Malonyl-CoA is a highly regulated molecule in fatty acid synthesis; as such, it inhibits the rate-limiting step

in beta-oxidation of fatty acids. Malonyl CoA inhibits fatty acids from associating with carnitine by
regulating the enzyme carnitine acyltransferase, thereby preventing them from entering
the mitochondria, where fatty acid oxidation and degradation occur.

The inhibition of carnitine acyl transferase I by malonyl-CoA ensures that the oxidation of fatty acids is
inhibited whenever the liver is amply supplied with glucose as fuel and is actively making triacylglycerol
from excess glucose.

A MPK phosphorylates several target enzymes including acetyl-Co A carboxylase which catalyses malonyl-
CoA synthesis. This phosphorylation and thus inhibition of acetyl-CoA carboxylase lowers the
concentration of malonyl-CoA, relieving the inhibition of fatty acyl-carnitine transport into mitochondria
and allowing B oxidation to replenish the supply of ATP.

Malonyl-CoA, the first intermediate in the cytosolic biosynthesis of long-chain fatty acids from acetyl-CoA
increases in concentration whenever the animal is well supplied with carbohydrate.

In untreated diabetes, when the insulin level is insufficient, extrahepatic tissues cannot take up glucose
efficiently from the blood, either for fuel or for conversion to fat. Under these conditions, Ievels of
malonyl-CoA (the starting material for fatty acid synthesis) fall, inhibition of carnitine acyltransferase is
relieved, and fatty acids enter mitochondria to be degraded to acetyl-CoA-which cannot pass through the
citric acid cycle because cycle intermediates have been drawn off for use as substrates in gluconeogenesis.

The formation of malonyl-CoA from acetyl-CoA is an irreversible process, catalysed by acetyl-CoA

carboxylase.

With FAS I systems, fatty acid synthesis leads to a single product, and no intermediates are released. When
the chain length reaches 16 carbons, that product leaves the cycle.

If fatty acid synthesis and B oxidation were to proceed simultaneously, the two processes would constitute
a futile cycle, wasting energy. We noted earlier (see Fig. 17-I2) that B oxidation is blocked by malonyl-CoA,
which inhibits carnitine acyltransferase I. Thus during fatty acid synthesis, the production of the first
intermediate malonyl-CoA, shuts down B oxidation at the level of a transport system in the mitochondrial
inner membrane.

By phosphorylating and inactivating acetyl-CoA carboxyIase AMPK inhibits fatty acid synthesis while
relieving the inhibition (by malonyl-CoA) of B oxidation.

The input to fatty acid synthesis is acetyl-CoA, which is carboxylated to malonyl-CoA.

Acetyl-CoA Carboxylase, which converts acetyl-CoA to malonyl-CoA, is the committed step of the fatty
acid synthesis pathway. The mammalian enzyme is regulated by phosphorylation, and there is allosteric
control via local metabolites.

AMP regulates fatty acid synthesis and catabolism by controlling availability of malonyl-CoA

AMP-Activated Kinase catalyzes phosphorylation of Acetyl-CoA Carboxylase causing inhibition of the ATP-
utilizing production of malonyl-CoA . Fatty acid synthesis is diminished by lack of the substrate malonyl-
CoA. Fatty acid oxidation is stimulated due to decreased inhibition by malonyl-CoA of transfer of fatty
acids into mitochondria
Palmitoyl-CoA, the product of Fatty Acid Synthase, promotes the inactive conformation of Acetyl-CoA
Carboxylase (diagram above), diminishing production of malonyl-CoA, the precursor of fatty acid synthesis

Citrate allosterically activates Acetyl-CoA Carboxylase. Citrate concentration is high when there is
adequate acetyl-CoA entering Krebs Cycle. Excess acetyl-CoA is then converted via malonyl-CoA to fatty
acids for storage.

This is an irreversible reaction. AcetylCoA carboxylation is a rate-limiting step of FA biosynthesis.

AcetylCoA carboxylase is under allosteric regulation. Citrate is a positive effector and palmitoyl CoA is a
negative effector.

Malonyl CoA and acetyl CoA inhibit β-oxidation.

Malonyl CoA inhibits the transport of acylCoA to mitochondria via inhibition of carnitine-acyl transferase.

Acetyl-CoA carboxylase (ACC) is a central enzyme involved in fatty acid β-oxidation and fatty acid
biosynthesis. ACC catalyzes the carboxylation of acetyl-CoA producing malonyl-CoA, which can be used by
fatty acid synthase for fatty acid biosynthesis [1]. While malonyl-CoA is used as a substrate for fatty acid
biosynthesis, malonyl-CoA is also a potent inhibitor of mitochondrial fatty acid uptake secondary to
inhibition of CPT1.

Generally, the level of malonyl-CoA is decreased when MCD activity is increased, resulting in an elevated
rate of fatty acid oxidation.

The CPT isoform, CPT1, resides on the inner surface of the outer mitochondrial membrane and is a major
site of regulation of mitochondrial fatty acid uptake [1]. As mentioned, CPT1 is potently inhibited by
malonyl-CoA, the product of ACC that binds to the cytosolic side of CPT1.

Previous studies have reported that the levels of malonyl-CoA are inversely correlated with fatty acid β-
oxidation rates.

Regulation also occurs via the regulation of the levels of acetyl-CoA and malonyl-CoA. AMPK inhibits ACC,
resulting in increased acetyl-CoA levels/decreased malonyl-CoA levels and increased fatty acid oxidation.
Malonyl-CoA inhibits fatty acid oxidation by inhibiting CPT1