Acetate Pathway: Production of fatty acids, polyketides
and m-oxygenated aromatics
Utilized in both plant & animal kingdoms in the
biosynthesis of
• fatty acids (FA), fats & oils
• signaling molecules derived from FA such as
prostaglandins
• anthraquinones and phenols found in certain
botanicals
• polyketides, such as macrolide antibiotics)
Initial assembly of 2C pieces uses a series of Claisen condensations
Fatty acid synthase is an enzyme complex that controls the condensation of
acetyl-CoA building blocks onto a starter unit
Fatty acid biosynthesis:
Poly-b-keto chains destined to become fatty acids are shuttled into
reductive pathway, where C=O are reduced to CH2
Fatty acids: Common long-chain carboxylic acids are shown in table 3.1
Some key points about fatty acid structure & properties:
1) The number of C in the chain is always even
Biosynthesis by the acetate pathway involves condensation of
decarboxylated malonyl esters contributing 2C each
2) Saturated fatty acids of between 12 and 20 C are common; overall
shape is straight-chain
3) Unsaturated fatty acids in nature are biosynthesized as cis (Z)
isomers; this puts a “kink” in the chains & affects 3-D structure
(trans-fatty acids only form synthetically)
4) As the number of double bonds increases (polyunsaturated fatty
acids) melting points decrease
Where does the unsaturation
come from?
Common end products constructed with fatty acids
Fats & oils (TAGs)
– energy storage
Phospholipids
- cell membranes
Some key points about structure and properties of triacylglycerols
1) TAG that are solid at room temperature are classified as fats (animalbased)
2) TAG that are liquid at room temp. are classified as oils (vegetablebased)
3) In general, the more unsaturated the FA in a TAG, the less solid it is
4) Most liquid TAG come from plant sources (olives, corn, safflower)
5) Most solid or primarily saturated fats come from animal sources
6) 3-D structure of FA affects packing which then affects melting point
Trans fatty acid is similar in shape to
a saturated fatty acid
TAGs composed of mostly unsaturated FA don’t
pack as tightly due to shape
Table 3.2 of Dewick: Fatty acid composition of some common oils and fats
from plant sources
Triacylglycerols (TAG, aka “triglycerides”)
O
H 2C
HC
H2 C
OH
OH
OH
+
HOOC
R1
HOOC
R2
HOOC
R3
H 2C
C
O
HC
O
C
O
O
H2 C
O
R1
R2
C
R3
Condensation of glycerol with three fatty acids produces a molecule of fat
or oil (FA may vary within a TAG)
Some key points
Chemistry
of TAG:about structure and properties of triacylglycerols
1) TAG that are solid at room temperature are classified as fats (animala) Saponification:
based) hydrolysis (NaOH) produces fatty acid salts + glycerol
Base-catalyzed
2) TAG that are liquid at room temp. are classified as oils (vegetablebased)
b) Hydrogenation:
Reaction with H2/Pt converts unsaturated carbons to saturated
3) In general, the more unsaturated the FA in a TAG, the less solid it is
c) Catabolism: TAG undergo acid-catalyzed hydrolysis in stomach
4) Most liquid TAG come from plant sources (olives, corn, safflower)
(digestion) Fatty acids are broken down 2 C at a time to acetyl-CoA which
enters citric acid cycle
5) Most solid or primarily saturated fats come from animal sources
enters citric acid cycle
d) Lipid peroxidation
and antioxidants
Polyunsaturated fatty acids are easily
oxidized by O2 or oxygen free radicals:
a peroxy radical
an alkyl hydroperoxide
Health ramifications: Oxidation of LDL initiates formation of “plaque”
(solid buildup) in blood vessels and onset of atherosclerosis/heart disease.
Fatty acids are a major component of:
 Lipoproteins, especially LDL (low-density lipoproteins)
 Cell membranes--oxidation degrades membranes making them less fluid
 Oils and fats in food; oxidation causes “rancidity”
Oxidation of fatty acids causes problems with
an alkyl hydroperoxide
• Lipoproteins – oxidation of the lipids causes dysfunction, induces an
inflammatory
response Oxidation of LDL initiates formation of “plaque”
Health
ramifications:
(solid buildup) in blood vessels and onset of atherosclerosis/heart disease.
• Cell membranes – oxidation degrades membranes, making them less
fluid and
flexible
Fatty
acids
are a major component of:

•

Lipoproteins, especially LDL (low-density lipoproteins)
Cell membranes--oxidation
less fluid
Stability/shelf
life – oxidationdegrades
of naturalmembranes
oils and fatsmaking
causesthem
“rancidity”
Oils and fats in food; oxidation causes “rancidity”
Antioxidant compounds react with free radicals (often by forming a more
stable free radical) and remove them from the site before damage occurs.
