Carnitine palmitoyltransferase II

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.

Figure 9-2. Carnitine palmitoyltransferase reaction. Palmitoyl-CoA is shown as a proto-typic substrate. Carnitine palmitoyltransferase I (CPT I) and carnitine palmitoyltransferase II (CPT II) are shown illustrating the direction of the reaction catalyzed by each enzyme during physiological fatty acid oxidation.

Carnitine palmitoyltransferase II deficiency is a metabolic disorder characterised by an... 

Ventura FV, Ijlst L, Ruiter J, Ofman R, Costa CG, Jakobs C, Duran M, Tavares de Almeida I, Bieber LL, Wanders RJ. Carnitine palmitoyltransferase II specificity towards beta-oxidation intermediates-evidence for a reverse carnitine cycle in mitochondria. Eur. J. Biochem. 1998 253 614-618. 

This transport is accomplished by carnitine (L-jS-hydroxy-y-trimethylammonium butyrate), which is required in catalytic amounts for the oxidation of fatty acids (Figure 18-1). Carnitine also participates in the transport of acetyl-CoA for cytosolic fatty acid synthesis. Two carnitine acyl-transferases are involved in acyl-CoA transport carnitine palmitoyltransferase I (CPTI), located on the outer surface of the inner mitochondrial membrane, and carnitine palmitoyltransferase II (CPTII), located on the inner surface. 

M. R. Pierce, G. Pridpan, S. Morrison, and A. S. Pickoff Fatal carnitine palmitoyltransferase II deficiency in a newborn New phenotypic features. Clinical Pediatrics 38, 13 (1999). 

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 mitochondrial matrix, carnitine palmitoyltransferase II (CPT II) catalyzes the reversible transfer of acyl residues with 10-18 carbon atoms between carnitine and CoA to form acyl-CoA thioesters that are the substrates of P-oxidation [4]. CPT II purified from mitochondria of bovine heart and rat liver has a subunit molecular mass of approximately 70 kDa. The crystal stmcture of CPT II revealed the presence of two antiparallel helices that are absent from soluble carnitine acyltransferases and are believed to facilitate the association with the inner mitochondrial membrane (M. Henning, 2006). 

Adapted from Wilke et al (2007). CYP Cytochrome P450, OATP organic anion transporter protein, ABCBl ABC transporter protein, CPT2 carnitine palmitoyltransferase II, PYGM glycogen phos-phorylase, muscle, COQ2 coenzyme Q2... 

Kopec, B. Fritz, I.B. (1973) Comparison of properties of carnitine palmitoylteansferase 1 with those of carnitine palmitoyltransferase II, and preparation of antibodies. J. Biol. Chem. 248, 4069-4073. 

Wieser, T, Dechauer, M. Zierz, S. (1998) Carnitine palmitoyltransferase II deficiency three novel mutations. Ann. Neurol. 42 414-415. 

Taroni, F, Verderio, E., Dworzak, F, Willems, PJ, Cavadini, P. DiDonato, S. (1993) Identification of a common mutation in the carnitine palmitoyltransferase II gene in familial recurrent myoglobinuria patients. Nat. Genet. 4 314-320. 

Carnitine acyltransferases in mitochondria, peroxisomes and the endoplasmic reticulum are different gene products and serve different metabolic fimctions in the cell. Here we summarize briefly evidence that carnitine octanoyltransferase (COT) from the peroxisomes and carnitine palmitoyltransferase II (CPT-II) from the mitochondria (both matrix facing enzymes) differ kinetically and demonstrate that they differ in their sensitivity to conformationally constrained inhibitors that mimic the reaction intermediate. Medium chain inhibitors are 15 times more effective on COT than on CPT-II and long chain inhibitors, such as hemipalmitoylcamitinium, 80 times more effective on the mitochondrial enzyme. Thus, it may be possible to develop inhibitors to inhibit mitochondrial P-oxidation with minimal effects on peroxisomal P-oxidation and other acyl-CoA dependent reactions. 

Demaugre, F. Bonnefont, J.P. Colonna, M. Cepanec, C. Leroux, J.P. Saudubray, J.M. (1991) / Clin. Invest. 87, 859 64 Infantile Form of Carnitine Palmitoyltransferase II Eleficiency with Hepatomuscular Symptoms and Sudden Death. 

Hug, G. Soukoup, S. l99l)NewEngl J. Med. 325, 1862-1864 Lethal neonatal multiorgan deficiency of carnitine palmitoyltransferase II. 

Scholte, H.R. Jennekens, F.G. Bouvy, J.J. (1979) J. Neurol. Sci. 40, 39-51 Carnitine palmitoyltransferase II deficiency with normal carnitine palmitoyltransferase I in skeletal muscle and leukocytes. Meola, G. Bresolin, N. Rimoldi, M. Velicogna, M. Fortunate, F. Scarlato, G. (1987) J. Neural. 235, 74-79 Recessive carnitine palmitoyl transferase deficiency biochemical studies in tissue cultures and platelets. 

Verderio, E. Cavadini, P. Montermini, L. Wang, H. Lamantea, E. Finocchiaro, G. DiDonato, S Gellera, C. Taroni, F. (1995) Hum. Mol. Genet. 4, 19-2, Carnitine palmitoyltransferase II deficiency structure of the gene and characterization of two novel disease-causing mutations. 

Wieser, T Deschauer, M. Zierz, S. (1997) J. Mol Med 75, B51 (Abstract) Carnitine Palmitoyltransferase II Deficiency Three Novd Mutations. 

Bonnefont, J.P. Taroni, F. Cavadini, R Cepanec, C. Brivet, M. Saudubray, J.M. Leroux, J.P. Demaugre, F. (1996) Am. J. Hum. Genet. S, 971-978 Molecular analysis of carnitine palmitoyltransferase II deficiency with hepatocardiomuscular expression. 

Taroni, F. Verderio, E. Fiorucci, S. Cavadini, P Finocchiaro, G. Uziel, G Lamantea, E. Gellera, C. DiDonato, S. (1992) Proc. Nat. Acad. Sci., USA. 89, 8429-8433 Molecular characterization of inherited carnitine palmitoyltransferase II deficiency. 

Orngreen MC, Ejstrup R, VLssing J. Effect of diet on exercise tolerance in carnitine palmitoyltransferase II deficiency. Neurology. 2003 61(4) 559-61. PubMed PMID 12939440. Epub 2003/08/27. eng. 

Bonnefont JP, Taroni F, Cavadini P, Cepanec C, Brivet M, Saudubray JM et al. Molecular analysis of carnitine palmitoyltransferase II deficiency with hepatocardiomus-cular expression. Am J Hum Genet 1996 58 971-978. 

Brown, N.F, feer, V, Gonzalez, A.D., Evans, C.T., Slaughter, C.A., Foster, D.W. McGarry, J.D. (1991) J. Biol. Chem., 266, 15446-15449. Mitochondrial import and processing of rat liver carnitine palmitoyltransferase II defines the amino terminus of the mature protein. Possibility of differential modification of the rat and human isoforms. 

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