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Biosynthesis of fatty acids

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Biosynthesis of Fatty acidsy Fatty acids are synthesized by an extra mitochondrial system,

which is responsible for the complete synthesis of palmitate fromacetyl-CoA in the cytosol.

y In most mammals, glucose is the primary substrate for lipogenesis,

 but in ruminants it is acetate, the main fuel molecule produced bythe diet.

y In birds, lipogenesis is confined to the liver, where it is particularlyimportant in providing lipids for egg formation.

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THEMAIN PATHWAY FOR DE NOVO SYNTHESIS OF FATT Y ACIDS

LIPOGENESIS) OCCURS IN THE CY TOSOL

y This system is present in many tissues, including

liver,kidney, brain, lung, mammary gland, and adipose

tissue.

y Its cofactor requirements include NADPH, ATP, Mn2+, biotin, and HCO3

ð (as a source of CO2).

y Acetyl-CoA is the immediate substrate, and free

palmitate is the end product.

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Production of Malonyl-CoA Is the Initial & Controlling Step in Fatty Acid Synthesis

y Bicarbonate as a source of CO2 is required in the initial reaction for thecarboxylation of acetyl-CoA to malonyl- CoA in the presence of ATP andacetyl-CoA carboxylase.

y Acetyl-CoA carboxylase has a requirement for the vitamin biotin. 

y The enzyme is a multienzyme protein containing a variable number of identical subunits, each containing biotin, biotin carboxylase, biotincarboxyl carrier protein, and transcarboxylase, as well as a regulatoryallosteric site.

y T

he reaction takes place in two steps: (1) carboxylation of biotin involvingATP and (2) transfer of the carboxyl to acetyl-CoA to form malonyl-CoA.

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Biosynthesis of malonyl-CoA. (Enz,

acetyl-CoA carboxylase.)

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All the reactions in the synthetic process are catalyzed

by a multienzyme complex, fatty acid synthase

y The Fatty Acid Synthase Complex Has Seven 

Different Active Sites

y Through outthe process, the intermediates remain covalently

attached as thioesters to one of two thiol groups of thesynthase complex. One point of attachment is the -SH group

of a Cys residue in one of the seven synthase proteins

(beta -ketoacyl-ACP synthase); the other is the -SH group of 

acyl carrier protein.y Acyl carrier protein (ACP) of  E. coli is a small protein 

containing the prosthetic group 4-phosphopantetheine

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y The 4-phosphopante-theine prosthetic group of ACP is

 believed to serve as a flexible arm, tethering the growing

fatty acyl chain to the surface of the fatty acid synthase

complex while carrying the reaction intermediates from one

enzyme active site to the next.

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Fatty Acid Synthase Receives the Acetyl

and Malonyl Groups

y Before the condensation reactions that build up the fatty

acid chain can begin, the two thiol groups on the enzyme

complex must be charged with the correct acyl groups.

y

First, the acetyl group of acetyl- CoA is transferred to theCys -SH group of the - ketoacyl-ACP synthase.This reaction

is catalyzed by acetyl-CoA²ACP transacetylase ,The second

reaction, transfer of the malonyl group from malonyl-CoA to

the -SH group of ACP, is catalyzed by malonyl-CoA²ACP

transferase , also part of the complex.

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The first four steps of this process

y Step 1 Condensation: The first reaction in the formation

of a fatty acid chain is condensation of the activated acetyl

and malonyl groups to form acetoacetyl-ACP, In this

reaction, catalyzed by beta-ketoacyl-ACP synthase (KS).

y Step 2 Reduction of the Carbonyl Group :The

acetoacetyl- ACP formed in the condensation step now

undergoes reduction of the carbonyl group at C-3 to form D-

- hydroxybutyryl-ACP.This reaction is catalyzed by -

ketoacyl-ACP reductase (KR) and the electron 

donor is NADPH.

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Microsomal elongase

system for fatty acid chain

elongation. NADH is alsoused by the reductases, but

NADPH is preferred.

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Production of Palmitate

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Acetate Is Shuttled out of Mitochondria

as Citrate

y Nearly all the acetyl- CoA us Intramitochondrial acetyl-CoA

first reacts with oxaloacetate to form citrate, in the citric

acid cycle reaction catalyzed by citrate synthase .

y

Citrate then passes through the inner membrane on thecitrate transporter. In the cytosol, citrate cleavage by citrate 

lyase regenerates acetyl-CoA in an ATPdependent reaction.

ed in fatty acid synthesis is formed in mito-

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Fatty Acid Biosynthesis Is Tightly

Regulated

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Long-Chain Saturated Fatty Acids Are

Synthesized from Palmitate