C
NH
C
OH
C
O
HO
C
H
HO
C
H
C
OH
H
C
OH
H
C
OH
H
C
OH
CH 2OH
CH2OH
7
8
Lys
N
HO
O
H2 C
NH
H
C
OH
HO
C
H
Lys
HO
NH
C
OH
HO
C
H
Lys
H
C
OH
OH
C
H
CH
C
H
CH
HC
C
H
HO
O
HO
OH
OH
HC
OH
CH2 OH
NH
C
NH
C
C
C
O
H2 C
H
OH
H2 C
C
L ys
C
H
CH2
- H2 O
H 2C
H
Lys
- H2 O
H2 C
NH
C
OH
HO
C
H
H
C
OH
C
OH
HC
OH
O
19
20
Lys
OH
H
OH
1657
L ys
18
HN
- H2O
NH
H2 N
Arg
Lys
L ys
N
N
HN
NH
HO
N
HO
Arg
- H+
Lys
H
N
N
NH
HO
N
HO
N
NH
HO
N
Arg
HO
Arg
H
21
Scheme 4.
oxidative stress and long-term protein damage in normal aging
and diabetes. It can be derived from a combination of glycation
and oxidation reactions [25, 57]. Although the oxidative
degradation of Amadori product accounts for its formation
during protein glycation, CML can be produced through several
other pathways such as Schiff base degradation through the
Namiki pathway [58, 59], the “autoxidative glycosylation”
comprising the reaction between lysine and glyoxal [58, 60, 61],
the reaction between lysine and ascorbate [62], or the metalcatalyzed oxidation of polyunsaturated fatty acids in the
presence of proteins [63]. Attempts to establish the relative
contribution of each of these pathways to the generation of CML
have so far been unconvincing and even contradictory. The
conclusion that the oxidative cleavage of Amadori product is
responsible for most of the CML produced is based on the
observation that aminoguanidine, a compound known to trap
glyoxal, only partially inhibited the formation of CML in vitro,
indicating that the contribution of the autoxidative
glycosylation to the formation of CML is negligible [56]. On
the other hand, in a model system using labeled glucose most of
the CML produced originated either from glucose autoxidation
or the Namiki pathway [64]. At low glucose and buffer
concentrations all three major pathways (cleavage of Amadori
product, Namiki and autoxidative pathways) afforded
comparable amounts of CML, whereas the production of CML
through the fragmentation of Amadori product was partially
inhibited at high glucose concentrations [64].
The oxidative cleavage of Amadori product (7) having two
enolizable protons at positions C1 and C3 may occur via two
competing pathways featuring either 1,2-enaminol (6) or 2,3ene-diol (8) as the key intermediates. These enolic intermediates
result from a base-catalyzed (hydroxide, phosphate) reaction,
although the formation of 2,3-ene-diol may also be catalyzed
via an intramolecular deprotonation by an amino group [65, 66].
Both 1,2-enaminol (6) and 2,3-ene-diol (8) undergo
spontaneous autoxidation in the presence of molecular oxygen
and under metal ion catalysis to produce superoxide anion, enediol oxy radicals, and hydrogen peroxide [67-70]. At high pH
and in the presence of a suitable electron acceptor, 1,2-enaminol
(6) loses a proton to form the enolate anion (24 ), which is
oxidized to the enaminol radical (25 ), as illustrated in Scheme
(6). Subsequent oxidation to the imine (26 ) followed by
hydrolysis yields 2-glucosone (27 ) as the oxidative cleavage
product through this pathway [71]. Under physiological
conditions, the Amadori product derived from fructose and
lysine forms CML (14 ) and erythronic acid (30 ) by oxidative
cleavage between C2 and C3 of the sugar residue [55]. 2,3-Enediol (8) has been suggested as an intermediate in CML
formation, and based on its structural homology with ascorbic
acid, a radical mechanism has been proposed [72]. Trace
amounts of metals in the buffer could be responsible for the
generation of the alkoxy radical (28 ) from 2,3-ene-diol (8), the
former being further oxidized to 1-amino-1,4-dideoxy-2,3-oxoglucosone (11 ), a putative α-dicarbonyl intermediate also
allegedly formed under non-oxidative cleavage of Amadori
1658
Current Medicinal Chemistry, 2007, Vol. 14, No. 15
H2 C
NH
C
O
HO
C
H
H
C
H
C
Cho et al.
Lys
HC
NH
C
OH
HO
C
H
+H+
OH
H
C
OH
- H2 O
OH
H
C
OH
CH2OH
CH2 OH
7
6
H
HN
Lys
HN
NH
C
OH
C
H
H
C
OH
H
C
OH
CH2 OH
A rg
N
H2 C
HN
H
OH
H
OH
N
H2 C
H
O
CH2
C
OH
H
C
OH
H
CH
OH
N
H
OH
H
OH
Arg
CH2 OH
Lys
H
N
N
H
Arg
- H2 O
OH
NH
HO
N
H
H
C
Lys
N
H2 C
- H2 O
NH
H
N
NH
Arg
H
N
N
- H+
HC
H
L ys
CH2 OH
Lys
L ys
NH
HO
- H2 O
HC
22
H
N
NH
H2 N
L ys
OH
CH2 OH
Arg
H
OH
21
23
Scheme 5.
product. As noted before, the presence of (11 ) in glycation
mixtures is still uncertain, and it should be emphasized that the
failure of aminoguanidine to inhibit CML formation does not
only suggest that autoxidative glycosylation is not the major
pathway leading to CML, but also provides evidence that the
dicarbonyl (11 ) is not an intermediate in the oxidative
degradation of Amadori product, as it should have been trapped
by aminoguanidine.
