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)

Carnitine palmitoyltransferase deficiency realizes two distinct clinical forms. We previously showed and confirmed in the present work that CPTII (identified as the carnitine palmitoyltransferase activity assayable in detergent conditions) is decreased in the muscular form whereas it is unaffected and CPTI is decreased in the hepatic form. The antibody previously prepared against human liver mitochondrial CPTII recognizes the same enzyme in muscle, liver, and fibroblasts. Immunoprecipitation experiments were performed in fibroblasts from patients with the muscular and hepatic forms of the defect. As compared with controls, cell lines from two patients with the hepatic form of the defect did not exhibit any qualitative nor quantitative abnormality of cross-reacting material, whereas cell lines from two patients with the muscular form of the defect exhibited a decreased amount of cross-reacting material. These data suggest that CPTII deficiency could result from a decreased production of protein. The amount of cross-reacting material in the two sets of patients only correlates with CPTII activity, which is decreased in the muscular presentation and unaffected in the hepatic form. These results strengthen the hypothesis of distinct proteins supporting CPTI and CPTII activities.
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PMID:Immunoquantitative analysis of human carnitine palmitoyltransferase I and II defects. 234 77

The influence of a non-ketonic, chronically diabetic state (60 mg/kg streptozotocin) on cardiac function and metabolism was studied under in vivo conditions by inserting a Millar-tip catheter into the left ventricle and in the model of the isolated perfused heart. In vivo heart rate and maximal left ventricular systolic pressure were reduced after a diabetes duration of 4 and 12 weeks. The maximal rise and fall in left ventricular pressure progressively declined with the duration of diabetes. The reduced myocardial function was associated with a loss in ATP and adenine nucleotides. In the perfused heart of chronically diabetic rats, heart function was also impaired and could not be restored in vitro by perfusion with glucose and insulin. In the presence of octanoate--a substrate which can be metabolized independently from insulin--heart function of diabetic rats was improved, but remained lowered as compared to controls. Since the content of myocardial creatine phosphate was reduced in diabetic hearts perfused with octanoate, these findings indicate that the suppression of cardiac performance is not only a result of an impaired glucose metabolism, but of a more general defect in energy provision and utilization. In contrast to hearts of acutely diabetic, ketotic rats most often used, the rate of lipolysis of endogenous triglycerides and the contribution of fatty acids to energy production was low in the chronically diabetic state. Inhibition of fatty acid oxidation by an inhibitor of carnitine palmitoyltransferase (CPTI) did not restore the reduced responsiveness of diabetic hearts to insulin. Analysis of intracardiac metabolites revealed that in the perfused heart of chronically diabetic rats glucose-6-phosphate and citrate do not accumulate as in hearts of ketotic, diabetic rats. Therefore, the impaired glucose metabolism presumably reflects a reduced uptake of glucose rather than in inhibition of glycolysis as in hearts of ketotic, diabetic rats.
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PMID:Myocardial performance and metabolism in non-ketotic, diabetic rat hearts: myocardial function and metabolism in vivo and in the isolated perfused heart under the influence of insulin and octanoate. 354 78

This study was designed to examine whether short- and long-term treatments by a low level of dietary L-carnitine are capable of altering enzyme activities related to fatty acid oxidation in normal Wistar rats. Under controlled feeding, ten days of treatment changed neither body weights nor liver and gastrocnemius weights, but succeeded in reducing the weight of peri-epididymal adipose tissues. Triacylglycerol contents were lowered in liver and ketone body concentrations were found slightly more elevated in blood. In the liver, mitochondrial carnitine palmitoyltransferase I (CPT I) exhibited a slightly higher specific activity and a lower sensitivity to malonyl-CoA inhibition, while peroxisomal fatty acid oxidizing system (PFAOS) was found to be less active. Carnitine supplied for one month reduced the mass of the periepididymal fat tissue, but not those of the other studied organs, and produced a slight but non-significant gain in body weight after ten days of treatment. In the liver, CPTI characteristics were comparable in control and treated groups, while PFAOS activity was less in rats receiving carnitine. Data show that L-carnitine at a low level in the diet exerted two paradoxical effects before and after ten days of treatment. Results are discussed in regard to fatty acid oxidation in mitochondria and peroxisomes, and to the possible altered acyl-CoA/acylcarnitine ratio with increased concentrations of L-carnitine in the liver.
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PMID:Effect of short- and long-term treatments by a low level of dietary L-carnitine on parameters related to fatty acid oxidation in Wistar rat. 855 64

