Regulation of the long‐chain carnitine acyltransferases

Abstract

Long-chain carnitine acyltransferases are a family of enzymes found in mitochondria, peroxisomes, and endoplasmic reticulum that catalyze the exchange of carnitine for coenzyme A in the fatty acyl-CoA. Conversion of the fatty acyl-CoA to fatty acylcarnitine renders the fatty acid more permeable to the various cellular membranes. The mitochondrial carnitine palmitoyltransferases are considered important in the regulation of mitochondrial beta-oxidation of long-chain fatty acids. However, palmitoylcarnitine produced by peroxisomal carnitine octanoyltransferase or by microsomal carnitine palmitoyltransferase is not different from that produced by the mitochondrial enzyme. Therefore, for there to be control of fatty acid oxidation by the long-chain carnitine acyltransferases, there would have to be some mechanism to coordinately regulate these varied enzymes. The first system of regulation involves inhibition by malonyl-CoA, an intermediate in the synthesis of fatty acids. Malonyl-CoA inhibits long-chain carnitine acyltransferase activity by all three enzymes at similar concentrations in the physiological range. In addition, the mitochondrial and peroxisomal enzymes are known to be regulated at the level of mRNA transcription by a number of shared factors. Although the microsomal enzyme is less well studied, there does, indeed, appear to be a pattern of coordinate regulation for this system.

Role of long-chain fatty acyl-CoA esters in the regulation of metabolism and in cell signalling

“…The most prominent intracellular fatty-acyl derivatives are the acylcarnitine esters, and evidence for a direct link between the long-chain acyl-CoA pool and the long-chain acylcarnitine pool was provided by Arduini et al [165]. Long-chain carnitine acyltransferases constitute a family of enzymes present in the outer membrane of mitochondria, peroxisomes and endoplasmic reticulum (reviewed in [166]). The equilibrium constant for CPT I has been reported to be approx.…”

“…The equilibrium constant for CPT I has been reported to be approx. 1 [166]. It must, therefore, be expected that there will be a free flow of acyl chains between the acyl-CoA and acylcarnitine pools, and the acylcarnitine pool will in this way act as buffer for activated acyl chains in i o (Figure 4).…”

Palmitoylcarnitine, a surface‐active metabolite

“…Palmitoyl-carnitine passes through a carnitine-acylcarnitine translocase to the inner part of the inner mitochondrial membrane, where a second coenzyme exchange takes place, opposite to the former one: carnitine palmitoyltransferase II converts fatty acylcarnitines into fatty acyl-CoAs, that can now undergo 13-oxidation in the mitochondrial matrix. More details on the carnitine palmitoyltransferases may be found in [19,20]. Long-chain carnitine acyltransferases are also found in peroxisomes, and in endoplasmic reticulum, that also exchange carnitine for coenzyme A and vice versa [20].…”

“…More details on the carnitine palmitoyltransferases may be found in [19,20]. Long-chain carnitine acyltransferases are also found in peroxisomes, and in endoplasmic reticulum, that also exchange carnitine for coenzyme A and vice versa [20].…”

Inhibition by etomoxir of rat liver carnitine octanoyltransferase is produced through the co-ordinate interaction with two histidine residues

“…Liverisoform (L-) and muscle-isoform (M-) CPT I [4,5] activities are down-regulated by this metabolite, but CPT II is not [6]. COT is also inhibited by malonyl-CoA, but to a lesser extent than CPT I. Physiological inhibition of CPT I and COT by malonyl-CoA plays a pivotal role in the regulation of the β-oxidation pathways in both mitochondria [3] and peroxisomes [7].…”