Based on the fact that experimental protein glycation yields
hydrogen peroxide as a by-product [73], Elgawish et al.
proposed [70] the Baeyer-Villiger oxidative cleavage of the C2C3 bond in diketone (11 ) as the pathway leading to CML and
erythronic acid via the anhydride (29 ), as presented in Scheme
(6). However, the participation of Baeyer-Villiger oxidation in
the formation of CML is unlikely, because the incubation of
glycated human serum albumin with 1mM H2 O2 failed to
generate CML in a model system [56]. Moreover, because no
accumulation of hydrogen peroxide in the incubation mixtures
was observed, it is reasonable to assume that H 2 O2 is further
reduced to free hydroxyl radicals [61]. Indeed, Nagai et al.
showed that hydroxyl radicals produced through a Fenton
reaction between Fe2+ and Amadori product-derived
endogenous hydrogen peroxide play an important role in the
oxidative cleavage of Amadori product into CML [74]. In
connection to this, a study involving the incubation of Amadori
products in the presence of scavengers of H2 O2 , superoxide, and
hydroxyl radicals found the formation of CML to be inhibited
by 88%, 100%, and 30%, respectively [55]. In another study, it
was reported that superoxide promoted CML formation more
efficiently than hydrogen peroxide and hydroxyl radicals [75].
A recent study using labeled glucose [76] has shed some
light on the mechanism of formation of CML. The mechanism
proposed implies tautomerization of the 3-deoxyosone formed
from the Amadori compound into a 2,4-dioxo compound (31 )
followed by hydration to lead to CML (14 ) and 3,4-dihydroxy2-butanone (32 ), as shown in Scheme (7). It has also been
reported that, although C1 and C2 contributed mostly to the
formation of CML, C5 and C6 in glucose become more and more
involved in CML formation with prolonged reaction times due
to the shifting of the oxo group along the sugar backbone.
Furthermore, evidence that the formation of CML via glyoxal is
not the main pathway has been provided [76].
Schiff Base Degradation and CML Formation by Namiki
Pathway (Stage iii)
The Schiff base formed during the initial stage of the
glycation reaction can also undergo degradation by retro aldol
cleavage reactions via the Namiki pathway to form short chain
carbonyl compounds such as glyoxal, glycoaldehyde, and their
corresponding imine analogs [56, 77]. The rate of Schiff base
degradation via the Namiki pathway increases with increasing
pH, as retro-aldolization is favored under basic conditions.
Although Namiki’s initial studies were conducted with basic
aliphatic amines in a heated reaction system, Glomb et al. have
shown that lysine derivatives of glyoxal and glycolaldehyde are
also formed under physiological conditions [56]. In a tentative
mechanism according to Scheme (8), the degradation may be
triggered by intramolecular hydrogen bonding between the
imine nitrogen atom and the C3 hydroxyl group hydrogen atom
to form a chair conformer of the Schiff base (3), in which the
retro-aldol cleavage of the C2-C3 bond is facilitated and
Reaction Mechanisms in the Formation of AGEs
H2C
NH
C
O
HO
C
H
H
C
OH
H
C
OH
Current Medicinal Chemistry, 2007 Vol. 14, No. 15
Lys
1,2-enolization
HC
NH
C
OH
HO
C
H
H
C
OH
H
C
OH
Lys
HC
-
H+
C
NH
O
HO
C
H
H
C
OH
H
C
OH
CH2 OH
CH2 OH
CH2 OH
7
6
24
Lys
HC
NBT2+
NH
Lys
.
C
O
HO
C
H
H
C
OH
H
C
OH
NBT+ .
1659
CH2 OH
25
N BT2+
2,3-enolization
NBT+
H2C
NH
C
OH
H
H
C
OH
C
OH
C
Lys
OH
HC
O
HC
N
C
O
C
O
HO
C
H
HO
C
H
H
C
OH
H
C
OH
H
C
OH
H
C
OH
+ H 2O
- H 2N
Lys
CH2 OH
Lys
CH2 OH
CH2 OH
8
27
M n+
26
M (n-1)+
H2 C
C
NH.
H2 C
H
L ys
H2C
C
OH
C
O
C
O
C
O
C
OH
C
OH
O2 -
O2
H
NH
C
OH
H
H
CH2 OH
C
H 2C
Lys
NH
C
O
C
O
C
OH
L ys
Baeyer-Villiger
H
H
OH
CH2 OH
14
+ H2O
COOH
OH
H
C
OH
CH2 OH
H
C
OH
C
Lys
O
OH
O
+ H2 O2
NH
CH2 OH
28
29
11
30
Scheme 6.
produces the Schiff base of glycolaldehyde (34 ). This
intermediate could undergo hydrolysis to glycolaldehyde (35 ),
which is subsequently oxidized to glyoxal (36 ), or could
rearrange to produce aminoaldehyde (37 ) which forms pyrazine
(38 ) upon cyclocondensation with a second molecule of
aminoaldehyde [56]. Oxidation of pyrazine (38 ) yields a N,Ndialkylpyrazinium radical cation which fragments to glyoxal or
di- and mono-Schiff bases of glyoxal (39 ) and (40 ) respectively.
H2 C
NH
C
O
HO
C
H
H
C
OH
H
C
OH
Lys
1,2-enoliz ation
CH2 OH
HC
NH
C
OH
HO
C
H
H
C
OH
H
C
OH
Glomb and Monnier have suggested that glyoxal and
glycoaldehyde generated in the Namiki pathway can lead to the
Lys
HC
- H2 O
CH2 OH
7
Glyoxal and its corresponding imine analogs are responsible for
the
formation
of
several
AGEs
including
CML,
(carboxymethyl)arginine
(CMA),
Nε-(carboxyethyl)lysine
(CEL), glyoxal-lysine dimer GOLD, arginine-lysine-glyoxal
crosslink GODIC and pentosidine.
N
C
OH
L ys
C
O
HO
+ H2O
CH2
H
C
O
C
OH
CH2OH
H
C
H
C
OH
H
C
OH
H
C
OH
H
C
OH
CH2OH
H2C
NH
C
CH2 OH
OH
Lys
C
H
NH
Lys
O
OH
CH2
14
CH3
C
O
C
OH
CH2 OH
31
Scheme 7.
Lys
OH
C
H2C
NH
NH
C
H
6
H2 C
HC
H
C
O
C
OH
CH2OH
32
Lys
1660
Current Medicinal Chemistry, 2007, Vol. 14, No. 15
HC
N
H
C
OH
HO
C
H
H
C
OH
H
C
OH
Cho et al.
