Carnitine acylcarnitine translocase

A few patients have been described with a defect involving the carnitine-acylcarnitine translocase system, which facilitates the movement of long-chain acylcarnitine esters across the inner membrane of the mitochondrion (Fig. 42-2). These patients have extremely low carnitine concentrations and minimal dicarboxylic aciduria [4]. 

Under physiologic conditions, carnitine is primarily required to shuttle long-chain fatty acids across the inner mitochondrial membrane for FAO and products of peroxisomal /1-oxidation to the mitochondria for further metabolism in the citric acid cycle [40, 43]. Acylcarnitines are formed by conjugating acyl-CoA moieties to carnitine, which in the case of activated long-chain fatty acids is accomplished by CPT type I (CPT-I) [8, 44]. The acyl-group of the activated fatty acid (fatty acyl-CoA) is transferred by CPT-I from the sulfur atom of CoA to the hydroxyl group of carnitine (Fig. 3.2.1). Carnitine acylcarnitine translocase (CACT) then transfers the long-chain acylcarnitines across the inner mitochondrial membrane, where CPT-II reverses the action of CPT-I by the formation of acyl-CoA and release of free un-esterified carnitine. 

A specific transport protein, the carnitine-acylcarnitine translocase, moves the fatty acylcarnitine into the mitochondrial matrix while returning carnitine from the matrix to the cytoplasm. Once inside the mitochondria, another enzyme, carnitine palmitoyltransferase II (CPT II), located on the matrix side of the mitochondrial inner membrane, catalyzes the reconversion of fatty acylcarnitine to fatty acyl-CoA. Intramitochondrial fatty acyl-CoA then undergoes (3-oxidation to generate acetyl-CoA.Acetyl-CoA can enter the Kreb s cycle for complete oxidation or, in the liver, be used for the synthesis of acetoacetate and P-hydroxybutyrate (ketone bodies). 

Figure 9-1- Role of carnitine in fatty acid oxidation. Long-chain fatty acids are activated as the thioester of CoA on the cytoplasmic side of the mitochondrial membrane. The fatty acyl group is then transferred to form the corresponding carnitine ester in a reaction catalyzed by carnitine palmitoyltransferase I (CPT ]) The acylcarnitine then enters the mitochondrial matrix in exchange for carnitine via the carnitine-acylcarnitine translocase. The acyl group is transferred back to CoA in the matrix by carnitine palmitoyltransferase II (CPT II). The intramitochondrial acyl-CoA can then undergo P-oxidation.

Carnitine acylcarnitine translocase inhibitors Pyruvate carboxylase inhibitors Phenacylimidazolium salts... 

A. A. M. Morris, S. I. Olpin, M. Brivet, et al. A patient with carnitine-acylcarnitine translocase deficiency with a mild phenotype. Journal of Pediatrics 132, 514 (1998). 

The fact that the mitochondrial inner membrane is virtually impermeable to long-chain fatty acyl-CoA, while the fatty acid oxidative machinery is located inside the mitochondrial matrix, a space enclosed by the inner membrane, might create a serious problem for cellular energy production. The problem is solved by the development of a transmembrane carnitine-dependent transport system for the long-chain acyl residue of acyl-CoA. Catalyzed by carnitine acyltransferase I (CAT-I), which is attached to the inner surface of the mitochondrial outer membrane, fatty acyl-CoA is converted to fatty acyl-carnitine by replacing the CoA residue with carnitine (Figure 3). Fatty acyl-carnitine is transported across the mitochondrial inner membrane in exchange for a molecule of free carnitine by carnitine-acylcarnitine translocase. After arrival in the mitochondrial matrix, fatty acyl-carnitine is converted back to acyl-CoA by carnitine acyltransferase II (CAT-II), an enzyme located on the inner surface of the mitochondrial inner membrane. 

Pande, S.V. (1975) A mitochondrial carnitine acylcarnitine translocase system. Proc. Natt. Acad. Sci. U.S.A. 72, 883-887. 

