Natural

Products Chemistry

Fa=y Acids
Biosynthesis

Week 7 Lecture 1
Dr. Taitusi Taufa
 Fa=y Acids
•  Fa=y acids are class of compounds containing a long hydrocarbon
chain and a terminal carboxylate group

 Fa=y Acids
•  The excess dietary carbohydrates and protein can be converted to
fa=y acids and are stores as triacylglycerols (triglycerides)



 Fa=y Acids
•  De novo synthesis of fa=y acids takes place in liver, kidney,
adipose Gssue and lactaGng mammary glands.

•  Site: Cytoplasm of the cell (cytosol)

•  Requirements:
–  Acetyl CoA – source of carbon
–  NADPH – provide reducing equivalents
–  ATP - energy


 Fa=y Acids
Some characteris7cs of Fa:y Acids

–  Amphipathic molecule (having both hydrophilic and

hydrophobic parts)
–  Polar carboxyl group
–  Non-polar hydrocarbon tail
–  Diverse structures (>100 different types)
–  Differ in chain length
–  Differ in degree of unsaturaGon
–  Differ in the posiGon of double bonds
–  Can contain oxygenated groups


 Fa=y Acids Primary Metabolites
Primary metabolites Fa3y Acids
•  fully saturated, linear carboxylic acids & derived
(poly)unsaturated derivaGves:

–  consGtuents of essenGal natural waxes, seed oils, glycerides (fats) &
phospholipids
–  structural role – glycerides & phospholipids are essenGal consGtuents of cell
membranes
–  energy storage – glycerides (fats) can also be catabolized into acetate →
citric acid cycle
–  biosynthe7c precursors – for elaboraGon to secondary metabolites
Fa=y Acids Primary Metabolites
 Fa=y Acids DerivaGves - Secondary
Metabolites
•  Secondary metabolites Fa3y Acids
–  further elaborated derivaGves of polyunsaturated fa=y acids (PUFAs)
•  e.g. polyacetylenes & ‘eicosanoids’ (prostaglandins, thromboxanes &
leukotrienes)

 Biosynthesis of Malonyl Coenzyme A

•  Bicarbonate is the source of the CO2:

–  the bicarbonate is first acGvated via phosphorylaGon by ATP
–  then the phosphorylated bicarbonate carboxylates bioGn to give
carboxybioGn
–  then the carboxybioGn carboxylates the enolate of acetyl CoA to give
malonyl CoA:
 Biosynthesis of Malonyl Coenzyme A

–  the carboxylaGon of bioGn & acetyl CoA are mediated by a single bioGn-
dependent enzyme (complex)
–  having both bioGn carboxylase and transcarboxylase acGve sites
NB. coupling to ATP ‘hydrolysis’ provides energy to drive carboxylaGon processes
 Biosynthesis of Fa=y Acids
•  Fa=y acids are biosynthesised from acetyl CoA as a starter unit by
iteraGve ‘head-to-tail’

•  OligomerisaGon involving:
–  condensaGon with malonyl CoA as an extender unit (with loss
of CO2) – a decarboxyla9ve Claisen Condensa9on
–  3-step reducGon of the resulGng ketone → methylene

•  a`er n = 2-8 iteraGons the C8-20 saturated fa=y acid is released

from the enzyme(s):
 Biosynthesis of Fa=y Acids

 ReducGon: Ketone → Methylene
•  ketone → methylene reducGon is achieved via a 3-step process:
1. NADPH-mediated ketone → alcohol reducGon catalysed by a keto reductase (KR)
2. syn-eliminataion of water catalysed by a dehydratase (DH)
3. NADPH-mediated hydrogenaGon of the double bond catalysed by an enoyl
reductase (ER)









•  all steps are generally stereospecific but stereospecificity varies from organism
to organism
–  indicated specificiGes are for human FAS
 Biosynthesis of Fa=y Acids – Overview of FAS
•  The in vivo process by which all this takes place involves a ‘molecular machine’ - Fa=y
Acid Synthase (FAS)
–  Type I FAS: single mulGfuncGonal protein complex (e.g. in mammals incl. humans)
–  Type II FAS: set of discrete, dissociable single-funcGon proteins (e.g. in bacteria)
–  All FASs comprise 8 components (ACP & 7 x catalyGc acGviGes): ACP, KS, AT, MT, KR,
DH, ER & [TE] :

 The Acyl Carrier Protein (ACP)
•  the Acyl Carrier Protein (ACP) is the key protein that allows the growing oligomer to
access the appropriate acGve sites
•  the ACP is first primed by the post-translaGonal modificaGon of one of its serine hydroxyl
groups:
–  the introducGon of a phosphopantetheine ‘swinging-arm’ by reacGon with acetyl coenzyme A:

–  this swinging-arm provides flexibility for module-module acyl transfer & provides binding
energy for catalysis
–  the ACP is inac7ve prior to priming
 Human Fa=y Acid Synthase (FAS)