Lys
L ys
N
HO
HOHC
O
retro-aldol
HC
H
CH OH
O
H
C
OH
H
C
OH
-
CH 2OH
CH2 OH
HC
NH
HC
OH
Lys
HC
N
H2 C
33
L ys
OH
34
+ H2 O
CH2OH
- H2 N
L ys
3
H2 C
NH
HC
Lys
O
37
HC
O
H2C
OH
35
O2
dimerization
O2
Lys
N
N
HC
O
HC
O
36
Lys
38
+ H2 O
- H2 N
- eLys
HC
N
N
HC
O
fragmentation
L ys
Lys
39
N
HC
N
Lys
Lys
HC
N
Lys
40
Scheme 8.
formation of CML [56]. Although there is no clear experimental
evidence of this, aminoaldehyde (37 ) seems to be the most
obvious intermediate from which CML can be derived through
either oxidative or non-oxidative pathways. As shown in
Scheme (9), the oxidation of aminoaldehyde (37 ) could be
achieved by any of the oxygen reactive species present in the
glycation mixture, or even by molecular oxygen under metal ion
HC
N
H
C
OH
HO
C
H
H
C
OH
H
C
OH
It is noteworthy to mention that Schiff base degradation
through the Namiki pathway is not the only way to generate
short chain carbonyl compounds such as glycolaldehyde or
L ys
Namiki
pathway
H2 C
NH
HC
O
H2 C
Lys
Cannizz aro
C
OH
37
CH2OH
14
3
oxidation
H2 C
C
OH
14
Scheme 9.
catalysis. Alternatively, aminoacetaldehyde (37 ) may lead to
CML (14 ) via a Cannizzaro reaction under non-oxidative
conditions, a hypothesis that is supported by complementary
experiments conducted with aminoacetaldehyde at pH 9 [56].
NH
O
L ys
NH
O
Lys
H2 C
+
CH 2
OH
NH
Lys
Reaction Mechanisms in the Formation of AGEs
Current Medicinal Chemistry, 2007 Vol. 14, No. 15
glyceraldehyde in vivo. For example, the former can be produced
by the action of myeloperoxidase–hydrogen peroxide–chloride
system on serine [78], whereas the latter could arise from the
glycolysis pathway.
incubation of glucose with RNase under oxidative conditions
[58]. A hypothetical mechanism for the formation of arabinose
and glyoxal through autoxidation, according to Scheme (10 ),
shows that the enol form of glucose-derived Schiff base or
Amadori product (7) can react with C1 of another molecule of
glucose via the enamine reaction to form the intermediate (41 ),
which rapidly rearranges to (42 ). Enolization of the aminoketose
(42 ) at the amino tethered α-carbon generates the enaminol (43 ),
whose chair conformation can drive a retro-aldol reaction that is
initiated by intramolecular hydrogen abstraction to form
arabinose. The cleavage of arabinose leaves behind the
iminoketoheptose (44 ) which rearranges to aminoaldoheptose
(45 ), an intermediate from which a second molecule of arabinose
splits off via a retro-aldol reaction to finally give the enaminol
(33 ), a precursor of glyoxal. According to this mechanism, the
ratio of arabinose to glyoxal formed during autoxidative
Formation of Arabinose from Glucose-Derived Amadori
Products (Stage iv)
A closer look at the structure of pentosidine clearly shows
that a pentose is required to generate its pyridine ring. However,
pentosidine can also be readily produced during the postAmadori stage of the glycation reaction when the starting sugars
are hexoses such as glucose or fructose [79]. Elucidation of the
mechanism of formation of pentosidine from glucose
incubation systems was a difficult challenge until Wells-Knecht
et al. reported the formation of glyoxal and arabinose during the
HC
NH
L ys
C
OH
HO
C
H
H
C
OH
H
C
OH
H
CH2 OH
HO
C
H
H
C
OH
enamine reac tion
HC
6
H
C
C
Lys
N
CH2 OH
CH2OH
(CHOH) 4
(CH2OH) 4
H
C
OH
CH
C
OH
HO
C
H
C
O
H
C
OH
HO
C
H
H
C
OH
H
C
OH
CH2 OH
H
C
OH
H
O
OH
OH
CH2 OH
OH
OH
HN
C
C
NH
Lys
C
H
H
C
OH
H
C
OH
HO
O4H9 C 4
OH
HO
NH
H2 C
(CH2 OH)4
C
OH
Lys
42
1
H
C
HC
CH2OH
41
CH2O H
Lys
C4 H9 O4
O
H
-
HC
O
HO
C
H
H
C
OH
H
C
OH
OH
C
N
Lys
H
C
OH
HO
C
H
H
C
OH
H
C
OH
CH2 OH
44
CH2 OH
CH2 OH
43
HC
OH
C
NH
H
C
OH
HO
C
H
L ys
O
HC
NH
H
C
O
HO
C
H
H
C
OH
H
H
C
OH
H
CH2 OH
HC
C
C
L ys
H
O
HO
C
H
H
C
OH
H
C
OH
HC
OH
HC
NH
OH
CH2 OH
H2 C
O
NH
36
H2C
OH
HC
N
34
CH2 OH
HC
Scheme 10.
Lys
33
-
45
HC
OH
1661
L ys
Lys
1662
Current Medicinal Chemistry, 2007, Vol. 14, No. 15
Cho et al.
glycosylation is 2:1, which is in good agreement with the
experimental observation that the incubation of glucose with
RNase produced arabinose and glyoxal in the ratio of about
2.5:1. The difference between the experimental results and the
theoretical value may be explained by the fact that the
aminoaldehyde (36 ) can undergo a wide range of
transformations leading to many other substances besides
glyoxal. In addition, the Girard-T reagent that was used to detect
the amount of glyoxal formed does not detect glycoaldehyde
and its imine derivatives (34 ), also arising from the
tautomerization of the enaminol (33 ).
identified in incubations of D-arabinose with lysine [48]. The
identification of (48 ) enabled the mechanistic elucidation of the
generation of pentosidine from arabinose as shown in Scheme
(11 ). The reaction begins with the formation of Amadori product
(46 ), which then undergoes enolization to yield 2,3-ene-diol
(47 ), which in turn undergoes sequential β-elimination
reactions that cause the double bond to migrate to the end of the
carbohydrate backbone to form a 5,6-ene-diol. Subsequent
dehydration and tautomerization of this 5,6-ene-diol leads to
the formation of the lysine-linked dideoxyosone (48 ), which
then undergoes intramolecular condensation between the amino
group and the terminal aldehyde to form the cyclic β-keto
iminium ion (49 ). Condensation of (49 ) with arginine leads to
pentosinane (50 ), an isolated intermediate which yields the
crosslink end product pentosidine (17 ) at the end of a reaction
sequence comprising oxidation, dehydration, and aromatization
[52]. Despite the obvious necessity of molecular oxygen for the
transformation of pentosinane into pentosidine, a study found
that the formation of pentosidine from arabinose proceeds even
under non-oxidative conditions (absence of oxygen and in the
presence of metal ion chelators) with a yield of about 50% [84].
