Carnitine palmitoyltransferase I

Carnitine palmitoyltransferase I (CPT1) also known as carnitine acyltransferase I, CPTI, CAT1, CoA:carnitine acyl transferase (CCAT), or palmitoylCoA transferase I, is a mitochondrial enzyme responsible for the formation of acyl carnitines by catalyzing the transfer of the acyl group of a long-chain fatty acyl-CoA from coenzyme A to l-carnitine. The product is often Palmitoylcarnitine (thus the name), but other fatty acids may also be substrates.^[5][6] It is part of a family of enzymes called carnitine acyltransferases.^[7] This "preparation" allows for subsequent movement of the acyl carnitine from the cytosol into the intermembrane space of mitochondria.

Three

CPT1 is an integral membrane protein that exists in three isoforms in mammalian tissues: CPT1A, CPT1B and CPT1C. The first two are expressed on the outer mitochondrial membrane of most tissues, but their relative proportions varies between tissues. CPT1A predominates in lipogenic tissues like liver, whereas CPT1B predominates in tissues like heart and skeletal muscle that have a high fatty acid oxidative capacity.brown adipose cells.^[8][9] Both isoforms are integral proteins of the mitochondrial outer membrane through two transmembrane regions in the peptide chain. The membrane topology of CPT1A was described by ^[10] It is polytopic, with both the N- and C-termini exposed on the cytosolic aspect of the OMM, with a short loop linking the two transmembrane domains protruding into the mitochondrial inter-membrane space.

The third isoform (CPT1C), was identified in 2002 and is expressed in both mitochondria and the endoplasmic reticulum.^[11] It is normally expressed only in neurones (brain), although its expression is altered in certain cancer cell types.^[12][13]

The exact structure of any of the CPT1 isoforms has not yet been determined, although a variety of in silico models for CPT1 have been created based on closely related carnitine acyltransferases, such as carnitine acetyltransferase (CRAT).^[14]

An important structural difference between CPT1 and CPT2, CRAT and carnitine octanoyltransferase (COT) is that CPT1 contains an additional domain at its N-terminal consisting of about 160 amino acids. It has been determined that this additional N-terminal domain is important for the key inhibitory molecule of CPT1, malonyl-CoA, and acts like a switch that makes CPT1A more or less sensitive to malonyl-CoA inhibition ^[15]

Two distinct

Because crystal structure data is currently unavailable, the exact mechanism of CPT1 is not currently known. A couple different possible mechanisms for CPT1 have been postulated, both of which include the histidine residue 473 as the key catalytic residue. One such mechanism based upon a carnitine acetyltransferase model is shown below in which the His 473 deprotonates carnitine while a nearby serine residue stabilizes the tetrahedral oxyanion intermediate.^[7]

A different mechanism has been proposed that suggests that a catalytic triad composed of residues Cys-305, His-473, and Asp-454 carries out the acyl-transferring step of catalysis.^[17] This catalytic mechanism involves the formation of a thioacyl-enzyme covalent intermediate with Cys-305.

Biological function

The carnitine palmitoyltransferase system is an essential step in the

Carnitine palmitoyltransferase I is the first component and

By acting as an acyl group acceptor, carnitine may also play the role of regulating the intracellular CoA:acyl-CoA ratio.[19]

Regulation

CPT1 is inhibited by malonyl-CoA, although the exact mechanism of inhibition remains unknown. The CPT1 skeletal muscle and heart isoform, CPT1B, has been shown to be 30-100-fold more sensitive to malonyl-CoA inhibition than CPT1A. This inhibition is a good target for future attempts to regulate CPT1 for the treatment of metabolic disorders.^[20]

Acetyl-CoA carboxylase (ACC), the enzyme that catalyzes the formation of malonyl-CoA from acetyl-CoA, is important in the regulation of fatty acid metabolism. Scientists have demonstrated that ACC2 knockout mice have reduced body fat and weight when compared to wild type mice. This is a result of decreased activity of ACC which causes a subsequent decrease in malonyl-CoA concentrations. These decreased malonyl-CoA levels in turn prevent inhibition of CPT1, causing an ultimate increase in fatty acid oxidation.^[21] Since heart and skeletal muscle cells have a low capacity for fatty acid synthesis, ACC may act purely as a regulatory enzyme in these cells.

Clinical significance

The "CPT1A" form is associated with carnitine palmitoyltransferase I deficiency.^[22] This rare disorder confers risk for hepatic encephalopathy, hypoketotic hypoglycemia, seizures, and sudden unexpected death in infancy.^[23]

CPT1 is associated with

Its importance in fatty acid metabolism makes CPT1 a potentially useful enzyme to focus on in the development of treatments of many other metabolic disorders as well.[26]

Interactions

CPT1 is known to interact with many proteins, including ones from the NDUF family, PKC1, and ENO1.^[27]

In HIV, Vpr enhances PPARbeta/delta-induced PDK4, carnitine palmitoyltransferase I (CPT1) mRNA expression in cells.^[28] Knockdown of CPT1A by shRNA library screening inhibits HIV-1 replication in cultured Jurkat T-cells.^[29]

See also

• Carnitine palmitoyltransferase II

References