Carnitine acylcamitine translocase

Hsu BY, lacobazzi V, Wang Z, Harvie H, Chalmers RA et al (2001) Aberrant mRNA splicing associated with coding region mutations in children with carnitine-acylcamitine translocase deficiency. Mol Genet Metab 74 248-255... 

Fig. 1. Camitine-dependent transfer of acyl groups across the inner mitochondrial membrane. Abbreviations ACS, acyl-CoA synthetase CPT I and CPT II, carnitine palmitoyltransferase I and II, respectively T, carnitine acylcamitine translocase.

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 cross 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 acylcamitine itself is also unable to diffuse into the mitochondrial matrix so that the transport is achieved by a specific protein, the carnitine acylcamitine translocase. Following transport across 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 acylcamitine outside the mitochondria. Hence, there are two CPTs, one associated with the inner aspect of the mitochondrial inner membrane, CPT-lP and one that lies... 

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

Stanley, C.A., Hale, D.E., Berry, G.T., Deleeuw, S., Boxer, J. Bonnefont, J.P. (1992). N Engl J Med 327 19-23. Brief report a deficiency of carnitine-acylcamitine 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-acylcamitine translocase deficiency with severe hypoglycemia and auriculo ventricular block. Translocase assay in permeabilized fibroblasts. 

Niezen-Koning, K.E., van Spronsen, F.J., Ijlst, L., Wanders, R.J., Brivet, M., Duran, M., Reijngoud, D.J., Heymans, H.S. Smit, G.P. (1995). J Inherit Metab Dis 18 230-232. A patient wift lethal cardiomyopathy and a carnitine-acylcamitine translocase deficiency. 

Following the eatalytic reaction to form long-chain fatty acyl-CoA, the enzymatic reaction of carnitine palmitoyltranferase I (CPT-1) replaces CoA with carnitine to form fatty acylcamitine [62]. This conversion allows fatty acids to be transported from the cytoplasm to the inner mitochondrial membrane via carnitine acylcamitine translocase. Once across the inner mitochondria membrane, fatty acylcamitine is reversely converted back to long-chain fatty acyl-CoA by carnitine palmitoyltrandferase II (CPT-2) for subsequent P-oxidation [63, 64]. Each p-oxidation cycle removes a two carbon unit and involves four main enzymes 1) aeyl-CoA dehydrogenase, 2) enoyl-CoA hydratase, 3) 3-hydroxyacyl-CoA dehydrogenase, and 4) P-ketothiolase [65]. The net reaction of each P-oxidation pathway is ... 

In muscle, most of the fatty acids undergoing beta oxidation are completely oxidized to C02 and water. In liver, however, there is another major fate for fatty acids this is the formation of ketone bodies, namely acetoacetate and b-hydroxybutyrate. The fatty acids must be transported into the mitochondrion for normal beta oxidation. This may be a limiting factor for beta oxidation in many tissues and ketone-body formation in the liver. The extramitochondrial fatty-acyl portion of fatty-acyl CoA can be transferred across the outer mitochondrial membrane to carnitine by carnitine palmitoyltransferase I (CPTI). This enzyme is located on the inner side of the outer mitochondrial membrane. The acylcarnitine is now located in mitochondrial intermembrane space. The fatty-acid portion of acylcarnitine is then transported across the inner mitochondrial membrane to coenzyme A to form fatty-acyl CoA in the mitochondrial matrix. This translocation is catalyzed by carnitine palmitoyltransferase II (CPTII Fig. 14.1), located on the inner side of the inner membrane. This later translocation is also facilitated by camitine-acylcamitine translocase, located in the inner mitochondrial membrane. The CPTI is inhibited by malonyl CoA, an intermediate of fatty-acid synthesis (see Chapter 15). This inhibition occurs in all tissues that oxidize fatty acids. The level of malonyl CoA varies among tissues and with various nutritional and hormonal conditions. The sensitivity of CPTI to malonyl CoA also varies among tissues and with nutritional and hormonal conditions, even within a given tissue. Thus, fatty-acid oxidation may be controlled by the activity and relative inhibition of CPTI. 

