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)

Five genes in the human genome are known to encode different active forms of related carnitine acyltransferases: CPT1A for liver-type carnitine palmitoyltransferase I, CPT1B for muscle-type carnitine palmitoyltransferase I, CPT2 for carnitine palmitoyltransferase II, CROT for carnitine octanoyltransferase, and CRAT for carnitine acetyltransferase. Only from two of these genes (CPT1B and CPT2) have full genomic structures been described. Data from the human genome sequencing efforts now reveal drafts of the genomic structure of CPT1A and CRAT, the latter not being known from any other mammal. Furthermore, cDNA sequences of human CROT were obtained recently, and database analysis revealed a completed bacterial artificial chromosome sequence that contains the entire CROT gene and several exons of the flanking genes P53TG and PGY3. The genomic location of CROT is at chromosome 7q21.1. There is a putative CPT1-like pseudogene in the carnitine/choline acyltransferase family at chromosome 19. Here we give a brief overview of the functional relations between the different carnitine acyltransferases and some of the common features of their genes. We will highlight the phylogenetics of the human carnitine acyltransferase genes in relation to the fungal genes YAT1 and CAT2, which encode cytosolic and mitochondrial/peroxisomal carnitine acetyltransferases, respectively.
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PMID:Genomics of the human carnitine acyltransferase genes. 1100 5

A 47-year-old man suffering from a bipolar disorder and intermittent myoglobinuria presented with acute rhabdomyolysis with renal failure after starting therapy with valproic acid. On morphological examination, skeletal muscle revealed increased lipid storage. Biochemically, decreased enzyme activity of carnitine palmitoyltransferase (CPT) type II with carnitine levels in the lower limit was found. Genetic analysis detected the common Ser113Leu substitution on one allele of the CPT2 gene. We conclude that valproic acid should be avoided in patients with CPT type II deficiency.
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PMID:Valproic acid triggers acute rhabdomyolysis in a patient with carnitine palmitoyltransferase type II deficiency. 1159 19

Aging affects oxidative metabolism in liver and other tissues. Carnitine acyltransferases are key enzymes of this process in mitochondria. As previously shown, the rate of transcription and activity of carnitine palmitoyltransferase CPT1 are also related to carnitine levels. In this study we compared the effect of dietary l-carnitine (100 mg l-carnitine/kg body weight/day over 3 months) on liver enzymes of aged rats (months 21-24) to adult animals (months 6-9) and age-related controls for both groups. The transcription rate of CPT1, CPT2, and carnitine acetyltransferase (CRAT) was determined by quantitative reverse transcription real-time PCR (RTQPCR) and compared to the activity of the CPT1A enzyme. The results showed that the transcription rates of CPT1, CPT2, and CRAT were similar in aged and adult control animals. Carnitine-fed old rats had a significant (p<0.05) 8-12-fold higher mean transcription rate of CPT1 and CRAT compared to aged controls, adult carnitine-fed animals, and adult controls, whereas the transcription rate of CPT2 was stimulated 2-3-fold in carnitine-fed animals of both age groups. With regard to the enzymatic activity of CPT1 there was a 1.5-fold increase in the old carnitine group compared to all other groups. RNA in situ hybridization also indicated an enhanced expression of CPT1A in hepatocytes from l-carnitine-supplemented animals. These results suggest that l-carnitine stimulates transcription of CPT1, CPT2, and CRAT as well as the enzyme activity of CPT1 in the livers of aged rats.
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PMID:Dietary l-carnitine stimulates carnitine acyltransferases in the liver of aged rats. 1179 39

Changes in key enzymes of oxidative metabolism at the mitochondrial level are known to be associated with the aging process, apoptosis, and many diseases. Considering the risk of acquiring a myelodysplastic syndrome (MDS) with age, the aim of this study was to quantify mRNA synthesis of the carnitine palmitoyltransferases (CPT1 and CPT2), carnitine acetyltransferase (CRAT), human specific microsomal CPT, and OCTN2 (organic cation transporter) in mononuclear cells of healthy humans of different age groups and MDS patients. Using quantitative reverse transcriptase real-time PCR we compared mRNA synthesis of the above mentioned enzymes in mononuclear cells from peripheral blood of 23 healthy persons (mean age 45 years), 9 blood and 22 bone marrow samples of 31 MDS patients with varying proportions of apoptotic cells (mean age 78 years), and blood samples of 30 age-matched controls. In addition, plasma carnitine levels were determined. Compared to younger adults, there was a 50% downregulation of CPT1 in elderly persons and in MDS patients. Reduction in CRAT, CPT 2, and OCTN2 was more than 85%. Reduction in microsomal CPT was more pronounced in MDS patients than in age-matched controls (96% vs. 43%). In MDS bone marrow cells there was a negative correlation of CPT1 and CRAT with the relative proportion of apoptotic cells. Plasma carnitine values were similar in all groups. The described reduction in transcription of different genes in blood cells which is well known in different tissues may reflect a systemic signaling process, associated with aging, apoptosis, and MDS.
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PMID:Downregulation of carnitine acyltransferases and organic cation transporter OCTN2 in mononuclear cells in healthy elderly and patients with myelodysplastic syndromes. 1280 1

