U01.01.119 Fatty acid metabolism

Fatty acid metabolism involves both synthesis and degradation processes that occur in different cellular compartments. Understanding the key enzymes and transport mechanisms is essential for USMLE Step 1 preparation.

Fatty Acid Synthesis

Fatty acid synthesis primarily occurs in the cytoplasm and is responsible for producing palmitate (16-carbon fatty acid) from acetyl-CoA. The process requires several steps and enzymes:

Malonyl-CoA Formation
- Enzyme: Acetyl-CoA carboxylase
- Source: Acetyl-CoA + CO₂ (requires biotin)
- Location: Cytoplasm
Fatty Acid Synthesis Pathway
- Key Enzyme: Fatty acid synthase (FAS)
- Building Block: Malonyl-CoA
- End Product: Palmitate (16-carbon fatty acid)
Citrate Shuttle
- Role: Transports citrate from the mitochondria to the cytosol for fatty acid synthesis.
- Involves: ATP citrate lyase, which breaks down citrate to form acetyl-CoA in the cytoplasm.
ATP and NADPH
- ATP: Required for the transport and breakdown of citrate.
- NADPH: Provides reducing equivalents needed for fatty acid elongation.

Key Enzyme	Substrate	Product	Location
Acetyl-CoA carboxylase	Acetyl-CoA + CO₂	Malonyl-CoA	Cytoplasm
ATP citrate lyase	Citrate	Acetyl-CoA	Cytoplasm
Fatty acid synthase (FAS)	Malonyl-CoA	Palmitate (16C fatty acid)	Cytoplasm

Fatty Acid Degradation

Fatty acid degradation, also known as β-oxidation, occurs in the mitochondrial matrix and involves the breakdown of fatty acids into acetyl-CoA, which enters the TCA cycle and can also be converted into ketone bodies.

Fatty Acyl-CoA Formation
- Key Enzyme: Fatty acyl-CoA synthetase
- Location: Cytoplasm
Carnitine Shuttle
- Key Enzymes:
  - Carnitine acyltransferase I & II (carnitine-dependent transport)
  - Role: Transports long-chain fatty acids (LCFAs) into the mitochondria for degradation.
β-Oxidation
- Enzymes: Acyl-CoA dehydrogenases (for various chain lengths)
- End Product: Acetyl-CoA, which feeds into the TCA cycle or can be converted to ketone bodies in the liver.

Key Enzyme	Substrate	Product	Location
Fatty acyl-CoA synthetase	Fatty acid + CoA	Fatty acyl-CoA	Cytoplasm
Carnitine acyltransferase I & II	Fatty acyl-CoA	Fatty acyl-carnitine	Mitochondrial membranes
Acyl-CoA dehydrogenases	Fatty acyl-CoA	Acetyl-CoA	Mitochondrial matrix

Key Points to Remember

Fatty Acid Synthesis (SYtrate)
- Synthesis occurs in the cytoplasm, and the citrate shuttle transports acetyl-CoA into the cytoplasm.
- Malonyl-CoA is the key intermediate for fatty acid elongation (palmitate formation).
Fatty Acid Degradation (CARnitine)
- Degradation occurs in the mitochondrial matrix, where the carnitine shuttle is critical for the transport of long-chain fatty acids (LCFAs) into mitochondria.
Systemic Primary Carnitine Deficiency
- Impairs fatty acid transport into mitochondria, causing toxic accumulation of LCFAs in the cytosol.
- Clinical features include hypotonia, weakness, hypoketotic hypoglycemia, and dilated cardiomyopathy.
Medium-Chain Acyl-CoA Dehydrogenase (MCAD) Deficiency
- Leads to the accumulation of fatty acyl carnitines in the blood and hypoketotic hypoglycemia.
- Causes vomiting, lethargy, seizures, and can lead to sudden death in infants.
- Treatment: Avoid fasting.

Study Tips for USMLE Step 1

Focus on the enzymes involved in both synthesis and degradation of fatty acids, including acetyl-CoA carboxylase, fatty acyl-CoA synthetase, and carnitine acyltransferase.
Understand the cellular locations: Fatty acid synthesis in the cytoplasm and degradation in the mitochondrial matrix.
Remember key metabolic intermediates: Malonyl-CoA in synthesis, fatty acyl-CoA in degradation, and acetyl-CoA as a key product.
Master the concept of transport: Citrate shuttle for synthesis and carnitine shuttle for degradation.

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