BIOSYNTHESIS OF FATTY ACID

Denovo Synthesis of FA
FATTY ACID BIO MEDICAL IMPORTANCE
• Fatty acids play several important roles
• High energy source of fuel
• Building blocks for phospholipids and
glycolipids
• Fatty acid derivatives are used as
hormones and intracellular messengers
 FATTY ACID SYTHESIS
• ORGANS Liver / Mammary glands

• Adipose tissue
• Sub cellular level CYTOSOL

• Precursor Acetyl CoA

• 1ST 2 CARBON from Acetyl CoA

• Remaining 14 CARBON from Malonyl CoA
 SOURCES OF ACETYL COA
• Major sources
• Glucose
• Fatty acid degradation
• Amino Acid catabolism
 REQUIREMENT OF FA SYNTHESIS
• Increase consumption of Glucose
• Excess Acetyl CoA
• Excess intracellular Citrate
• High ATP
• Increase NADPH (HMP Pathway)
 Transportation of Acetyl COA
• From MITOCHONDRIA TO CYTOSOL
• Via Citrate shuttle
Citrate Shuttle
 Formation of Malonyl COA
• Formation of malonyl–CoA is the committed
step in fatty acid synthesis.
• Formation of Malonyl CoA is the
committed step in fatty acid synthesis
(irreversible reaction).
It takes place in two steps:
carboxylation of biotin (involving ATP)
transfer of the carboxyl to acetyl-CoA to
form malonyl-CoA.
Reaction is catalyzed by acetyl-CoA
carboxylase. It is a multienzyme protein
 Regulation Of Acetyl CoA Carboxylase
• Short Term Regulation
• Allosteric
• Citrate Activator / fatty acid inhibitor
AMP activated Protein kinase & Phosphatases
• Hormonal
• Insulin
• Epinephrine & Glucagon
• Long term Regulation
• High calorie intake or increased consumption
of CHO
Regulation Of Acetyl CoA Carboxylase

Citrate is a positive
effector and
palmitoyl CoA is a
negative effector
REGULATION BY HORMONE
 Fatty acid synthase complex
• Multienzyme complex
• It is dimer of two polypeptide chain
• Contains Acyl Carrier Protein (ACP) (Activator of
FA)
• ACP contains the vitamin pantothenic acid in the
form of 4'-phosphopantetheine
• Seven distinct enzyme activities required for fatty
acid biosynthesis
• Monomer is inactive
• each monomer is identical
• Dimer is arranged in a "head to tail" configuration
 Acyl carrier protein attached with
Phosphopantetheine
Phosphopantetheine
H H HO CH3
O

HS-CH2-CH2-N-C-CH2-CH2-N-C-C-C-CH2-O-P-O-CH2-Ser- ACP
Cysteamine
O O O
H H

H H HO CH3 O O
HS-CH2-CH2-N-C-CH2-CH2-N-C-C-C-CH2-O-P-O-P-O-CH2 Adenine
O
O O H H O O

O H
Coenzyme A
O-P-O OH

OH
ACYL CARRIER PPROTEIN
• Fatty acid biosynthesis is a stepwise
assembly of acetyl-CoA units (mostly as
malonyl-CoA) ending with palmitate (C16
saturated)
• Four-step repeating cycle, extension
by 2-carbons / cycle
• – Condensation
• – Reduction
• – Dehydration
• – Reduction
 TRANSFER OF ACETYL GROUP TO ACP

• an Acetyl moiety is transferred from

• acetyl CoA to the ACP phosphopantetheinyl
• sulfhydryl group of one subunit,and then to
• the cysteinyl sulfhydryl group of the other
• subunit
• Catalyzed by AcetylCoA Transacylase
 TRANSFER OF Malonyl GROUP TO ACP
• The malonyl moiety from malonyl CoA then
attaches to the Vacant ACP
phosphopantetheinyl sulfhydryl group of the
first subunit.

• Catalyzed by Malonyl CoA Transacylase

 Condensation reaction

• The acetyl and malonyl moieties condensed,

• A 4-carbon -keto acyl chain is now attached
to the ACP phosphopantetheinyl sulfhydryl
group
The reaction is catalyze by KETOACYL ACP
SYNTHASE
 Reduction /dehydation / Reduction
• A series of three reactions reduces the 4-
carbon keto group to an alcohol,
removes water to form a double bond,
and reduces the double bond .
• NADPH provides the reducing
equivalents for these reactions.
• The net result is that the original acetyl
group is elongated by two carbons.
 Sources of NADPH
• Major
• HMP Shunt Pathway
• Minor
• Malic enzyme
Principal Reactions of Fatty Acids
 Fatty Acid Synthesis
• Step 1: Loading – transferring acetyl- and malonyl-
groups from CoA to ACP
• Step 2: Condensation – transferring 2 carbon unit
• from malonyl-ACP to acetyl-ACP to form 4 carbon
keto-acyl-ACP
• Step 3: Reduction – conversion of keto-acyl-ACP to
hydroxyacyl-ACP (uses NADPH)
• Step 4: Dehydration – Elimination of H2O to form
• Enoyl-ACP
• Step 5: Reduction – Reduce double bond to form 4
carbon fully saturated acyl-ACP (uses NADPH)
 ELONGATION OF FATTY ACID
• Palmitate can be elongated by addition of two
carbons and converts in to new fatty acid
• Location Endoplasmic reticulum( Microsomal)
and mitochondria
• Enzyme fatty acid elongase
• 2-carbon fragments derived from malonyl-CoA
and NADPH provides the reducing equivalents
• Products 18 cabon cantaining FA Stearic acid
• Brain VLCF ( 22 Carbon ) for brain lipids
 Desaturation of fatty acid chain
• Site of process EPR
• Requirement
• Fatty acid, desaturases enzyme NADPH,
Mixed function oxidases and O2
• RESULT ( Products )
• The first double bond inserted b/w
• carbons 9 and 10, producing primarily
• oleic acid, 18:1(9), and small amounts of
palmitoleic acid, 16:1(9)
Nutritional importance of Essential
Fatty acids
• polyunsaturated Fatty acids ω-6 linoleic
and ω-3Linolenic vitals for the body
• WHY
• Humans have carbon 9, 6, 5, and 4
desaturases but lack the ability to
introduce
double bonds from carbon 10 beyond
towards the ω end of the chain
Triglyceride synthesis
 Synthesis of triacylglycerol in
liver and adipose tissue
Glycerol 3-phosphate is produced from
glucose in both tissues.
• It is also produced from glycerol in liver,
but not in adipose tissue, which lacks
glycerol kinase. The steps from glycerol
3-phosphate are the same in the two
tissues.
Synthesis of TG
TG /PHOPHATIDIC ACID
 Fat or Neutral Fat or TG

• Mono-, di-, and triacylglycerols consist

of one, two, or three molecules of fatty
acid esterified to a molecule of glycerol