Doctor of Diet and Nutrition Sciences Medical Biochemistry (MB-813) Semester - 2

De Novo Synthesis of Fatty Acids

Fatty acids are obtained from both diet and de novo (new) synthesis. Because most fatty acids have
multiples of two carbon atoms, they are synthesized from successive addition of two carbon units,
the donor of which is acetyl CoA. NADPH is required for the reductive reactions of the path- way
which occurs in the cytosol of the cell. The elongation of the fatty acid chain stops upon formation
of palmitate (16-C). Further elongation (and desaturation) are carried out by other enzyme systems.
In humans, liver and lactating mammary glands are the main organs for the endogenous synthesis
of fatty acids, although adipose tissue, brain and kidneys are involved to a lesser extent. Liver
convert excess dietary carbohydrates into fatty acids and triacylglycerol.

The pathway of synthesis of fatty acids involves condensation of two carbon units, in the form of
acetyl CoA, to form long hydrocarbon chain a series of reaction. The reactions are carried out on
fatty acid synthase complex using NADPH as reductant.

The biosynthetic pathway occurs in 3 stages:

a) Transport of 2-carbon units (acetyl CoA) to cytosol.

1. Transport of Two Carbon Units to Cytosol

Fatty acid synthesis occurs in the cytosolic compartment of the cell. However, acetyl CoA, the
precursor, is generated in the mitochondrial matrix as end product of various catabolic processes.
It must reach cytosol by crossing the mitochondrial membranes. But the inner mitochondrial
membrane (IMM) is impermeable to most molecules and ions, including acetyl CoA. Transport
of acetyl CoA across the inner mitochondrial membrane requires that it is fi rst converted to
citrate which is capable of moving across the IMM.

In the cytosol the citrate is cleaved to regenerate acetyl CoA (Fig. 11.14).

Thus, by the coordinated action of two enzymes - citrate-synthase and -lyase, the acetyl CoA is
effectively transported from mitochondrial matrix to the cytosol. While it is used for fatty acid
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Doctor of Diet and Nutrition Sciences Medical Biochemistry (MB-813) Semester - 2

synthesis, oxaloacetate is shuttled back into the mitochondrion either as malate or as pyruvate. It
is converted to malate via malate dehydrogenase that uses NADH as the proton donor. Malate is
then converted to pyruvate by malic enzyme and form NADPH so which becomes available for
lipogenesis. Pyruvate is then translocated across the mitochondrial membrane to be cycled again
in TCA cycle.

Transport of acetyl CoA across inner mitochon- drial membrane (IMM). It combines with
oxaloacetate to form citrate, which readily crosses the membrane. In the cytosol citrate is cleaved
to regenerate oxaloacetate.

The malic enzyme reaction can theoretically supply half of the NADPH required for fatty acid
synthesis. The remaining NADPH has to be obtained from the pentose phosphate pathway.

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Doctor of Diet and Nutrition Sciences Medical Biochemistry (MB-813) Semester - 2

2. Conversion of Acetyl CoA to Malonyl CoA

The key reactions of fatty acid synthesis are the carbon- to-carbon condensations. They require
input of consid- erable energy and are, therefore, thermodynamically unfavorable. To overcome
this energy barrier, acetyl CoA needs to be converted to activated form, which will serve as the
donor of carbon units to the growing fatty acid chain. Malonyl CoA, a 3-carbon compound, is one
such activated form. It is produced by carboxylation of acetyl CoA. The reaction is catalyzed by
the enzyme acetyl CoA carboxylase, and requires free energy which is pro- vided by ATP
hydrolysis.

This is a typical ATP-dependent carboxylation reaction, with enzyme-bound biotin serving as a

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Doctor of Diet and Nutrition Sciences Medical Biochemistry (MB-813) Semester - 2

this reaction is the committed step of fatty acid synthesis. It also serves as a control point, since
activity of acetyl CoA carboxylase is allosterically modulated by citrate.

The first committed step in fatty acid synthesis is the carboxylation of acetyl CoA to form
malonyl CoA which is catalyzed by the biotin containing enzyme, acetyl CoA carboxylase.

3. Reactions Catalyzed by Fatty Acid Synthase.

Synthesis of fatty acid from acetyl CoA precursor occurs on a cytoplasmic polyprotein called fatty
acid synthase (MW 400,000). FAS has more than one enzymatic activities. Fatty acid synthase is
a dimer formed from two identical chains of polyprotein.

These domains are arranged in such a way that they catalyze the successive steps in the fatty acid
synthesis cycle.

Sources of NADPH

NADPH, which plays a key role in fatty acid synthesis, is generated from various sources.

1. Reactions of HMP shunt (PPP pathway): Two of the reactions of this pathway yield an
NADPH each. These reactions are catalyzed by the enzymes glucose 6-phosphate
dehydrogenase (G6PD) and 6-phosphogluconate dehydrogenase, respectively.
2. Malate to pyruvate conversion also yields a NADPH molecule. The reaction is catalyzed
by the malic enzyme.
3. Isocitrate to α-ketoglutarate conversion by the cytosolic isocitrate dehydrogenase (ICDH)
is also source of NADPH.

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Doctor of Diet and Nutrition Sciences Medical Biochemistry (MB-813) Semester - 2

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