With a cDNA probe encoding rat muscle type carnitine palmitoyltransferase I (CPTI), we isolated cDNA and genomic clones encoding the human homologue and deduced the primary structure of human muscle type CPTI. By Northern analysis, we confirmed the dominant expression of this isoform in heart and skeletal muscle.
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PMID:Isolation and characterization of cDNA and genomic clones encoding human muscle type carnitine palmitoyltransferase I. 867

We isolated a human muscle type of carnitine palmitoyltransferase I (CPTI-M) genomic clone and determined its entire nucleotide sequence. By comparison of the nucleotide sequence of the genomic clone with that of cDNA, we determined the intron/exon junctions. For detection of the exon(s) in the 5'-region of the CPTI-M gene, we isolated cDNA clones corresponding to the 5'-region of its transcript by 5'-rapid amplification of cDNA ends (5'-RACE method). Results showed two alternative exons, 1A and 1B, that do not encode amino acids in the 5'-region of the human CPTI-M gene. The gene encoding human CPTI-M was found to consist of two 5'-non-coding exons, 18 coding exons and one 3'-non-coding exon spanning approximately 10 kbp. Furthermore, on analysis of the 5'-flanking region, a putative gene encoding a 'choline kinase homologue' was found to be located only about 300 bp upstream from exon 1A of the human CPTI-M gene. Comparison of the gene structure of human CPTI-M with the reported partial gene structure of human liver type CPTI (CPTI-L) showed that the intron insertion sites were completely conserved in these two genes.
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PMID:Structural features of the gene encoding human muscle type carnitine palmitoyltransferase I. 922 98

To assess the role of the 130 N-terminal amino acid residues of rat liver carnitine palmitoyltransferase I (L-CPTI) on malonyl-CoA sensitivity and binding, we constructed a series of mutants with deletions of the 18, 35, 52, 73, 83, or 129 most N-terminal amino acid residues. The deletion mutants were expressed in the yeast Pichia pastoris. We determined the effects of these mutations on L-CPTI activity, malonyl-CoA sensitivity, and binding in isolated mitochondria prepared from the yeast strains expressing the wild-type and deletion mutants. The mutant protein that lacked the first 18 N-terminal amino acid residues, Delta18, had activity and kinetic properties similar to wild-type L-CPTI, but it was almost completely insensitive to malonyl-CoA inhibition (I50 = 380 microM versus 2.0 microM). In addition, loss of malonyl-CoA sensitivity in Delta18 was accompanied by a 70-fold decrease in affinity for malonyl CoA (KD = 70 nM versus 1.1 nM) compared to wild-type L-CPTI. Deletion of the first 35, 52, 73, and 83 N-terminal amino acid residues had a similar effect on malonyl-CoA sensitivity as did the 18-residue deletion mutant, and there was a progressive reduction in the affinity for malonyl-CoA binding. By contrast, deletion of the first 129 N-terminal amino acid residues resulted in the synthesis of an inactive protein. To our knowledge, this is the first report to demonstrate a critical role for these perfectly conserved first 18 N-terminal amino acid residues of L-CPTI in malonyl-CoA sensitivity and binding.
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PMID:Deletion of the conserved first 18 N-terminal amino acid residues in rat liver carnitine palmitoyltransferase I abolishes malonyl-CoA sensitivity and binding. 969 98

We have recently shown by deletion mutation analysis that the conserved first 18 N-terminal amino acid residues of rat liver carnitine palmitoyltransferase I (L-CPTI) are essential for malonyl-CoA inhibition and binding (Shi, J., Zhu, H., Arvidson, D. N. , Cregg, J. M., and Woldegiorgis, G. (1998) Biochemistry 37, 11033-11038). To identify specific residue(s) involved in malonyl-CoA binding and inhibition of L-CPTI, we constructed two more deletion mutants, Delta12 and Delta6, and three substitution mutations within the conserved first six amino acid residues. Mutant L-CPTI, lacking either the first six N-terminal amino acid residues or with a change of glutamic acid 3 to alanine, was expressed at steady-state levels similar to wild type and had near wild type catalytic activity. However, malonyl-CoA inhibition of these mutant enzymes was reduced 100-fold, and high affinity malonyl-CoA binding was lost. A mutant L-CPTI with a change of histidine 5 to alanine caused only partial loss of malonyl-CoA inhibition, whereas a mutant L-CPTI with a change of glutamine 6 to alanine had wild type properties. These results demonstrate that glutamic acid 3 and histidine 5 are necessary for malonyl-CoA binding and inhibition of L-CPTI by malonyl-CoA but are not required for catalysis.
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PMID:A single amino acid change (substitution of glutamate 3 with alanine) in the N-terminal region of rat liver carnitine palmitoyltransferase I abolishes malonyl-CoA inhibition and high affinity binding. 1009 22

