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)

The role of inhibition of the CPT enzymes responsible for accumulation of long chain acylcarnitines (LCAC) during hypoxia in the proximal tubule has not been previously examined. We have characterized CPT enzyme activities in mitochondrial fractions of rabbit proximal tubules. Malonyl CoA-sensitive CPT I activity (1.1 +/- 0.3 nmol/min/mg protein), and detergent-solubilized, malonyl CoA-insensitive CPT II activity (2.3 +/- 0.4 nmol/min/mg protein) were readily detected in proximal tubule mitochondrial fractions. Subjecting rabbit proximal tubules to various periods of hypoxia did not significantly change mitochondrial CPT I or CPT II activities. Thirty minutes of hypoxia resulted in an increase in lysophospholipid mass from 440 +/- 105 to 720 +/- 93 pmol/mg protein, N = 5, LCAC mass from 79 +/- 11 to 618 +/- 34 pmol/mg protein, N = 5, and lactate dehydrogenase (LDH) release from 9 +/- 1% to 46 +/- 3%, N = 8. Pretreatment of proximal tubules with two different CPT inhibitors, glybenclamide (Glyb) 400 microM and oxfenicine (Oxfe) 1 mM, resulted in reduction in the magnitude of hypoxia-induced lysophospholipid formation 490 +/- 160 (Glyb), 342 +/- 150 pmol/mg protein (Oxfe), N = 4, hypoxia-induced LCAC formation 295 +/- 27 (Glyb), 128 +/- 16 pmol/mg protein (Oxfe). N = 5, and LDH release 25 +/- 1% (Glyb) and 19 +/- 2% (Oxfe), N = 8. The protective effect of CPT inhibition was also associated with increased production of lactate suggesting the modulation of a substrate-mediated metabolic switch. Immunoblots demonstrated that hypoxia caused a time dependent hydrolysis of fodrin-alpha subunit and that CPT inhibition protected against hypoxia-induced fodrin proteolysis. These data suggest a unifying hypothesis that links phospholipase A2 (PLA2) activation, and hypoxia-mediated fodrin proteolysis to the proximal tubule mitochondrial CPT system. I propose that CPT inhibition may represent a novel mechanism to ameliorate proximal tubule cell death during hypoxia.
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PMID:Carnitine palmitoyl-transferase enzyme inhibition protects proximal tubules during hypoxia. 926 98

Four missense mutations have been reported to be associated with the typical, adult form of carnitine palmitoyltransferase II (CPT II) deficiency: Three amino acid substitutions (R631C. P50H and D553N) appear to be rare, while the S113L mutation was found to be common in a group of European patients with CPT II deficiency. We analyzed genomic DNA from 20 American patients with recurrent episodes of myoglobinuria as well as DNA from 10 normal controls in order to determine the frequency of the reported missense mutations in our patient population. The three previously described rare mutations were not found in our group of patients. The S113L mutation was found in 19 of our patients: 5 patients were homozygous, 14 patients were heterozygous. Given the high frequency of this mutation in our series of patients we concluded that the clinical diagnosis of CPT II deficiency can be confirmed by a 'blood test' without resorting to a muscle biopsy.
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PMID:Carnitine palmitoyltransferase II deficiency: diagnosis by molecular analysis of blood. 930 94

The relationship between peroxisomal and mitochondrial oxidation of the methyl branched fatty acids, phytanic acid and pristanic acid, was studied in normal and mutant human skin fibroblasts with established enzyme deficiencies. Tandem mass spectrometry was used for analysis of the acylcarnitine intermediates. In normal cells, 4,8-dimethylnonanoylcarnitine (C11:0) and 2,6-dimethylheptanoylcarnitine (C9:0) accumulated after incubation with either phytanic acid or pristanic acid. These intermediates were not observed when peroxisome-deficient cells from Zellweger patients were incubated with the same compounds, pointing to the involvement of peroxisomes in the formation of these acylcarnitine intermediates. Similar experiments with fibroblasts deficient in carnitine palmitoyltransferase I, carnitine-acylcarnitine translocase or carnitine palmitoyltransferase II revealed that mitochondrial carnitine palmitoyltransferase I is not required for the oxidation of phytanic acid or pristanic acid, whereas both carnitine-acylcarnitine translocase and carnitine palmitoyltransferase II are necessary. These studies demonstrate that both phytanic acid and pristanic acid are initially oxidized in peroxisomes to 4,8-dimethylnonanoyl-CoA, which is converted to the corresponding acylcarnitine (presumably by peroxisomal carnitine octanoyltransferase), and exported to the mitochondrion. After transport across the mitochondrial membrane and transfer of the acylgroup to coenzyme A, further oxidation to 2,6-dimethylheptanoyl-CoA occurs.
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PMID:Phytanic acid and pristanic acid are oxidized by sequential peroxisomal and mitochondrial reactions in cultured fibroblasts. 946 87

