Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.3.1.21 (CPT)
4,580 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We report the isolation and characterization of a full-length cDNA encoding rat liver carnitine palmitoyltransferase I (CPT I). Oligonucleotides corresponding to two tryptic peptides derived from the malonyl-CoA/etomoxir-CoA-binding protein of rat liver mitochondria (Esser, V., Kuwajima, M., Britton, C. H., Krishnan, K., Foster, D. W., and McGarry, J. D. (1993) J. Biol. Chem. 268, 5810-5816) were used to screen a rat liver cDNA library constructed in the plasmid cloning vector, pcDV. The clone obtained consisted of a 102-nucleotide 5'-untranslated region, a single open reading frame of 2,319 bases predicting a protein of 773 amino acids (M(r) = 88,150), and a 3'-untranslated segment of 1,957 nucleotides followed by the poly(A)+ tail. A 0.9-kilobase fragment of the cDNA recognized a single species of mRNA (approximately 4.7 kilobases in size) in rat liver. The identity of the cDNA was confirmed by the findings that (i) the open reading frame encoded all four peptides found in the original protein; (ii) transfection of COS cells with the cDNA subcloned into the expression vector, pCMV6, resulted in a selective and 10-20-fold induction of a malonyl-CoA- and etomoxir-CoA-sensitive CPT activity; and (iii) the overexpressed product was readily detected on Western blots by an antibody raised against the starting material. It seems likely that the de novo synthesized enzyme is targeted to the mitochondrial outer membrane via a leader peptide and that the mature protein achieves membrane anchoring through a stretch of 20 amino acids present near its amino terminus. The predicted amino acid sequence of the protein shows regions of strong identity with those of three other rat acyltransferases, namely, liver CPT II, liver carnitine octanoyltransferase, and brain choline acetyltransferase. The findings provide the first insight into the structure of a CPT I isoform. They also establish unequivocally that CPT I and CPT II are distinct proteins and that inhibitors of CPT I interact within its catalytic domain, not with an associated regulatory component.
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PMID:Cloning, sequencing, and expression of a cDNA encoding rat liver carnitine palmitoyltransferase I. Direct evidence that a single polypeptide is involved in inhibitor interaction and catalytic function. 844 48

In order to investigate the long-chain fatty acid oxidative capacity of tumour cells, carnitine palmitoyltransferase I (CPT I) and CPT II were selected for study because they are rate-limiting regulatory enzymes. Measurable activities of both CPT I and CPT II were detected in several human and rat tumour cell types and in mouse fibroblasts. The activities were comparable with those previously reported for rat liver CPT I and II, ranging from 1-3 nmoles/min/mg protein for both CPT I and II. Walker 256 tumour tissue also contained detectable CPT I and II activities, thereby demonstrating that tumour tissue in vivo also has the capacity for the processing of fatty acyl CoA's in the mitochondrion. The possible regulation of tumour CPT I and II was investigated using the hormone insulin, both in vitro and in vivo. Insulin was found to increase CPT II activity in the T24/83 human bladder tumour in vitro and in the Walker 256 rat tumour in vivo. The results suggest that insulin may exert some control over the activity of CPT II in certain types of tumour. In contrast, insulin was without effect on CPT I activity in any of the tumours studied, either in vitro or in vivo.
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PMID:Human and rat tumour cells possess mitochondrial carnitine palmitoyltransferase I and II: effects of insulin. 858 32

We conducted a quantitative study of the effect of carnitine deficiency on the mRNA level of carnitine palmitoyltransferase II in the liver, muscle and heart of mice with juvenile visceral steatosis, a strain that is systematically deficient in carnitine. The amount of carnitine palmitoyltransferase II mRNA was increased in liver and muscle of homozygotes, as compared with heterozygotes and normal controls, at 2, 4, and 8 wk of age. The mRNA levels of this enzyme were normalized after carnitine administration. The mRNA level of carnitine palmitoyltransferase II in the heart was increased only at 8 wk, and was not affected by carnitine administration. These results suggest that carnitine displays some effect on the mRNA level of the carnitine palmitoyltransferase II gene in liver and muscle, probably through fatty acid metabolic change.
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PMID:Altered expression of carnitine palmitoyltransferase II in liver, muscle, and heart of mouse strain with juvenile visceral steatosis. 860 22