The authors inferred that the formation of pentosidine either
occurs via a mechanism that is difficult to inhibit by
antioxidative conditions, or that the oxidative mechanism
might involve intermolecular redox processes rather than
oxygen-dependent reactions. The results of this study is in
agreement with the observation made by Biemel et al. that the
partial transformation of pentosinane to pentosidine could not
be prevented by applying antioxidative conditions as employed
in the synthesis of pentosinane from pentoses [52].
Pentosidine Formation from Schiff Base via Biemel’s Pathway
(Stage v)
Pentosidine is a fluorescent protein crosslink AGE that can
be derived from lysine-sugar-arginine interaction. It
accumulates in collagenous tissues with age and its
accumulation is accelerated in diabetic patients [80]. It is also
the first AGE used as a biomarker for the assessment of
glycation in biological systems [81]. Like other glycoxidation
products, pentosidine can result from a plethora of pathways,
the starting point being either the Schiff base (3) or the Amadori
product (7). For example, pentosidine can result from the
reaction between lysine, arginine and glyceraldehyde or
glycoaldehyde during the early stage of the glycation reaction.
Farboud et al. [82] demonstrated that pentosidine was generated
in significant amounts in a time and concentration dependent
manner when BSA was incubated under physiological
conditions with glycoaldehyde, a product of Schiff base
degradation through Namiki pathway. Recently, Chellan and
Nagaraj [83] have shown that glyceraldehyde resulting from the
fragmentation of glucose [46] also produces high levels of
pentosidine in a model system, and proposed that the
mechanism of pentosidine formation may be initiated by
glyceraldehyde-arginine condensation reaction. However, the
major pathway for pentosidine formation presumably involves
the ring closure with arginine residues of the novel
dideoxyosone (48 ), a reasonable α-dicarbonyl precursor
HC
N
HO
C
H
H
C
H
C
Lys
HC
NH
HO
C
OH
H
C
OH
OH
H
C
OH
CH2 OH
Generation of -Dicarbonyls from Glucose (Stage vi)
The production of reactive α-dicarbonyls involved in the
formation of AGEs occurs beyond protein glycation. Simple
monosaccharides autoxidise at pH 7.4 and 37°C to produce βketoaldehydes via a process involving free radicals, as
illustrated in Scheme (12 ). Enolization is a prerequisite for
monosaccharide autoxidation, and trace metal ions may catalyse
L ys
H 2C
HO
H
CH2 OH
NH
L ys
H2 C
C
HO
C
H
C
OH
C
OH
C
OH
C
OH
CH2 OH
46
NH
CH2 OH
47
H 2C
NH
HO
C
H
H
C
OH
C
OH
HC
OH
L ys
H2 C
HO
C
NH
Lys
H2 C
H
HO
CH
C
HC
C
NH
OH
O
L ys
Lys
H
N
+ H+
CH2
- H2O
C
O
HC
O
+
- H2 O
HO
48
HN
L ys
NH
H2 N
N
Arg
- H+
N+
N
NH
N
HO
H
50
Arg
O
49
Lys
- H2 O
Scheme 11.
L ys
H
N
NH
- H2 O
N
- H17
Arg
Reaction Mechanisms in the Formation of AGEs
Current Medicinal Chemistry, 2007 Vol. 14, No. 15
monosaccharide autoxidation, but only up to a maximum rate
limited by the rate of monosaccharide enolisation [85].
Spontaneous degradation of glucose in buffered solution at
37°C leads to glyoxal, methylglyoxal and 3-DG [46]. Glyoxal
(36 ) is formed in the degradation of glucose by retro-aldol
condensation reactions activated by deprotonation of the 2- or
3-hydroxy groups, along with erythrose (51 ) or erythrol (52 ).
Deprotonation of C-2 is a common initial activation step in the
formation of glucosone (54 ) and 3-deoxyglucosone (3-DG) (10 ).
Re-distribution of the electron density between C-1 and C-2
leads to the formation of 1,2-ene-diol (53 ), whereas redistribution of the electron density between C-2 and C-3
followed by dehydration leads to 2,3-enol (55 ) and thereby 3DG (10 ). Methylglyoxal (12 ) is formed by fragmentation of 3DG (10 ), along with glyceraldehyde (13 ). The initial rates of
formation of glyoxal, methylglyoxal and 3-DG were dependent
on phosphate buffer. This may be due to the catalytic action of
phosphate dianion HPO4 2- in the activation of the
deprotonation of glucose [85]. The marked inhibition of
-
glyoxal formation by a metal ion chelator is consistent with
redox active metal ions (Fe3+ and Cu 2+ ) catalysing the
autoxidation of glycoaldehyde leading to the formation of
glyoxal and hydroxyl radical [85]. 3-DG formation was also
decreased by a metal ion chelator, suggesting that trace metal
ion–phosphate complexes may be involved in the activation of
glucose for 3-DG formation [46].
AGEs Derived from -Dicarbonyls (Stage vii)
Despite their relatively low concentration in reaction
mixtures compared to the concentration of the parent
carbohydrates, α-dicarbonyls are a class of intermediates
responsible for most of the AGE formation, including a
significant number of crosslinks, due to their high reactivity.