Fatty acids have been shown to regulate the expression of mRNA for both lipogenic and glycolytic enzymes in rat liver. The role of fatty acids in the regulation of carnitine palmitoyltransferase (CPT) I and II activity in tumour cells was investigated. The polyunsaturated fatty acids, gamma-linolenic and arachidonic acid, caused 60-70% inhibition of tumour cell CPT I activity and 45-50% inhibition of [14C]-palmitic acid oxidation to 14CO2. These effects were blocked by the cyclooxygenase inhibitor, indomethacin. Prostaglandins E1 and E2 caused marked inhibition of both CPT I and CPT II activity and inhibition of cell proliferation. Prostaglandin E2 production by tumour cells was increased in the presence of arachidonic acid and inhibited when indomethacin was present. The proliferation of the HT29 cell line was unaffected as was its CPT I and II activity by both fatty acids and prostaglandins. CPT I mRNA expression was not inhibited by fatty acids, indeed it increased-in the presence of arachidonic acid and prostaglandin E1. These results strongly suggest that polyunsaturated n-6 fatty acids are able, via prostaglandin products, to regulate the CPT activity of certain tumour cells. This may have a considerable impact on mitochondrial beta-oxidation and cellular metabolism of fatty acids, reflected in the marked inhibition of cell proliferation by these fatty acids.
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PMID:Regulation of tumour cell fatty acid oxidation by n-6 polyunsaturated fatty acids. 950 57

The syndrome of cancer cachexia is accompanied by several alterations of lipid metabolism, especially that in the liver. In this study we have investigated a possible mechanism whereby the presence of the Walker 256 carcinosarcoma affects hepatic fatty acid oxidative capacity in tumour-bearing rats. Hepatic mitochondrial outer membrane carnitine palmitoyltransferase I (CPT I), generally accepted as the main site of regulation of fatty acid oxidation, was unaffected by the presence of the extra-hepatic tumour. However, mitochondrial inner-membrane carnitine palmitoyltransferase II (CPT II) activity was markedly decreased in mitochondria isolated from the liver of tumour-bearing rats. Immuno-detection by Western blotting using a CPT II-specific antibody identified two bands (corresponding to M(r) 69,000 and 54,000) in tumour-bearing rats whereas only the normal-sized CPT II was present (at the expected M(r) 69,000) in mitochondria from control rats. It is suggested that the emergence of the second, smaller protein may represent a catalytically less active protein that arises in vivo, since its appearance was not affected by the inclusion of proteolysis inhibitors in the mitochondrial preparation buffers. Treatment of the tumour-bearing rats with indomethacin, a prostaglandin (including PGE2) synthesis inhibitor, increased CPT II activity to levels even higher than those found in the control animals. It is suggested that PGE2 may play a role in the control of CPT II expression in the liver of tumour-bearing rats. Indomethacin treatment did not affect either of the two CPT activities of the mitochondria isolated from tumour tissue.
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PMID:Carnitine palmitoyltransferase II activity is decreased in liver mitochondria of cachectic rats bearing the Walker 256 carcinosarcoma: effect of indomethacin treatment. 950 62

Carnitine palmitoyltransferase II (CPT II) deficiency is an autosomal recessive disorder of mitochondrial fatty-acid oxidation which presents as three distinct phenotypes (neonatal, infantile, and adult onset). CPT II exons from an adult-onset CPT II-deficient patient were amplified and directly sequenced to further investigate the molecular basis of this disorder. A novel mutation, C471T, in exon 4 of the carnitine palmitoyltransferase II gene was found which created a stop codon, TGA, at residue 124 of the protein (R124Stop). This mutation would result in severe protein truncation. This unique mutation was found on one allele while the S113L mutation, previously reported, was present on the other allele.
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PMID:A novel mutation identified in carnitine palmitoyltransferase II deficiency. 956 64

We evaluated the activities of carnitine palmitoyltransferase (CPT), carnitine octanoyltransferase (COT), and carnitine acetyltransferase (CAT) in the frontal cortex, temporal cortex, parietal cortex, hippocampus, and cerebellum of Alzheimer disease (AD) patients and normal human brains. There were no significant differences in total CPT activity, its inhibition by malonyl-CoA, the effect of the detergent Triton X-100 on CPT activity, COT activity, and CAT activity in any of the brain regions examined whether activities were expressed as grams of wet weight or corrected for noncollagen protein content. The addition of Triton X-100 increased CAT activity by 50%. Our results suggest that there is no defect of fatty acid transport within the AD brain cell. Total CPT activity, COT activity, and CAT activity are not affected in AD nor is the ratio of CPT I to CPT II altered in the AD versus the normal human brain.
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PMID:Carnitine acyltransferases are not changed in Alzheimer disease. 965 Nov 34

