What is required for fatty acid synthesis?

January 3, 2026 •

2 min read

Overconsumption of carbohydrates leads to their conversion into fats for long-term storage, a process known as lipogenesis. For this conversion to occur, a complex set of molecular requirements must be met, primarily involving key substrates, specialized enzymes, and high-energy cofactors, all regulated to prevent wasteful energy expenditure.

Quick Summary

Fatty acid synthesis requires acetyl-CoA, malonyl-CoA, and NADPH, relying on a multienzyme complex called fatty acid synthase. The process is orchestrated in the cytoplasm, converting excess carbohydrates into fatty acids for energy storage and cellular structure.

Key Points

Acetyl-CoA: The foundational two-carbon unit is sourced from mitochondrial citrate, which is transported to the cytosol and cleaved by ATP-citrate lyase.
Malonyl-CoA: The activated three-carbon intermediate is created by acetyl-CoA carboxylase (ACC), the key regulatory enzyme, and acts as the immediate donor for chain elongation.
NADPH: This is the required reducing equivalent for the synthetic pathway, derived mainly from the pentose phosphate pathway and the malic enzyme reaction.
Fatty Acid Synthase (FAS): This multienzyme complex catalyzes the repeated four-step cycle of condensation, reduction, dehydration, and reduction to build the fatty acid chain.
ATP: A significant amount of energy in the form of ATP is required, particularly for the initial carboxylation of acetyl-CoA.
Regulation: The process is tightly controlled by hormones like insulin and glucagon, as well as allosteric effectors like citrate and palmitoyl-CoA, to prevent futile cycling.

Fatty acid synthesis, or lipogenesis, is a metabolic pathway generating fatty acids from simpler precursors, primarily in the cytosol of liver cells, adipose tissue, and mammary glands. The synthesis requires specific substrates, enzymes, reducing power, and energy, all tightly regulated for cellular efficiency. Understanding these requirements is key to comprehending energy storage and related metabolic diseases.

The Fundamental Building Blocks: Acetyl-CoA and Malonyl-CoA

Acetyl-CoA: The Carbon Source

Acetyl-CoA is the main two-carbon building block. Most acetyl-CoA is produced in mitochondria but must be transported to the cytosol for synthesis. It is converted to citrate in mitochondria, transported to the cytosol, and then cleaved back to acetyl-CoA by ATP-citrate lyase.

Malonyl-CoA: The Activated Intermediate

Acetyl-CoA carboxylase (ACC) catalyzes the formation of malonyl-CoA from acetyl-CoA. This rate-limiting step requires ATP and uses bicarbonate. Malonyl-CoA serves as the donor for subsequent two-carbon additions to the growing fatty acid chain.

The Power and Machinery: NADPH and Fatty Acid Synthase

NADPH: The Reducing Power

Fatty acid synthesis is a reductive process requiring NADPH. NADPH is primarily sourced from the Pentose Phosphate Pathway (PPP) and the malic enzyme reaction.

The Fatty Acid Synthase (FAS) Complex

The central enzyme is the Fatty Acid Synthase (FAS) complex. In mammals, this multienzyme polypeptide synthesizes palmitate from acetyl-CoA and malonyl-CoA. It operates through repeated cycles, adding two carbons each time, utilizing an acyl carrier protein (ACP).

The Fatty Acid Synthesis Cycle Steps

The FAS cycle involves four main steps:

Condensation: Combining the acetyl and malonyl groups, releasing $CO_2$.
Reduction: Reducing a $\beta$-keto group using NADPH.
Dehydration: Removing water to form a double bond.
Second Reduction: Reducing the double bond using NADPH.

This cycle continues until palmitate is formed and released.

Regulatory Mechanisms and Compartmentalization

Hormonal Control

Hormones regulate synthesis based on energy status. Insulin promotes it by activating ACC, while glucagon and epinephrine inhibit it by inactivating ACC.

Allosteric Regulation

Citrate activates ACC, signaling excess acetyl-CoA. Palmitoyl-CoA, the product, inhibits ACC, providing feedback.

Comparison of Fatty Acid Synthesis and Oxidation

These are distinct pathways with key differences:


Feature	Fatty Acid Synthesis	Fatty Acid Oxidation (Beta-Oxidation)
Location	Cytosol	Mitochondria
Carriers	Acyl Carrier Protein (ACP)	Coenzyme A (CoA)
Substrates	Acetyl-CoA, Malonyl-CoA	Fatty Acyl-CoA
Redox Cofactor	NADPH	NAD+, FAD
Process	Reductive, Anabolic	Oxidative, Catabolic
Key Enzyme	Fatty Acid Synthase (FAS), Acetyl-CoA Carboxylase (ACC)	Multiple, separate enzymes

Synthesis Beyond Palmitate

Longer fatty acids and double bonds are introduced by elongase and desaturase enzymes in the endoplasmic reticulum. Mammals require essential fatty acids from the diet.

Conclusion

Fatty acid synthesis is vital for energy storage and lipid structure, requiring acetyl-CoA, malonyl-CoA, NADPH, and the FAS complex. It's regulated hormonally and allosterically, separate from degradation. Disruptions are linked to metabolic diseases, highlighting the need for balanced lipid metabolism. Further research aims to understand and target this pathway for therapeutic purposes.

Learn more about fatty acid metabolism and its regulation on The Medical Biochemistry Page

Frequently Asked Questions

The primary substrates are acetyl-CoA, which provides the initial two-carbon unit, and malonyl-CoA, which is the activated three-carbon unit for subsequent additions to the growing fatty acid chain.

Fatty acid synthesis occurs in the cytosol, a cellular compartment separate from the mitochondria where fatty acid oxidation takes place.

NADPH serves as the electron donor, providing the reducing power necessary for the reduction steps that occur during the synthesis of fatty acids.

The FAS complex is a large multienzyme complex that catalyzes the entire sequence of reactions needed to synthesize palmitate from acetyl-CoA and malonyl-CoA.

The inner mitochondrial membrane is impermeable to acetyl-CoA, so it must be converted to citrate to be transported to the cytosol, where it is then converted back to acetyl-CoA.

Synthesis is regulated by hormones like insulin (activates) and glucagon (inhibits), as well as allosterically by citrate (activates) and palmitoyl-CoA (inhibits).

The final product of de novo fatty acid synthesis, catalyzed by the FAS complex, is typically the 16-carbon saturated fatty acid, palmitate.