In the heart, fatty acid oxidation defects can cause cardiomyopathy. The cardiomyopathy is usually associated with a degree of hypertrophy. Cardiomyopathy is typical for severe fatty acid oxidation defects of long-chain fatty acids. Cardiomyopathy in those with carnitine transporter defect is typically dilated in nature without hypertrophy. Severe ventricular arrhythmias (ventricular tachycardia, ventricular fibrillation, torsades de pointes) occur in fatty acid oxidation defects. They are frequent in severe fatty acid oxidation defects of long-chain fatty acids and particularly prominent in camitine-acylcamitine translocase deficiency but can also occur in MCAD deficiency during decompensation. Atrioventricular block can occur but is rare. 

Figure 8. The mitochondrial carnitine shuttle. Abbreviations CPTl, camitine-palmitoyl transferase 1 CPT2, camitine-palmitoyl-transferase 2 camitine/acylcamitine translocase (CAC or CACT) [127].

Camitine-acylcamitine translocase deficiency Carnitine palmitoyltransferase type II deficiency 2... 

The transport is accomplished with the participation of carnitine, which takes up the acyl from acyl-CoA on the outer membrane side. Acylcamitine assisted by carnitine translocase diffuses to the inner side of the membrane to give its acyl to the CoA located in the matrix. The process of reversible acyl transfer between CoA and carnitine on the outer and inner sides of the membrane is effected by the enzyme acyl-CoA-camitine transferase. 

Carnitine palmitoyltransferase I (CPTI also called carnitine acyltransferase I, CATI), the enzyme that transfers long-chain fatty acyl groups from CoA to carnitine, is located on the outer mitochondrial membrane (Fig. 23.5). Fatty acylcamitine crosses the inner mitochondrial membrane with the aid of a translocase. The fatty acyl group is transferred back to CoA by a second enzyme, carnitine palmitoyl-transferase II (CPTII or CATII). The carnitine released in this reaction returns to the cytosolic side of the mitochondrial membrane by the same translocase that brings fatty acylcamitine to the matrix side. Long-chain fatty acyl CoA, now located within the mitochondrial matrix, is a substrate for (3-oxidation. 

One property of the translocase is specially noteworthy its affinity for long-chain acylcamitine is very much higher than for carnitine itself. This suggests a basic role for carnitine, additional to the acetylation buffer already mentioned. Every fourth reaction of the P-oxidation spiral (the excision of an acetyl unit by a thiolase enz5mie) requires free CoASH, so that if the CoA of the mitochondrial matrix became over-acy-lated the whole process would come to a halt. If acyl-CoA were formed directly from fatty acids in the same compartment (the matrix) as oxidation this might readily happen. However, the carnitine system guards against this fail-nonsafe situation, because if the acyl-CoA/CoASH ratio (and hence the acylcamitine/camitine ratio) rises the translocase will selectively export acylcamitine from the matrix and import carnitine this will lower the ratio and restore P-oxidation. It remains (I think ) to be seen if this effect can be conclusively demonstrated. 

The CPT system consists not only of the translocase but also of two functionally separate forms of CFTs. CPT 1 which catalyses the formation of acylcamitine from carnitine and Acyl-CoA, and CPT n which catalyses the formation of Acyl-CoA from acylcamitine and CoA. 

Carnitine serves as a cofactor for several enzymes, including carnitine translo-case and acyl carnitine transferases I and II, which are essential for the movement of activated long-chain fatty acids from the cytoplasm into the mitochondria (Figure 11.2). The translocation of fatty acids (FAs) is critical for the genaation of adenosine triphosphate (ATP) within skeletal muscle, via 3-oxidation. These activated FAs become esterified to acylcamitines with carnitine via camitine-acyl-transferase I (CAT I) in the outer mitochondrial membrane. Acylcamitines can easily permeate the membrane of the mitochondria and are translocated across the membrane by carnitine translocase. Carnitine s actions are not yet complete because the mitochondrion has two membranes to cross thus, through the action of CAT II, the acylcar-nitines are converted back to acyl-CoA and carnitine. Acyl-CoA can be used to generate ATP via 3-oxidation, Krebs cycle, and the electron transport chain. Carnitine is recycled to the cytoplasm for fumre use. 

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