Besides the AGEs already shown in Fig. (1), a series of other
compounds, mainly crosslinks resulting from α-dicarbonyls are
presented in Fig. (2) and Fig. (3). Glyoxal was identified as an
H2 C
OH
H
C
OH
H
C
OH
CH2 OH
52
retro-aldol
HC
O
H
C
OH
HO
C
H
H
H
C
C
HC
H
retro-a ldol
C
O
OH
+
H
OH
C
OH
HC
OH
HC
O
HC
OH
H2C
OH
OH
35
51
1
1,2-enolization
HC
OH
HC
O
C
OH
C
O
HO
C
H
HO
C
H
H
C
OH
H
C
OH
H
C
OH
H
C
OH
M n+
O2
O2
CH2O H
CH2 OH
53
54
–H2 O
HC
O
OH
C
O
C
H
CH2
C
OH
H
C
OH
OH
H
C
OH
HC
C
H
H
Scheme 12.
C
O
re tro-aldol
CH2 OH
CH2O H
55
10
Mn+
O2
CH2 OH
CH2 OH
1663
HC
O
C
O
CH3
12
HC
H
C
O
OH
CH2OH
13
HC
O
HC
O
O2
36
1664
Current Medicinal Chemistry, 2007, Vol. 14, No. 15
Cho et al.
HN
HN
COOH
(CH2) 4
O
CH2
(CH2 )4
HN
N
N
NH
NH
C
(CH2 )4
N
(CH2) 3
(CH2) 3
HN
CO
NH
NH
(CH2 )3
CO
HN
CO
N
NH
NH
N
HN
CO
CO
HN
56
58
57
HN
COOH
H3C
NH
N
(CH2 )4
(CH2) 4
60
OH
H3 C
H3 C
CH3
N
CH3
H3C
OH
N
O
N
NH
NH
NH
HN
CO
59
OH
N
CH2
HN
CO
(CH2 )4
CH2
CO
(CH2) 3
(CH2 )3
CO
N
HN
61
O
CO
CO
H 3C
62
63
CO
HN
(CH2 )4
H3 C
O
O
H3 C
H3 C
N
HN
N
N
H3C
NH 2
N
NH
O
(CH2 )3
NH
(CH2 )3
(CH2 )3
CO
HN
HN
CO
CO
64
NH
NH2
N
(CH2 )3
HN
N
N
HN
65
66
CO
67
Fig. (2).
intermediate able to react with the ε-amino group of lysine
residues in proteins to form CML [58] and an imidazolium
crosslink known as glyoxal-lysine dimer (GOLD) (56 ) [86-88],
which has been detected in human serum and lens protein. The
modification of the guanidine function in arginine residues by
glyoxal leads to N ω-(carboxymethyl)arginine (CMA) (57 ) [89,
90], which was found in skin collagen and human serum protein,
and an imidazolone designated as Glarg (58 ) [91, 92]. Lederer et
al. identified an arginine-lysine-glyoxal crosslink tagged
GODIC (59 ) from a D-glucose-BSA incubation mixture [93],
which was found later in human material [50, 51].
Methylglyoxal irreversibly modifies lysine residues in proteins
under physiological conditions to give a higher homologue of
CML, CEL (60 ) [94, 95], and an imidazolium crosslink labeled
methylglyoxal-lysine dimer (MOLD) (61 ) [96] which has been
found in human lens protein [87, 97] and human serum [98].
Several adducts of methylglyoxal with arginine residues have
been reported as well. Argpyrimidine (62 ) was acknowledged as
a major fluorescent AGE in glycated bovine lenses [99] and
discovered later in tissue proteins [100], human lens proteins
[101, 102], and even in amyloid deposits [103] and in human
cancer tissues [104]. A methylglyoxal-arginine adduct having a
tetrahydropyrimidine structure (63 ) was also identified as a
non-fluorescent product in a BSA incubation [105], along with
methylglyoxal-derived hydroimidazolone MG-H1 (64 ) [106];
the isomeric hydroimidazolones MG-H2 (65 ) and MG-H3 (66 )
have also been reported [107]. The arginine-lysinemethylglyoxal crosslink coined as MODIC (67 ) is an analog of
Reaction Mechanisms in the Formation of AGEs
Current Medicinal Chemistry, 2007 Vol. 14, No. 15
Besides
α-dicarbonyls,
hydroxyaldehydes
such
as
glycoladehyde and glyceraldehyde have also been shown to be
the starting materials for the recently discovered AGEs GApyridine (73 ) [120, 121], OP-lysine (74 ) [122] and GLAP (75 )
[123-125].
GODIC, and was synthesized and detected in a D-glucose-BSA
incubation mixture [93], human serum albumin and lens protein
[50], and senescent human extracellular matrix [51]. The acid
labile pyrraline (16 ) [108, 109] and imidazolone (15 ) [110] are
the most representative AGEs with a 3-DG-modified lysine
structure, the former being detected in human diabetic lenses
[111]. Skovsted et al. have isolated a derivative of the
imidazolium crosslink 3-deoxyglucosone-lysine DOLD (68 )
from the reaction between N2 -hippuryl-lysine and 3-DG [112],
but the actual crosslink has not yet been detected in vivo. Along
with imidazolone (15 ), hydroimidazolone (69 ) was reported to
result from 3-DG and arginine derivatives [113, 114], the former
being immunohistochemically detected in diabetic patients
[115]. DOGDIC (23 ), the corresponding arginine-lysine
crosslink derived from 3-DG was also prepared [93] and
identified in vivo [50, 51]. Other crosslinks that have been only
scarcely reported in the literature are the acid-stable cationic
fluorophores vesperlysines A (R = H) and B (R = CH 3 ) (70 ),
vesperlysine C (71 ) [116, 117] and crosslines (72 ) [118, 119].
CO
HN
H
H
HOH 2C
H
(CH2 )4
HN
(CH2 )4
HN
CO
OH
N
NH
N
(CH2 )3
(CH2 )4
HN
68
OC
N
N
OH OH
HN
O
OH OH
N
H
Immunological approaches using monoclonal
and
polyclonal antibodies specific for AGE-modified proteins have
been developed and have been used to confirm the presence of
AGEs in vivo [126]. Furthermore, antibody libraries for AGE
structures are important tools for the discovery of novel AGE
structures in vitro and in vivo. The initial studies in this realm
proved the existence of a common structure among AGEs
derived from different glycated proteins and the specificity of
these antibodies for AGEs, but not for early-stage glycation
products such as Schiff base or Amadori product [127, 128].