Using isolated rat liver mitochondria, in the absence or presence of malonyl-CoA (an inhibitor of carnitine palmitoyltransferase I), we have found that carnitine palmitoyltransferase II (CPT II) is active with palmitoyl-CoA as well as with its beta-oxidation intermediates. A partially purified CPT II fraction from rat liver mitochondria was shown to be able to convert 3-hydroxypalmitoyl-CoA to 3-hydroxypalmitoylcarnitine, which could be identified by fast-atom-bombardment mass spectrometry. This apparent broad specificity of CPT II was further evaluated by kinetic studies using purified CPT II. It was found that CPT II readily accepts 3-oxopalmitoyl-CoA, palmitoyl-CoA, 3-hydroxypalmitoyl-CoA and 2,3-unsaturated palmitoyl-CoA as substrates with decreasing order of affinity. The apparent Vmax values found for the first three compounds were of the same order of magnitude; the 2,3-unsaturated acyl-CoA was the poorest substrate. Kinetic studies with purified CPT II showed 3-hydroxypalmitoyl-CoA to have the lowest K0.5 value (20 +/- 6 microM) of all the CoA esters studied; the highest K0.5 value (65 +/- 17 microM) was found for the 3-oxo intermediate. These findings support the hypothesis that CPT II is involved in the export of toxic long-chain acyl-CoA esters from the mitochondria by first converting them into the corresponding carnitine esters, followed by transport out of the mitochondria and subsequently out of the cell.
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PMID:Carnitine palmitoyltransferase II specificity towards beta-oxidation intermediates--evidence for a reverse carnitine cycle in mitochondria. 965 57

Here we report on a patient with severe ("non-classic") carnitine palmitoyltransferase type II (CPT II) deficiency. Hypoglycemia prompted by an infectious episode and associated with non-ketotic dicarboxylic aciduria orientated diagnosis towards beta-oxidation deficiency disorders. Blood carnitine levels revealed a secondary carnitine deficiency that was responsive to oral L-carnitine supplementation. Blood acylcarnitine profiles were abnormal and included acetyl (C2:0), butyryl/isobutyryl (C4:0), isovaleryl/2-methylbutyryl (C5:0), hexanoyl (C6:0), myristoyl (C14:0), palmitoyl (C16:0), hexadecenoyl (C16:1), oleyl (C18:1) and stearoyl (C18:0) carnitine. In urine, excess excretion of dicarboxylylcarnitines, mainly dodecanedioylcarnitine, was noticed. Upon carnitine supplementation, C8 to C12 fatty acylcarnitines, with decanoylcarnitine as well as C10 to C14 dicarboxylylcarnitines being prominent, were observed in urine. Biochemical measurements disclosed a severe reduction of mitochondrial CPT II activity (7% of normal values). Correlations of metabolic findings in the patient and physiological roles of CPT II are briefly discussed.
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PMID:Metabolic studies in a patient with severe carnitine palmitoyltransferase type II deficiency. 965 46

Because we had found whole testis from adult rats to be much richer in the messenger RNA for the muscle (M) than for the liver (L) form of mitochondrial carnitine palmitoyltransferase I (CPT I), we sought to determine which cell type(s) accounts for this expression pattern and how it might relate to reproductive function. Studies with immature (14-day-old) and adult animals included 1) Northern blot analysis of testis mRNA; 2) in situ hybridization with slices of testis; 3) enzyme assays for CPT I, CPT II, and carnitine acetyltransferase (CAT) in testicular germ cells and nongerm cells, together with measurement of the malonyl-coenzyme A (CoA) sensitivity and affinity for carnitine of CPT I; 4) labeling of testicular CPT I with [3H]etomoxir, a covalent inhibitor of the enzyme; and 5) the response of testicular and nontesticular CPT I to dietary etomoxir. The data established the following: 1) L-CPT I was the sole isoform detected in immature testis. 2) Expression of the M-CPT I gene was associated only with meiotic and postmeiotic germ cells. 3) Adult testis contains a mixture of the L- and M-CPT I enzymes, the L and M form dominating in extratubular cells and spermatids, respectively. Mature epididymal spermatozoa appear to be devoid of CPT I activity while possessing abundant levels of CPT II and CAT. 4) Five days of dietary etomoxir treatment at a dose that resulted in essentially complete inhibition of CPT I in liver, heart, skeletal muscle, and kidney was totally without effect on either the L- or M-type enzyme in the testis of mature rats. The data point to an important role for transient expression of M-CPT I, coupled with sustained activity of CAT, in the maturation and/or function of rat sperm. They also suggest that, at least in the case of one CPT I inhibitor (etomoxir), the testis is unusually resistant to the agent when given orally.
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PMID:Expression and possible role of muscle-type carnitine palmitoyltransferase I during sperm development in the rat. 982 84


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