Common antioxidants include substituted phenols, vitamins E, A & C
Omega classification of fatty acids:
structure and health effects
• “Omega” system: position of C=C are counted from methyl
end of chain
• w-3 fatty acids: a-linolenic, DHA, EPA
• found mainly in fish, nuts, seeds and seed oils
Why fish? See http://marine-
life.suite101.com/article.cfm/why_do_fish_have_omega3_fatty_acids
w-3 are good for your health!
w-6 fatty acids are more common in Western diet
Most omega-3’s are highly unsaturated, and they improve the
lipoprotein ratio (HDL:LDL)
• Omega-3’s believed to reduce inflammation throughout the
body (see prostaglandins and precursors) by competitive
inhibition of enzymes used in production of PG 2-series
prostaglandins (the really bad ones)
•
•
•
Recent findings on omega-3
• Animal study: rats supplemented with E-EPA (vs. palm oil)
showed better levels of neuro-transmitter acetylcholine,
improved memory
• Babies who consumed formula supplemented with DHA had
better vision by 1 yr of age
• In vitro studies show inhibition of oral microbial pathogens
• Japanese study showed elderly with higher dietary intake of
DHA had significanly lower incidence of periodontal disease –
linked to antiinflammatory
• Patients with metastatic breast cancer taking DHA during
chemotherapy survived longer
• Chemistry matters: ALA has some heart benefits, but longerchain EPA, DHA more effective in most studies
From Simopoulos, A. (2002) Omega-3 Fatty Acids in Inflammation and Autoimmune
Diseases. J. Am. Coll. Nutr. 21: 495-505.
• Among the fatty acids, the omega-3 polyunsaturated fatty acids
(PUFA) possess the most potent immunomodulatory activities.
• Among omega-3, those from fish oil (EPA and DHA) are more
biologically potent than ALA.
• Some of the effects of omega-3 PUFA are brought about by
modulation of the amount and types of eicosanoids made.
• Other effects come from eicosanoid-independent mechanisms:
actions upon intracellular signaling pathways, transcription factor
activity and gene expression.
• Animal experiments and clinical intervention studies indicate that
omega-3 fatty acids have anti-inflammatory properties that might be
useful in managing inflammatory and autoimmune diseases.
From Simopoulos, A. (2002) Omega-3 Fatty Acids in Inflammation and
Autoimmune Diseases. J. Am. Coll. Nutr. 21: 495-505.
• Coronary heart disease, major depression, aging and cancer
are characterized by an increased level of interleukin 1 (IL-1),
a proinflammatory cytokine.
• Many autoimmune diseases (arthritis, Crohn’s, colitis, lupus)
are characterized by high levels of IL-1 and proinflammatory
LTB4 - produced by omega-6 fatty acids.
• Clinical trials have assessed the benefits of dietary fish oils in
inflammatory and autoimmune diseases (RA, Crohn’s, colitis,
psoriasis, lupus, MS, migraine)
• Many trials of fish oil in chronic inflammatory diseases reveal
significant benefit, including decreased disease activity and a
lowered use of anti-inflammatory drugs.
From Simopoulos, A. (2002) Omega-3 Fatty Acids in Inflammation and
Autoimmune Diseases. J. Am. Coll. Nutr. 21: 495-505.
Prostaglandins and related signaling molecules
Bioactivities of the prostaglandins
• contraction and relaxation of smooth muscle (uterus, cardiovascular, intestinal tract, lungs)
• inhibit gastric acid secretion
• control blood pressure and suppress blood platelet aggregation
• second messengers, modulate hormone stimulation and metabolic response
• produce inflammation
Formation
of prostaglandins
and prostacyclins:
Role of COX
Prostaglandin precursors
Thromboxanes
Activity of TXA2 >> TXB2
• Blood platelet aggregation  forming a clot or thrombus
• increases cytoplasmic calcium concentrations
• opposite effect to PGI2; thrombosis may be due to imbalance in the two activities
Leukotrienes are involved in allergic responses and inflammatory processes.
An antigen–antibody reaction  release of histamine or slow reacting substance
of anaphylaxis (SRSA) which mediate hypersensitive reactions like asthma, hay fever
SRSA = a mixture of LTC4, LTD4, LTE4
Unusual fatty acids are found among some families
1) Modifications on the chain post-synthesis can lead to rings, alkyne groups
2) Use of unusual starter units as a basis for growing chain
Acetylenic fatty acids
Alkylamides found in Echinacea purpurea are derived from acetate pathway
Unusual starter
units lead to
complex molecules
flavonoids and
stilbenes
many steps
2 isoprenes