CML (14 ) was shown to be a major immunological epitope
among AGEs [129, 130], and the use of AGE-modified BSA as an
antigen allowed the preparation of a monoclonal anti-AGE
antibody (6D12) in mice specific for CML [128]. The carbonyl
HOH2 C
(CH2 )4
CO
HN
R
CO
70
69
HN
OC
NH
(H2 C) 4
(H2 C)4
CO
CH2OH
N
N
HN
HN
OH
CO
(CH2 )4
OC
OH
(CH2) 4
N
HO
N
CH
HO
-
HOH2 C
(CH2 )4
(CH2 )4
CO OH
HN
CO
73
HN
HO
H
N
O
COOH
O
Fig. (3).
HN
OH
+
N
74
OH
72
+
N
H2 N
(CH2) 4
CH2 OH
71
O
+
N
OH
H
H
OH
CH2 OH
H
N
H
N
NH
OH
OH
HO
N
H
O
75
1665
76
1666
Current Medicinal Chemistry, 2007, Vol. 14, No. 15
group in CML plays an important role in its recognition by the
antibody, and it has recently been found that 6D12 and
conventionally prepared polyclonal anti-CML antibody crossreact with CEL (60 ) because of its structural similarity to CML
[131]. A novel monoclonal antibody specific for CML (CMS-10)
has been prepared, and its reactivity was highly correlated with
the CML content determined by high performance liquid
chromatography [131]. Several polyclonal anti-AGE antibodies
specific for other epitopes (non-CML) have also been prepared
and characterized [132], but the structure of these epitopes
remains unknown. The antibodies developed for glyoxalmodified proteins were able to recognize GOLD (56 ) [133],
whereas the ones prepared for methylglyoxal-modified proteins
identified argpyrimidine (62 ), MOLD (61 ), and GOLD (56 ) [105,
134]. Another series of non-CML anti-AGE antibodies that
recognize a broad range of serum proteins modified by 3-DG
(10 ), glyceraldehyde (13 ), glycolaldehyde (35 ), methylglyoxal
(12 ), glyoxal (36 ), and glucose (1) has also been developed
[135, 136]. Using immunochemical methods, pentosidine (17 )
was detected in biological samples [137] and in vitro [138], 3DG-imidazolone (15 ) was identified in brain tissues [139] and
atherosclerotic lesions [110], pyrraline (16 ) was evidenced in
diabetic tissues [140] and in familial amyotrophic lateral
sclerosis patients [141], and CEL (60 ) was recognized by its
antibody in diabetic rats [142], spinal cord astrocytes [143], and
corneas [144]. Novel AGEs such as the non-fluorescent, acidlabile, imidazole-based arginine-lysine cross-link ALI (76 )
[145] or GA-pyiridine (73 ) [120] have also been evidenced
through immunochemical studies.
Finally, the issue of recognition of AGEs by the receptor for
advanced glycation end products (RAGE) has to be briefly
addressed. Receptors binding AGEs were initially thought to be
scavenger receptors implicated in the removal of AGEs, and
faulty disposal of AGE-modified proteins was believed to be
relevant in aging and diseases such as diabetes or
atherosclerosis [146, 147]. The cloning and subsequent
characterization of RAGE [148] provided evidence that binding
of AGEs to RAGE did not lead to an accelerated clearance and
degradation with all the expected beneficial effects. Instead,
ligand–receptor interaction resulted in post-receptor signalings
that comprise but are not limited to activation of p21 ras, MAP
kinases, and the NF-κB pathway [149-151]. Therefore, the
concept of RAGE as a scavenger/clearance receptor for AGEs has
to be amended and extended. Nevertheless, the precise chemical
nature of AGE structures mediating RAGE binding have not
been identified, but some evidence supports a role for CML as a
RAGE ligand [152]. In addition, one study [153] reported that
RAGE binding affinity for AGEs showed some dependence on
the CML content, whereas fluorescence and pentosidine content
did not robustly predict RAGE binding, suggesting that
fluorescent AGEs and pentosidine do not bind to RAGE.
Glyceraldehyde- and glycolaldehyde-derived AGEs were shown
to bind to RAGE with estimated K d values of 300 nM and 1.4
µM, respectively, whereas glucose-derived AGEs exhibited a
lower ability to bind to RAGE [154].
Inhibition of Protein Glycation
Protein glycation is a complex natural process involving a
cascade of reactions dependent on the pH of the medium and the
presence of reactive oxygen species and metal ions. A series of
intermediates that are very often more reactive towards proteins
than the starting carbohydrates are generated through multiple
pathways and at different stages of the reaction. Because protein
glycation can not be avoided, strategies involving its
prevention or even its reversal are to be envisaged. To the best
of our best knowledge, no positive biological effects of
glycation have been reported. This makes the inhibition of
glycation by a selective inhibitor a rather unique approach in
Cho et al.
the sense that no negative effects are to be expected. The
thorough understanding of the chemistry of glycation under
physiological conditions could prove to be a useful tool in the
successful discovery of safe and effective anti-glycation agents
for use as therapeutic agents.
One of the current therapeutic strategies for the prevention,
cure and management of age and diabetes related health
complications involves the use of anti-glycation agents. These
are chemical compounds that can slow down, inhibit the
glycation process, or even reverse its negative consequences
[155, 156]. Generally, anti-glycation agents can suppress the
formation of AGEs, either through preventing glycoxidations or
by sequestering the reactive α-dicarbonyls. Recently,
compounds that break down the protein cross-links have also
been included in this category. The design of drugs to inhibit
AGEs formation considerably challenges the pharmaceutical
industry, because these inhibitors must react stoichiometrically
with a wide range of structures, trap low molecular weight
soluble reactive intermediates, which they must intercept in the
presence of much higher concentrations of reactive functional
groups on proteins. Lysine residues are the major site of
chemical modification of proteins by sugars, and a
concentration near 50 mM of plasma proteins requires that an
AGE formation inhibitor (whose concentration in plasma during
therapy is much lower) be significantly more reactive than
lysine. Alternatively, the inhibitor may intercept the formation
of AGEs at a stage either preceding the formation of the
reactive carbonyl intermediates or after the formation of a
reactive adduct with protein. The inhibitor should display in the
same time all these activities without interfering with the
normal metabolism of aldehydes or ketones in vivo. The
structures of the currently known anti-glycation inhibitors are
shown in Fig. (4).