In the rat, the gene for liver mitochondrial carnitine palmitoyltransferase I (CPT I), though dormant prior to birth, is rapidly activated postnatally. We sought to elucidate which hormonal and/or nutritional factors might be responsible for this induction. In cultured hepatocytes from 20-day-old rat fetus, the concentration of CPT I mRNA, which initially was very low, increased dramatically in a dose-dependent manner after exposure of the cells to dibutyryl cAMP (Bt2cAMP). Similar results were obtained when long-chain fatty acids (LCFA), but not medium-chain fatty acids, were added to the culture medium. The effects of Bt2cAMP and LCFA were antagonized by insulin, also dose dependently. In contrast, CPT II gene expression, which was already high in fetal hepatocytes, was unaffected by any of the above manipulations. Bt2cAMP stimulated CPT I gene expression even when endogenous triacylglycerol breakdown was suppressed by lysosomotropic agents suggesting that the actions of cAMP and LCFA were distinct. Moreover, half-maximal concentrations of Bt2cAMP and linoleate produced an additive effect CPT I mRNA accumulation. While linoleate and Bt2cAMP stimulated CPT I gene transcription by twofold and fourfold, respectively, the fatty acid also increased the half-life of CPT I mRNA (50%). When hepatocytes were cultured in the presence of 2-bromopalmitate, (which is readily converted by cells into its non-metabolizable CoA ester) CPT I mRNA accumulation was higher than that observed with oleate or linoleate. Similarly, the CPT I inhibitor, tetradecylglycidate, which at a concentration of 20 microM did not itself influence the CPT I mRNA level, enhanced the stimulatory effect of linoleate. The implication is that induction of the CPT I message by LCFA does not require mitochondrial metabolism of these substrates; however, formation of their CoA esters is a necessary step. Unlike linoleate, the peroxisome proliferator, clofibrate, increased both CPT I and CPT II mRNA levels and neither effect was offset by insulin. It thus appears that the mechanism of action of LCFA differs from that utilized by clofibrate, which presumably works through the peroxisome proliferator activated receptor. We conclude that the rapid increase in hepatic CPT I mRNA level that accompanies the fetal to neonatal transition in the rat is triggered by the reciprocal change in circulating insulin and LCFA concentrations, coupled with elevation of the liver content of cAMP.
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PMID:Cyclic AMP and fatty acids increase carnitine palmitoyltransferase I gene transcription in cultured fetal rat hepatocytes. 865 30

Deficiency of carnitine palmitoyltransferase type II (CPT II) is a clinically heterogeneous autosomal recessive disorder of lipid metabolism. The most common mutation in the CPT II gene is the S113L mutation, which substitutes leucine for serine at amino acid position 113. We studied an inbred family with three affected cousins with CPT II deficiency and found the S113L mutation to be present in a homozygous state in all three patients. Pedigree analysis traced the S113L mutation back to one common ancestor. Although the patients in this family have an identical genotype at the CPT II locus, their clinical picture ranges from asymptomatic to lethal.
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PMID:Inheritance of the S113L mutation within an inbred family with carnitine palmitoyltransferase enzyme deficiency. 878 66

Disorders of glycogen, lipid or mitochondrial metabolism may cause two main clinical syndromes, namely (1) progressive weakness (eg, acid maltase, debrancher enzyme, and brancher enzyme deficiencies among the glycogenoses; long- and very-long-chain acyl-CoA dehydrogenase (LCAD, VLCAD), and trifunctional enzyme deficiencies among the fatty acid oxidation (FAO) defects; and mitochondrial enzyme deficiencies) or (2) acute, recurrent, reversible muscle dysfunction with exercise intolerance and acute muscle breakdown or myoglobinuria (with or without cramps) (eg, phosphorylase (PPL), phosphorylase b kinase (PBK), phosphofructokinase (PFK), phosphoglycerate kinase (PGK), phosphoglycerate mutase (PGAM), and lactate dehydrogenase (LDH) among the glycogenoses and carnitine palmitoyltransferase II (CPT II) deficiency among the disorders of FAO or (3) both (eg, PPL, PBK, PFK among the glycogenoses; LCAD, VLCAD, short-chain L-3-hydroxyacyl-CoA dehydrogenase (SCHAD), and trifunctional enzyme deficiencies among the FAO defects; and multiple mitochondrial DNA (mtDNA) deletions). Myoadenylate deaminase deficiency, a purine nucleotide cycle defect, is somewhat controversial and is characterized by exercise-related cramps leading rarely to myoglobinuria.
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PMID:Metabolic myopathies. 879 43

