Carnitine palmitoyltransferase I

Carnitine palmitoyltransferase I (CPT1) is a mitochondrial enzyme that plays a crucial role in the metabolism of fatty acids by facilitating their transport into the mitochondria for oxidation. It is the first enzyme in the carnitine shuttle pathway, which is essential for the beta-oxidation of long-chain fatty acids. CPT1 is located on the outer mitochondrial membrane and catalyzes the conversion of long-chain fatty acyl-CoA to acyl-carnitine, which can then be transported across the mitochondrial membrane.

Function

CPT1 serves as a key regulatory point in fatty acid metabolism. It controls the entry of long-chain fatty acids into the mitochondria, where they can be oxidized for energy production. This process is particularly important during periods of fasting, exercise, or any condition that requires increased energy expenditure. The enzyme's activity is regulated by malonyl-CoA, a derivative of acetyl-CoA, which inhibits CPT1 to prevent the oxidation of fatty acids when glucose levels are sufficient for energy production.

Isoforms

There are three known isoforms of CPT1 in mammals:

• Carnitine palmitoyltransferase I alpha (CPT1A) - predominantly found in the liver, kidney, and heart.
• Carnitine palmitoyltransferase I beta (CPT1B) - primarily expressed in muscle tissues.
• Carnitine palmitoyltransferase I gamma (CPT1C) - located in the brain and other tissues.

Each isoform is encoded by a separate gene and has tissue-specific expression patterns and regulatory mechanisms, reflecting the diverse energy requirements of different tissues.

Clinical Significance

Mutations in the genes encoding CPT1 isoforms can lead to Carnitine palmitoyltransferase I deficiency (CPT1 deficiency), a rare metabolic disorder characterized by an impaired ability to oxidize long-chain fatty acids. This can result in hypoketotic hypoglycemia, liver dysfunction, and potentially fatal episodes of metabolic crisis, especially during periods of fasting or illness. Diagnosis is typically made through genetic testing and measurement of enzyme activity in tissues.

Treatment

Management of CPT1 deficiency involves dietary modifications to limit the intake of long-chain fatty acids and to provide alternative energy sources, such as medium-chain triglycerides (MCTs), which bypass the carnitine shuttle and can be directly oxidized by mitochondria. Regular feeding schedules and avoidance of fasting are also crucial to prevent metabolic decompensation.

Research

Ongoing research is focused on understanding the detailed mechanisms of CPT1 regulation and its role in metabolic diseases beyond CPT1 deficiency, including obesity, diabetes, and cardiovascular diseases. Insights into CPT1 function may lead to new therapeutic strategies for these conditions.

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  Carnitine palmitoyltransferase I

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  Carnitine palmitoyltransferase I mechanism

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  Acyl-CoA transport to mitochondrial matrix