Aminoguanidine (77 ), the prototype AGE inhibitor [157], is
one of the most studied anti-glycation agents that have been
evaluated for their potential use as therapeutic agents. The antiglycation property of aminoguanidine is based on its ability to
scavenge α- and β-dicarbonyl species formed during glycation
to produce stable hydrazones or 3-amino-1,2,4-triazine
compounds [158]. In spite of the beneficial effects of
aminoguanidine in reducing the deleterious effects of glycation,
its clinical trial was terminated due to safety concerns. Like
most of anti-glycation agents that act as reactive carbonyls
trappers, aminoguanidine also sequesters pyridoxal phosphate
and may adversely affect vitamin B6 metabolism [159] and
inhibit nitric oxide synthase [160] and semicarbazide sensitive
amine oxidase [161] at the pharmacological concentration
required for its anti-glycation activity [162]. Designed based on
the structural motif of aminoguanidine, the novel inhibitor
ALT-946 (78 ) proved to be a more potent inhibitor of AGEderived protein modification than aminoguanidine and devoid
of nitric oxide synthase inhibitory action [163]. Metformin
(79 ), a bisguanidine which has been used in the treatment of
type II diabetes was shown to reduce blood glucose levels via a
serine–threonine protein kinase termed LKB1, which
phosphorylates and activates adenosine monophosphateactivated protein kinase [164]. Metformin is a moderate AGE
inhibitor due to its ability to trap methylglyoxal and form the
corresponding dihydroimidazolone derivative, although it is
not as reactive as aminoguanidine [165].
Pyridoxamine (80 ) was reported as a novel, less toxic AGE
inhibitor in studies evaluating analogs of vitamins involved in
the metabolism of carbonyl compounds such as thiamine or
pyridoxine [20, 166]. Like aminoguanidine, pyridoxamine
inhibited the modification of lysine residues and the loss of
enzymatic activity of RNase in the presence of glyoxal and
glycolaldehyde, as well as the formation of BSA-derived CML
[167]. In contrast to aminoguanidine, pyridoxamine proved to
Reaction Mechanisms in the Formation of AGEs
Current Medicinal Chemistry, 2007 Vol. 14, No. 15
1667
H2 N
NH
NH
NH
H
N
H2 N
H2 N
N
H
N
H
N H2
HO
CH3
CH3
H2 N
N
H
N
H
N
N
78
79
80
O
H3C
O
O
H3C
N
N
Br
C6 H5
S
NH
Br
O
H3 C
S
S
81
H3C
82
N
CH 3
83
O
CH3
O
O
CH3
COOH
H3C
N
H
CH3
N
N
H
Br
O
HOOC
CH3
CH3
O
77
OH
NH
N
H
N
H
Cl
N
H
Cl
84
N
N
N
HN
N
N
N
HN
CH3
N
O
H3 C
N
N
O
HOOC
O
NH2
N
H
H3 C
HOOC
O
CH3
CH3
OH
O
O
N
O
HN
86
85
87
NH2
CH3
O
O
N
S
N
N H2
HN
NH
88
PO3H
O
N
CHO
S
H3C
N H2
89
90
Fig. (4).
be a potent inhibitor of AGE formation from glycated proteins,
which granted it the name of “Amadorin”, a post-Amadori
inhibitor of AGE formation [168]. Besides its ability to trap αdicarbonyl intermediates, evidence that pyridoxamine blocks
Amadori product-to-CML conversion by interfering with the
catalytic role of redox metal ions that are required for this
glycoxidative reaction has been provided [169]. The
acknowledgment that pyridoxamine has a limited potential to
react with dicarbonyl precursors of AGE fueled a rational
mechanism-based approach to design second-generation low-
nucleophilicity Amadorins with improved specificity only for
inhibiting post-Amadori pathway. This effort has successfully
produced prototypical compounds such as BST-4997 [170]. An
overview of the results of animal model studies concerning the
use of pyridoxamine for inhibiting AGE formation and the
development of complications of diabetes [171] and its
hypothetical mechanism of action have been recently reviewed
[172, 173].
A relatively novel potential therapeutic approach for the
AGE-derived pathologies is the development of a class of
1668
Current Medicinal Chemistry, 2007, Vol. 14, No. 15
compounds capable of breaking already existing AGE–protein
crosslinks, and thus reverse cardiovascular and dermatological
stiffness related to aging and diabetes. This constitutes an
exciting approach since it would address the issue of
preaccumulated AGEs and subsequently allow their clearance
via the kidney. The prototype compound in this class is N(phenacyl)thiazolium bromide, which has been shown to cleave
glucose-derived protein crosslinks both in vitro and in vivo
[174]. Doubts raised about the effectiveness of N(phenacyl)thiazolium bromide due to its hydrolysis under
physiological conditions [175] have led to the development of
a stable analog, ALT-711 (Alagebrium) (81 ). The exact
mechanism of crosslink breaking is not clearly understood at
the present time. Based on the structural characteristics of the
AGE–protein breaker compounds and the predicted dicarbonyl
structural motif of the crosslinks, a mechanism for breaking
AGE–protein crosslinks has been proposed in vivo [174]. This
mechanism precludes the action of crosslink breakers on other
AGE–protein crosslinks such as MOLD, GOLD, glucosepane,
DOGDIC, MODIC, and GODIC, and whether these crosslink
motifs are amenable to breaking by crosslink breakers is not
clear at present. Thiazolium salts are among the most potent
inhibitors of ascorbate oxidation [176], showing that their
antioxidant characteristics can contribute, at least in part, to
their AGE-inhibiting properties through the attenuation of
glycoxidation. Regardless of its mechanism of action, the
results of pre-clinical and clinical studies [177] show that ALT711 offers a potential therapy for the pathological conditions
caused by AGE–protein crosslinks. The emergence of these
thiazolium halides has paved the way for the design of other
AGE-breakers such as C16 (82 ) [178].