Biosynthesis of Fa=y Acids
Biosynthesis of Fa=y Acids
Biosynthesis of Fa=y Acids
Biosynthesis of Fa=y Acids
Biosynthesis of Fa=y Acids
Biosynthesis of Fa=y Acids
Biosynthesis of Fa=y Acids
Biosynthesis of Fa=y Acids
Biosynthesis of Fa=y Acids
Biosynthesis of Fa=y Acids
Biosynthesis of Fa=y Acids
Biosynthesis of Fa=y Acids
Biosynthesis of Fa=y Acids
Biosynthesis of Fa=y Acids
Biosynthesis of Fa=y Acids
Biosynthesis of Fa=y Acids
Biosynthesis of Fa=y Acids
Biosynthesis of Fa=y Acids
Biosynthesis of Fa=y Acids
Biosynthesis of Fa=y Acids
Biosynthesis of Fa=y Acids
Biosynthesis of Fa=y Acids
Biosynthesis of Fa=y Acids
Biosynthesis of Fa=y Acids
Biosynthesis of Fa=y Acids
Biosynthesis of Fa=y Acids
Biosynthesis of Fa=y Acids
Biosynthesis of Fa=y Acids
Biosynthesis of Fa=y Acids
 Biosynthesis of Unsaturated Fa=y Acids

•  two mechanisms are known for the introducGon of double bonds

into fa=y acids:
–  in BACTERIA: anaerobic [O] → monounsaturated FAs (MUFAs)
–  in MAMMALS, INSECTS & PLANTS: aerobic [O] → MUFAs & polyunsaturated
FAs (PUFAs)

Biosynthesis of Prostaglandins & Thromboxanes
•  Prostaglandins & thromboxanes are derived from further oxidaGve processing
of arachiodonic acid
•  both are important hormones which control e.g. smooth muscle contrac7lity
(blood pressure), gastric secre7on, platelet aggrega7on & inflamma7on (<nM
acGvity)
–  various pharmaceuGcals including corGcosteroids & aspirin inhibit biosynthetheGc
steps in these pathways
 Biosynthesis of Leukotrienes
•  leukotrienes are the other main class of 2° metabolites derived from
arachiodonic acid
–  they are potent (<nM) inflammatory substances released during allergic
reacGons
 Summary
•  The enzymes of fa=y acids synthesis are packaged together in a complex called
as fa=y acid synthase (FAS)

•  The product of FAS acGon is palmiGc acid (16:0)

•  ModificaGons of this primary FA leads to other longer (and shorter) FA and
unsaturated FA

•  The fa=y acid molecule is synthesized 2 carbons at a Gme

•  FA synthesis begins from the methyl end and proceeds toward the carboxylic
acid end. Thus, C16 and C15 are added first and C2 and C1 are added last

•  C15 and C16 are derived directly from acetyl COA. For further step-wise 2-
carbon extensions, acetyl COA is first acGvated to malonyl CoA, a 3-carbon
compound, by the addiGon of a CO2
 Nomenclature of Fa=y Acids
•  In this system we use –oic (in case of saturated fa=y acids) and –enoic (in case
of unsaturated fa=y acids with single double bond), -dienoic (for unsaturated
fa=y acids with two double bonds) and –trienoic (for unsaturated fa=y acids
with three double bonds) along with the total number of carbon atoms

For example

•  If the total number of carbon atoms is 18 and it is saturated fa=y acid then its
name will be wri=en as octadecanoic acid

•  If the total number of carbon atoms is 18 and it is unsaturated fa=y acid with:
–  one double bond, octadecanoic acid
–  two double bonds, octadecadienoic acid
–  three double bonds, octadecatrienoic acid
Nomenclature of Fa=y Acids
Nomenclature of Fa=y Acids
 Nomenclature of Fa=y Acids
Delta (Δ) and Omega Systems (ω)

•  Delta and omega systems are other nomenclature of fa=y acids

•  The delta system Δ the notaGon describe the chain and the
number and posi7on of the double bonds

•  The linoleic acid notaGon is 18:2 Δ9,12

•  This means 18 carbons in the chain, 2 double bond at posiGon 9

and 12

•  In delta numbering start from the carboxyl end of the fa=y acid
 Nomenclature of Fa=y Acids
Delta (Δ) and Omega Systems (ω)

•  The omega systems ω counts from the methyl end of fa=y acid
hydrocarbon chain; the notaGon for linoleic acid is 18:2 ω 6 or
18:2 n 6

•  This means that carbon number of linoleic acid is 18 and 2

indicates the number of double bond in posiGon 6 counGng from
methyl group end of the carbon chain

•  The suggesGon is that; the double bond in fa=y acid always

separated by three carbon so if the locaGon of double bond of
omega number one known the other double bond will be know
Nomenclature of Fa=y Acids
Nomenclature of Fa=y Acids
Nomenclature of Fa=y Acids
Nomenclature of Fa=y Acids