Disorders of mitochondrial fatty acid oxidation are a common cause of exercise-induced rhabdomyolysis and myoglobinuria. We report three adult patients from a family with symptoms of recurrent exercise-induced rhabdomyolysis. This presentation closely resembles adult-type carnitine palmitoyltransferase II deficiency except that these patients had an associated peripheral neuropathy. Investigation of fatty acid oxidation in the patients revealed a deficiency of the mitochondrial trifunctional enzyme of beta-oxidation, a newly described fatty acid oxidation disorder with multiorgan involvement and a usually fatal outcome in early childhood. Our cases therefore represent a new phenotype of the disease, which is characterized by recurrent rhabdomyolysis and peripheral neuropathy, but without involvement of other organs, and which is associated with prolonged survival beyond the fourth decade. A low-fat/high-carbohydrate diet proved beneficial in one of the patients, drastically reducing the frequency of rhabdomyolytic episodes. Our findings suggest that mitochondrial trifunctional enzyme deficiency should be considered in patients with recurrent episodes of myoglobinuria and peripheral neuropathy presenting in later life.
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PMID:Trifunctional enzyme deficiency: adult presentation of a usually fatal beta-oxidation defect. 887 79

The purpose of the study was to separate the mitochondrial proteins of rat Walker 256 tumour tissue and perform immunodetection studies to identify the carnitine palmitoyltransferase I (CPT I) and CPT II proteins previously reported to be present in this tumour. CPT I protein was undetectable using antibody raised against rat liver CPT I and was therefore considered to be immunologically different from that found in normal rat tissues such as heart, liver and skeletal muscle. In contrast, CPT II protein was readily detected in Walker 256 tumour and had an apparent Mr of approximately 70,000, as was found for rat liver. The in vivo treatment of tumour-bearing rats with insulin caused an increase in the expression of CPT II protein in the tumour tissue. The data confirm that CPT II can be regulated by insulin and also demonstrate that tumour CPT I may be a different isoform from that present in rat liver.
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PMID:Immunodetection of rat Walker 256 tumour mitochondrial carnitine palmitoyltransferase I and II: evidence for the control of CPT II expression by insulin. 893 31

First conceptualized as a mechanism for the mitochondrial transport of long-chain fatty acids in the early 1960s, the carnitine palmitoyltransferase (CPT) system has since come to be recognized as a pivotal component of fuel homeostasis. This is by virtue of the unique sensitivity of the outer membrane CPT I to the simple molecule, malonyl-CoA. In addition, both CPT I and the inner membrane enzyme, CPT II, have proved to be loci of inherited defects, some with disastrous consequences. Early efforts using classical approaches to characterize the CPT proteins in terms of structure/function/regulatory relationships gave rise to confusion and protracted debate. By contrast, recent application of molecular biological tools has brought major enlightenment at an exponential pace. Here we review some key developments of the last 20 years that have led to our current understanding of the physiology of the CPT system, the structure of the CPT isoforms, the chromosomal localization of their respective genes, and the identification of mutations in the human population.
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PMID:The mitochondrial carnitine palmitoyltransferase system. From concept to molecular analysis. 906 39

Cardiac ischemia is associated with an impairment in long-chain fatty acid metabolism. We studied carnitine palmitoyltransferase (CPT) in left ventricular biopsies of 6 transplant recipients with ischemia due to atherosclerosis, 4 patients with dilated cardiomyopathy, and 5 donor hearts. Total CPT activity was not significantly different between the three groups (7.9 +/- 3; 6.7 +/- 2, and 8 +/- 3 nmol/min/mg noncollagenous protein). Residual CPT activity after inhibition by malonyl-CoA (0.4 mM) was 38 +/- 11, 36 +/- 5 and 38 +/- 7%. There were no difference in IC50 values. Residual CPT activity after the addition of the detergent Triton X-100 (0.5%) was 58 +/- 17, 54 +/- 2 and 50 +/- 8% (nonsignificant). Our results suggest that (i) total CPT activity and (ii) the sensitivity of the interaction of CPT I with its regulator malonyl-CoA are not affected by cardiac ischemia, and (iii) the ratio of CPT I to CPT II is not altered in cardiac ischemia.
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PMID:Carnitine palmitoyltransferase in patients with cardiac ischemia due to atherosclerotic coronary artery disease and in patients with idiopathic dilated cardiomyopathy. 912 47


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