Carnitine-acylcarnitine translocase deficiency Carnitine palmitoyltransferase type II deficiency 2... 

Fig. 3. Fatty acid degradation. Role of carnitine in the transport of long-chain fatty acids through the inner mitochondrial membrane. Carnitine-acylcarnitine translocase is an integral membrane exchange transport system. Carnitine acyltransferases I and II are located on the outer and inner surfaces, respectively, of the inner mitochondrial membrane.

Defects of fatty acid catabolism, with the exception of SCAD deficiency, generally have elevation of more than one characteristic metabolite. MCAD deficiency is characterized by accumulation of C6, C8 (mainly) and C10 l species. LCAD and VLCAD are characterized by accumulation of C14 l, C14 2 and (usually) C16 and C18 l species. LCHADD and TFP deficiencies are characterized by the accumulation of OH-C16, 0H-C18 1 and usually at least one of the other long-chain species C14 1, C16 and C18 l. The CPT-II and CAT (carnitine/acylcarnitine translocase) deficiencies are characterized by marked elevation of both C16 and C18 1, but not C14 1. Multiple acyl-CoA deficiency (MAD) has several different etiologies, including electron transferring protein (ETF) deficiency, ETF-dehydrogenase deficiency and riboflavin deficiency. Disease patterns vary considerably. In severe forms of the disorder, a generalized marked elevation of mxiltiple intermediates is observed. CPT-I should be suspected when both C16 and Cl8 1 are very low in whole blood, especially if free carnitine is normal or elevated. 

Before long-chain fatty acids can enter the mitochondria and get access to the p-oxidation pathway, they must first be activated to acyl-CoA in a reaction that requires ATP and coenzyme-A. The acyl-CoA still cannot ctoss the mitochondrial inner membrane and must react with carnitine to form the corresponding carnitine ester. This reaction is catalyzed by the enzyme carnitine palmitoyltransferase (CPT). The acylcarnitine itself is also unable to diffuse into the mitochondrial matrix so that the transport is achieved by a specific protein, the carnitine acylcarnitine translocase. Following transport aaoss the mitochondrial inner membrane, acylcamitines are converted back to the corresponding acyl-CoA and carnitine. This reaction is catalyzed by another carnitine palmitoyltransferase which is a different enzyme than that involved in the formation of the acylcarnitine outside the mitochondria. Hence, there are two CPTs, one associated with the inner aspect of the mitochondrial inner membrane, CPT-lF and one that lies... 

DJ., Heymans, H.S.A. Smit, G.P. (1995) J. Inker. Metab. Dis., 18, 230-232. A patient with lethal cardiomyopathy and a carnitine-acylcarnitine translocase deficiency. 

J Inherit Metab Dis 20 714-715. Carnitine-acylcarnitine translocase deficiency—a mild phenotype. 

Stanley, C.A., Hale, D.E., Berry, G.T., Deleeuw, S., Boxer, J. Bonnefont, J.P. (1992). N EnglJ Med 327 19-23. Brief report a deficiency of carnitine-acylcarnitine translocase in the inner mitochondrial membrane. 

Pande, S.V., Brivet, M., Slama, A., Demaugre, R, Aufrant, C. Saudubray, J.M. (1993). J Clin Invest 91 1247-1252. Carnitine-acylcarnitine translocase deficiency with severe hypoglycemia and auriculo ventricular block. Translocase assay in permeabilized fibroblasts. 

Carnitine-acylcarnitine translocase (CACT), located in the inner mitochondrial membrane, carries the fatty acyl-carnitine inside the mitochondrion in exchange for a free carnitine molecule. CPT2, located inside the mitochondrion, then catalyzes the reversal of the CPTl reaction. Thus, the concerted actions of CPTl, CACT, and CPT2 effectively translocate fatty acyl-CoA across the inner mitochondrial membrane. 

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