Fatty Acid Biosynthesis: Pathway, Regulation & Enzymes

Fatty Acid Biosynthesis

Lipogenesis

For medical students3 min readUpdated 2026-10-10

Lipogenesis is the process of synthesizing fatty acids from carbohydrate metabolism products with their subsequent rapid incorporation into fats and phospholipids. It occurs predominantly in liver cells during the absorptive (postprandial) state.

Main organLiver (to a lesser extent, adipose tissue and lactating mammary glands)

Key enzymeAcetyl-CoA carboxylase (coenzyme: biotin)

Main productPalmitic acid (palmitate, C16:0)

ConditionsAbsorptive state, high glucose concentration

Substrate Preparation and the Citrate Shuttle

Fatty acid synthesis requires three main components: building blocks (acetyl-CoA), reducing equivalents (NADPH), and energy (ATP). All of these are generated through the activation of glycolysis and the pentose phosphate pathway.

The main challenge is that carbon chain assembly takes place in the cytosol, whereas the starting substrate (acetyl-CoA) is produced in the mitochondrial matrix via pyruvate oxidative decarboxylation. The mitochondrial membrane is impermeable to acetyl-CoA. To bypass this barrier, the citrate shuttle mechanism is utilized:

Inside the mitochondria, acetyl-CoA condenses with oxaloacetate in a reaction catalyzed by citrate synthase to form citrate.
Citrate is transported into the cytoplasm via the tricarboxylate translocase.
In the cytosol, the enzyme ATP-citrate lyase cleaves citrate back into oxaloacetate and acetyl-CoA (consuming ATP and utilizing HS-CoA). The goal is achieved: acetyl-CoA is now in the cytoplasm.

The remaining oxaloacetate is reduced to malate by cytosolic malate dehydrogenase. Malate then undergoes oxidative decarboxylation to pyruvate by malic enzyme. This reaction generates NADPH, which is required for lipogenesis, and pyruvate returns to the mitochondrion.

First and Regulatory Reaction

Lipogenesis begins with the conversion of acetyl-CoA into malonyl-CoA (the donor of two-carbon units for chain elongation).

This carboxylation reaction is catalyzed by the ligase enzyme acetyl-CoA carboxylase. It requires ATP, carbon dioxide, and the coenzyme biotin. This step is the rate-limiting and primary regulatory point, tightly controlled by hormones.

Multienzyme Complex: Fatty Acid Synthase

Subsequent assembly of the molecule is carried out by a multienzyme complex—fatty acid synthase (palmitate synthase). It is a homodimer consisting of two identical polypeptide chains. Each chain contains seven active domains and a specialized acyl carrier protein (ACP). The role of the ACP is to shuttle the growing molecule from one active center to another.

The structure of the synthase contains two important SH (thiol) groups: one belonging to a cysteine residue, and the other to a phosphopantetheine group.

The process is a cyclic elongation of the chain by 2 carbon atoms per pass:

Acetyl-CoA serves merely as a "primer" (providing the first two carbons).
Malonyl-CoA acts as the donor for all subsequent two-carbon units.
The reduction of the $\beta$-keto group and the saturation of the double bond consume hydrogen from NADPH.

The final product of this complex is always the 16-carbon palmitic acid.

Regulation Mechanisms of Lipogenesis

Synthesis activity depends on the state of the regulatory enzyme, acetyl-CoA carboxylase. It is controlled via two main mechanisms: covalent modification (phosphorylation) and allosteric control (assembly/disassembly of protomers).

Activation (absorptive state):

High glucose levels stimulate insulin release.
Insulin activates a phosphatase that removes a phosphate group from acetyl-CoA carboxylase. The dephosphorylated form is active.
Accumulation of cytosolic citrate (an allosteric activator) promotes the aggregation of enzyme protomers into active polymers.
Furthermore, during prolonged excess carbohydrate intake, insulin induces the transcriptional synthesis of lipogenic enzymes, leading to enhanced conversion of glucose into fat and subsequent obesity.

Inhibition (fasting or stress):

Glucagon (during fasting) or epinephrine (during exercise) activates the adenylate cyclase system and protein kinase A.
Protein kinase A attaches a phosphate group to the enzyme. The phosphorylated form is inactive.
The end product of synthesis, palmitoyl-CoA (an allosteric inhibitor), causes the polymer to dissociate into inactive individual protomers.

Subsequent Fate: Triacylglycerol Synthesis

Synthesized fatty acids are rapidly stored as triacylglycerols (TAGs) in the liver.

The backbone is derived from the glycolytic intermediate dihydroxyacetone phosphate, which is reduced to glycerol-3-phosphate. Two activated fatty acids (acyl-CoA molecules) are attached to form phosphatidic acid. Following the removal of the phosphate group by a phosphatase, diacylglycerol (DAG) is formed, which accepts a third fatty acid to yield the final fat—TAG.

Mnemonic

To remember the regulation of the key enzyme: "Insulin and Citrate Assemble (activate via dephosphorylation and polymerization), whereas Glucagon and Palmitoyl-CoA Disassemble (inactivate via phosphorylation and dissociation)."

Frequently asked questions

What is the structure of fatty acid synthase (palmitate synthase)?

Fatty acid synthase is a multifunctional enzyme complex functioning as a homodimer of two identical subunits.

Polypeptide chains — composed of two identical chains.
Composition of a single chain — includes 7 active domains and an acyl carrier protein (ACP).
Acyl carrier protein — shuttles the growing chain between catalytic domains.
Binding sites — each chain contains two sites with thiol (SH) groups belonging to cysteine and phosphopantetheine.

What reactions comprise a single cycle of fatty acid synthase?

One chain-elongation cycle on the multienzyme complex consists of four sequential reactions:

Condensation — decarboxylation of malonyl (released as $CO_2$) and attachment of the acyl group.
Reduction — reduction of the $\beta$-keto group utilizing NADPH.
Dehydration — removal of a water molecule from the intermediate.
Reduction — saturation of the double bond using NADPH, resulting in a saturated acyl chain (butyryl in the first cycle).

How do elongation and desaturation of fatty acids occur after palmitate formation?

Following palmitic acid synthesis, other fatty acids can be produced via elongation and desaturation:

Elongation — extension of the carbon skeleton using malonyl-CoA; for example, the synthesis of stearic acid from palmitic acid.
Desaturation — stearoyl-CoA desaturase acts on saturated fatty acids to introduce monounsaturated bonds; for example, palmitic acid (C16:0) is converted to palmitoleic acid (C16:1).

Human cells cannot introduce double acids at positions beyond the 9th carbon atom from the carboxylic acid end.

What is the purpose of the citrate shuttle in metabolism?

It is necessary to transport acetyl-CoA from the mitochondrial matrix, where it is produced from carbohydrate breakdown, into the cytosol, where the enzymes for fatty acid synthesis are located.

What is the role of NADPH and what are its sources?

NADPH is used as a hydrogen donor (reducing agent) in synthetic reactions on the fatty acid synthase complex. The main sources of NADPH are the pentose phosphate pathway and the cytosolic malic enzyme reaction.

By how many carbon atoms does the chain lengthen in a single cycle of synthase activity?

The carbon chain of a fatty acid is extended by exactly 2 carbon atoms per cycle. Malonyl-CoA serves as the source of these two-carbon units.

Go deeper

Structure and mechanism of action of the acyl carrier protein (ACP)
Biochemical reactions within the fatty acid synthase complex
Transcriptional induction of lipogenic enzymes by insulin
Role of malic enzyme in linking carbohydrate and lipid metabolism