fatty acid synthase
Summary
Fatty acid synthase (FAS) is a large multi-enzyme complex that catalyzes the synthesis of palmitate (16-carbon saturated fatty acid) from acetyl-CoA and malonyl-CoA, using NADPH as a reducing agent. It is the key enzyme of de novo lipogenesis, active primarily in the liver, adipose tissue, and lactating mammary gland during the fed state.
Detail
Fatty acid synthase is a homodimeric, multifunctional enzyme complex located in the cytoplasm that carries out the entire process of fatty acid synthesis using a single polypeptide with seven distinct catalytic domains plus an acyl carrier protein (ACP) domain. The process begins with acetyl-CoA carboxylase (ACC, the rate-limiting enzyme) converting acetyl-CoA to malonyl-CoA using biotin and ATP. FAS then repeatedly adds 2-carbon units (from malonyl-CoA) to a growing acyl chain attached to ACP, using NADPH (derived from the pentose phosphate pathway and malic enzyme) as the electron donor for reduction, dehydration, and further reduction steps in each elongation cycle. This cycle repeats seven times to produce the 16-carbon saturated fatty acid palmitate, which is then released and can be elongated/desaturated by other enzymes (elongases, desaturases) into other fatty acids.
Clinical/biochemical significance: - Citrate is the key allosteric activator of ACC (and thus indirectly promotes FAS activity) by shuttling acetyl-CoA from mitochondria to cytoplasm via the citrate shuttle when energy/glucose is abundant. - Insulin stimulates fatty acid synthesis (upregulates ACC and FAS transcription via SREBP-1c) in the fed state, promoting energy storage as triglycerides. - Glucagon and epinephrine inhibit ACC (via phosphorylation), shifting metabolism from fatty acid synthesis to fatty acid oxidation during fasting. - FAS is often overexpressed in various cancers (breast, prostate, ovarian) supporting membrane biogenesis and rapid proliferation, making it a potential therapeutic target (FAS inhibitors like orlistat and cerulenin are being studied as anticancer agents). - Malonyl-CoA, the FAS substrate, also inhibits carnitine acyltransferase I, preventing simultaneous fatty acid synthesis and oxidation (a key regulatory checkpoint in lipid metabolism).
This pathway is high-yield for USMLE Step 1 biochemistry questions related to lipid metabolism regulation, contrasting fed vs. fasting states, and understanding metabolic disease and cancer biology.
Sources
- First Aid for the USMLE Step 1
- Lehninger Principles of Biochemistry
- Harper's Illustrated Biochemistry
- Robbins and Cotran Pathologic Basis of Disease
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