Mitochondrial carnitine palmitoyltransferases I and II (CPTI and CPTII), together with the carnitine carrier, transport long-chain fatty acyl-CoA from the cytosol to the mitochondrial matrix for beta-oxidation. Recent progress in the expression of CPTI and CPTII cDNA clones in Pichia pastoris, a yeast with no endogenous CPT activity, has greatly facilitated the characterization of these important enzymes in fatty acid oxidation. It is now well established that yeast-expressed CPTI is a catalytically active, malonyl CoA-sensitive, distinct enzyme that is reversibly inactivated by detergents. CPTII is a catalytically active, malonyl CoA-insensitive, distinct enzyme that is detergent stable. Reconstitution studies with yeast-expressed CPTI have established for the first time that detergent inactivation of CPTI is reversible, suggesting that CPTI is active only in a membrane environment. By constructing a series of deletion mutants of the N-terminus of liver CPTI, we have mapped the residues essential for malonyl CoA inhibition and binding to the conserved first six N-terminal amino acid residues. Mutation of glutamic acid 3 to alanine abolished malonyl CoA inhibition and high affinity malonyl CoA binding, but not catalytic activity, whereas mutation of histidine 5 to alanine caused partial loss in malonyl CoA inhibition. Our mutagenesis studies demonstrate that glutamic acid 3 and histidine 5 are necessary for malonyl CoA inhibition and binding to liver CPTI, but not catalytic activity.
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PMID:Functional characterization of mammalian mitochondrial carnitine palmitoyltransferases I and II expressed in the yeast Pichia pastoris. 1072 94

Carnitine palmitoyltransferase I catalyzes the conversion of long-chain acyl-CoA to acylcarnitines in the presence of l-carnitine. To determine the role of the conserved arginine and tryptophan residues on catalytic activity in the liver isoform of carnitine palmitoyltransferase I (L-CPTI), we separately mutated five conserved arginines and two tryptophans to alanine. Substitution of arginine residues 388, 451, and 606 with alanine resulted in loss of 88, 82, and 93% of L-CPTI activity, respectively. Mutants R601A and R655A showed less than 2% of the wild type L-CPTI activity. A change of tryptophan 391 and 452 to alanine resulted in 50 and 93% loss in carnitine palmitoyltransferase activity, respectively. The mutations caused decreases in catalytic efficiency of 80-98%. The residual activity in the mutant L-CPTIs was sensitive to malonyl-CoA inhibition. Mutants R388A, R451A, R606A, W391A, and W452A had no effect on the K(m) values for carnitine or palmitoyl-CoA. However, these mutations decreased the V(max) values for both substrates by 10-40-fold, suggesting that the main effect of the mutations was to decrease the stability of the enzyme-substrate complex. We suggest that conserved arginine and tryptophan residues in L-CPTI contribute to the stabilization of the enzyme-substrate complex by charge neutralization and hydrophobic interactions. The predicted secondary structure of the 100-amino acid residue region of L-CPTI, containing arginines 388 and 451 and tryptophans 391 and 452, consists of four alpha-helices similar to the known three-dimensional structure of the acyl-CoA-binding protein. We predict that this 100-amino acid residue region constitutes the putative palmitoyl-CoA-binding site in L-CPTI.
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PMID:Identification by mutagenesis of conserved arginine and tryptophan residues in rat liver carnitine palmitoyltransferase I important for catalytic activity. 1080 31

Multiple adult morbidities are associated with intrauterine growth retardation (IUGR) including dyslipidemia. We hypothesized that uteroplacental insufficiency and subsequent IUGR in the rat would lead to altered hepatic fatty acid metabolism. To test this hypothesis, we quantified hepatic mRNA levels of acetyl-CoA carboxylase (ACC), carnitine palmitoyltransferase (CPTI), the beta-oxidation-trifunctional protein (HADH), fasting serum triglycerides, and hepatic malonyl-CoA levels at different ages in control and IUGR rats. Fetal gene expression of all three enzymes was decreased. Juvenile gene expression of CPTI and HADH continued to be decreased, whereas gene expression of ACC was increased. Serum triglycerides were unchanged. A sex-specific response was noted in the adult rats. In males, serum triglycerides, hepatic malonyl-CoA levels, and ACC mRNA levels were significantly increased, and CPTI and HADH mRNA levels were significantly decreased. In contrast, the female rats demonstrated no significant changes in these variables. These results suggest that uteroplacental insufficiency leads to altered hepatic fatty acid metabolism that may contribute to the adult dyslipidemia associated with low birth weight.
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PMID:Uteroplacental insufficiency alters hepatic fatty acid-metabolizing enzymes in juvenile and adult rats. 1112 50


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