Another inhibitor of advanced glycation, OPB-9195 (83 )
belongs to a group of thiazolidine derivatives known as
hypoglycemic drugs, but its action of inhibiting both AGEderived cross-linking and the formation of AGEs does not
involve the lowering of blood glucose levels but rather an
interaction with carbonyl groups and prevention of the initial
Schiff base formation [179]. The use of OPB-9195 decreased
pentosidine yield in uremic plasma from unspecified carbonyl
compounds (“carbonyl stress”) in a similar manner to
aminoguanidine, allowing a structure–activity supposition
based on the fact that both inhibitors share a hydrazine function
(available in the case of OPB-9195 after hydrolysis) capable of
forming hydrazones with the carbonyls [180]. Furthermore, the
concentrations of three major glucose-derived reactive carbonyl
compounds (glyoxal, methylglyoxal and 3-DG) have been
significantly reduced in the presence of OPB-9195 [181], and
CML accumulation in diabetic nephropathy has also been
deterred [182]. However, at milimolar concentration, OPB-9195
and other AGE inhibitors used in studies in vitro have very
strong metal ion binding activity, and their inhibition of AGE
formation is likely to be the result of their chelating or
antioxidant activity rather than their carbonyl trapping activity
[176].
A large series of phenoxyisobutyric acid derivatives
initially developed as allosteric effectors of hemoglobin for
lowering oxygen affinity of human blood [183] have been
reported to be potent inhibitors of glycation [184]. The
mechanism of action of this class of compounds is unknown.
Evidence suggests that that they act in the early stage, but
mostly inhibit the post-Amadori glycation, and a good
number of them are inhibitors of AGE–protein crosslinking.
Structure–activity relationship investigations have shown that
compounds with an additional aryl- and heteroaryl-ureido or
aryl- and heteroaryl-carboxamido structure show higher
inhibitory effects, leading to inhibitors which are
approximately 40 times more potent than aminoguanidine, and
in the same time 2 to 3 times more effective than pyridoxine.
Cho et al.
From a second series of compounds, including several
substituted aryl and heteroaryl carboxylic acids and substituted
phenoxyacetic acids, LR-90 (84 ) has emerged as a potent in
vitro inhibitor of AGE–collagen crosslinks formation [185]. LR90 manifested the same inhibitory effects in vivo, presumably
by inhibiting the autoxidation pathways before and after the
formation of reactive carbonyl species due to its strong metal
chelating property [186].
Carnosine (β-alanyl-L-histidine) (85 ) is a naturally
occurring non-toxic dipeptide and a commercially available
drug that acts both as an antioxidant and an anti-glycation
agent [187]. It inhibits protein glycation and crosslinking by
acting as an alternative and competitive glycation target [188,
189] as it directly reacts with glycating agents through its
primary amino group, whereas its imidazole moiety plays a
supportive role either by stabilizing the pyrazinium adduct
formed between the glycating agent and carnosine or by
chelation to ion metals [190]. The antioxidant properties of
carnosine [191], which are directed towards scavenging
hydroxyl radicals [192, 193] and peroxyl radicals [194], also
contribute to its anti-glycation activity. The most striking antiglycation property of carnosine is its ability to reverse preexisting glycation [195], possibly through a transglycation
reaction involving the Schiff bases of sugars [196]. Other
protective processes may involve “carnosylation”, carnosine’s
reaction with glycated and oxidized proteins having carbonyl
functions [197], and subsequent facilitation of the
inactivation/removal of such deleterious proteins [198].
However, the AGE-inhibitory action of carnosine is not
comparable with that of aminoguanidine. N-Acetylcarnosine, a
prodrug for carnosine is useful for age-related cataract
management and prevention in human and canine eyes [199].
Several other compounds such as the angiotensin II receptor
antagonists olmesartan (86 ) [200] and valsartan (87 ) [201], antiinflammatory drug tenilsetam (88 ) [202, 203], 2,3diaminophenazine (89 ) [204, 205], and the liposoluble thiamine
derivative benfotiamine (90 ) [206] were also reported to inhibit
the formation of AGEs in vitro or in vivo, but their application
in therapeutics appears to be limited. The screening of a large
library of drugs yielded over a hundred hits [207], most of them
being anti-inflammatory drugs with antioxidant activity.
Among these drugs, catechins, tetracyclines and adrenalines are
the most potent with the IC50 values around 20 µM.
CONCLUSIONS
Nonenzymatic glycation of proteins in vivo and its resulting
advanced glycation end products have been implicated in the
development of several health complications associated with
the normal aging process and diabetes. Studies conducted to
elucidate the chemistry of the glycation reaction and the
mechanisms by which glycation induces protein damage that
results in health complications have led to the general
consensus that protein glycation in vivo involves a complex
cascade of reactions including condensations, rearrangements,
fragmentations, and oxidative steps. Several AGEs, such as CML
and pentosidine, have been identified as biomarkers that can be
used to indicate the extent of the glycation in biological
systems. Most in vitro glycation investigations conducted
under physiological conditions with the view to elucidate the
reaction pathways leading to these biomarkers have only
presented generalized schemes focusing on a certain stage of
glycation, without placing the findings in a larger context, nor
showing clear details on the multitude of pathways involved in
the formation of AGEs. Due to the complexity of the processes
involved in glycation, the redundancy of some stages, and in
several cases the multiples possibilities for the generation of
the same AGE, it is difficult to conceive that a unique successful
Reaction Mechanisms in the Formation of AGEs
inhibitor could be designed. The critical review of the current
stage of the development of glycation inhibitors not only
clearly shows that several types of inhibitors such as carbonyl
trapping compounds, antioxidants and metal ions chelators had
a limited efficiency but also hints to the long road ahead. The
overall detailed mechanistic analysis of the glycation reaction
pathways leading to the formation of AGEs presented in this
paper definitely sets the stage for the development of
mechanism-based chemical agents to prevent and manage the
glycation related health complications.
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