Patients with the myopathic form of carnitine palmitoyltransferase II (CPT II) deficiency typically experience muscle pain, cramps, and myoglobinuria during prolonged exercise. It has been suggested that carriers of CPT2 gene mutations also may have milder clinical symptoms, but fatty acid oxidation (FAO) has never been investigated in vivo in this group. We studied fuel utilization by indirect calorimetry and stable isotope methodology in four patients with CPT II deficiency, three subjects who carried one CPT2 gene mutation, and five healthy control subjects. Cycle exercise at a constant workload of 50% of maximal oxygen uptake capacity was used to facilitate FAO. We found that in vivo oxidation of long-chain fatty acids was normal at rest but severely impaired during prolonged, low-intensity exercise in patients with CPT II deficiency, and that two of the single CPT2 gene mutation carriers, who displayed symptoms of CPT II deficiency, had an FAO comparable with the patients. These results indicate that residual CPT II activity is sufficient to maintain long-chain FAO at rest in CPT II deficiency but not to increase FAO during exercise. The findings also suggest that single CPT2 gene mutations may exert a dominant-negative effect on the tetrameric CPT II protein.
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PMID:Fuel utilization in subjects with carnitine palmitoyltransferase 2 gene mutations. 1562 36

Carnitine-acylcarnitine translocase (CACT) deficiency is a rare disorder of fatty acid oxidation associated with high mortality. Two female newborns of different ethnic origin (the first Anglo-Celtic and the second Palestinian Arab) both died after sudden collapse on day 2 of life. Both had elevated bloodspot long-chain acylcarnitines consistent with either CACT or carnitine palmitoyltransferase II (CPT2) deficiency; the latter was excluded by demonstrating normal CPT2 activity in fibroblasts. Direct sequencing of all SLC25A20 (CACT) gene exons and exon-intron boundaries revealed that Patient 1 was compound heterozygous for a novel c.609-3c>g (IVS6-3c>g) mutation on the paternal allele and a previously described c.326delG mutation on the maternal allele. Patient 2 was homozygous for the same, novel c.609-3c>g mutation. Previously reported SLC25A20 mutations have been almost exclusively confined to a single family or ethnic group. Analysis of fibroblast cDNA by RT-PCR, agarose gel electrophoresis and sequencing of extracted bands showed that both mutations produce aberrant splicing. c.609-3C>G results in exon 7 skipping leading to a frameshift with premature termination seven amino acids downstream. c.326delG was confirmed to produce skipping of exons 3 or 3 plus 4. CACT activity in both patients' fibroblasts was near-zero. For both families, prenatal diagnosis of an unaffected fetus was performed by mutation analysis on CVS tissue in a subsequent pregnancy. Due to the urgency of prenatal diagnosis in the second family, molecular diagnosis was performed prior to demonstration of CACT enzyme deficiency, illustrating that mutation analysis is a rapid and reliable approach to first-line diagnosis of CACT deficiency.
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PMID:A novel SLC25A20 splicing mutation in patients of different ethnic origin with neonatally lethal carnitine-acylcarnitine translocase (CACT) deficiency. 1691 90

We report a patient with severe infantile carnitine palmitoyltransferase II (CPT II) deficiency who died at the age of 3 months. Genetic analysis of the CPT2 gene revealed that the patient was homozygous, and her parents were heterozygous, for a R503C missense mutation. Heterozygosity for R503C, without a second mutation, has previously been reported in symptomatic patients from two families, one with the mild adult myopathic form and one with malignant hyperthermia. In contrast, the R503C heterozygous parents of the patient were entirely asymptomatic, suggesting that additional genetic and/or environmental factors must have contributed to the occurrence of symptoms in previously reported carriers. Our findings indicate that the mutation R503C should be added to the handful of mutations associated with the severe phenotype when present in the homozygous state or combined with another severe mutation.
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PMID:Severe infantile type of carnitine palmitoyltransferase II (CPT II) deficiency due to homozygous R503C mutation. 1737 54

The pathogenesis of hypoketotic hypoglycemia and cardiomyopathy in patients with fatty acid oxidation (FAO) disorders is still poorly understood. In vitro studies are hampered by the lack of natural mutants to asses the effect of FAO inhibition. In addition, only a few inhibitors of FAO are known. Furthermore, most inhibitors of FAO are activating ligands of peroxisome proliferator-activated receptors (PPARs). We show that l-aminocarnitine (L-AC), a carnitine analog, inhibits FAO efficiently, but does not activate PPAR. L-AC inhibits carnitine palmitoyltransferase (CPT) with different sensitivities towards CPT1 and CPT2, as well as carnitine acylcarnitine translocase (CACT). We further characterized L-AC using fibroblasts cell lines from controls and patients with different FAO defects. In these cell lines acylcarnitine profiles were determined in culture medium after loading with [U-(13)C]palmitic acid. In control fibroblasts, L-AC inhibits FAO leading to a reduction of C2-acylcarnitine and elevation of C16-acylcarnitine. In very long-chain acyl-CoA dehydrogenase (VLCAD)-deficient fibroblasts, L-AC decreased the elevated C14-acylcarnitine and increased C16-acylcarnitine. In CACT and CPT2-deficient cell lines, L-AC did not change the already elevated C16-acylcarnitine level, showing that CPT1 is not inhibited. Oxidation of pristanic acid was only partly inhibited at high L-AC concentrations, indicating minimal CACT inhibition. Therefore, we conclude that in intact cells L-AC inhibits CPT2. Combined with our observation that l-AC does not activate PPAR, we suggest that L-AC is useful to simulate a FAO defect in cells from different origin.
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PMID:Characterization of L-aminocarnitine, an inhibitor of fatty acid oxidation. 1807 98

Influenza-associated encephalopathy (IAE) is characterized by persistent high fever, febrile convulsions, severe brain edema, and high mortality in otherwise apparently healthy individuals. We have reported that a large proportion of patients suffering from disabling or fatal IAE, with transiently elevated serum acylcarnitine during high fever, exhibit a thermolabile phenotype of compound homo-/heterozygous variants of carnitine palmitoyltransferase II (CPT II, gene symbol CPT2). We characterized the enzymatic properties of five single and three compound CPT II variants in patients with IAE. The kinetic characteristics of WT and variant CPT IIs, expressed in COS-7 cells, indicated that the variants exert a dominant-negative effect on the homotetrameric protein of the enzyme. Among the variants, three compound variations found in patients with severe encephalopathy; [c.1055T>G (p.Phe352Cys); c.1102G>A (p.Val368Ile)], [c.1511C>T (p.Pro504Leu); c.1813G>C (p.Val605Leu)], and [c.1055T>G (p.Phe352Cys); c.1102G>A (p.Val368Ile); c.1813G>C (p.Val605Leu)], showed reduced activities, thermal instability, and short half-lives compared with the WT. Like other disease-causing mutant proteins, these variant proteins were poly-ubiquitinated and rapidly degraded by a lactacystin-sensitive proteasome pathway. COS-7 cells transfected with the compound variants had their fatty acid beta-oxidation decreased to 30-59% and intracellular ATP levels to 48-79%, and a marked reduction of mitochondrial membrane potential at 41 degrees C, compared with control cells transfected with WT at 37 degrees C. The unstable CPT II variants with decreased enzymatic activities may bring mitochondrial fuel utilization below the phenotypic threshold during high fever, and thus may play an important etiopathological role in the development of brain edema of IAE.
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PMID:Thermal instability of compound variants of carnitine palmitoyltransferase II and impaired mitochondrial fuel utilization in influenza-associated encephalopathy. 1830 70

Three distinct clinical manifestations of carnitine palmitoyltransferase II (CPT II) deficiency have been defined including a mild adult onset myopathy, a severe infantile disorder and a lethal neonatal form. In this study we have examined the genomic DNA of five patients, 3 with the lethal neonatal form and 2 with the severe infantile form of the disease and identified two disease-causing mutations in the CPT2 gene for each patient, three of which are novel. In addition, based on currently available structural, biochemical and clinical data, we have classified all 64 known disease-causing mutations into groups with different predicted phenotypes depending on their CPT2 allelic counterparts.
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PMID:CPT2 gene mutations resulting in lethal neonatal or severe infantile carnitine palmitoyltransferase II deficiency. 1855 Apr 8


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