Human liver mitochondrial carnitine palmitoyltransferase I: characterization of its cDNA and chromosomal localization and partial analysis of the gene.

Britton, Charles H.; Schultz, Roger A.; Zhang, Bingqing; Esser, Victoria; Foster, Daniel W.; McGarry, Julie

doi:10.1073/pnas.92.6.1984

Cited by 135 publications

(83 citation statements)

References 34 publications

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“…Acylcarnitine transverses the inner mitochondrial membrane by means of a specific translocase and fatty acyl-CoAs within the matrix are regenerated by CPT2. CPT1, by virtue of its inhibition by malonyl-CoA is the main regulatory point in fatty acid β-oxidation with increasing levels of malonyl-CoA favouring fatty acid utilisation in biosynthesis This process is central in maintaining an effective fuel "cross talk", which according to the energy needs of the organism can lead to either catabolism or biosynthesis of fatty acids in a variety of tissues such as the liver, heart, and the skeletal muscle (Britton et al, 1995). Consequently, the study of CPT1 in mammals has gathered considerable interest as one potential target for the pharmacological control of fatty acid oxidation.…”

Section: Introductionmentioning

confidence: 99%

Molecular characterization of a gilthead sea bream (Sparus aurata) muscle tissue cDNA for carnitine palmitoyltransferase 1B (CPT1B)

Boukouvala

Leaver

Favre-Krey

et al. 2010

Comparative Biochemistry and Physiology Part B: Biochemistry an

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Understanding the control of piscine fatty acid metabolism is important for determining the nutritional requirements of fish, and hence for the production of optimal aquaculture diets. The regulation and expression of carnitine palmitoyltransferase 1 (CPT1; EC No 2.3.1.21) are critical processes in the control fatty acid metabolism, and here we report a cDNA from gilthead sea bream (Sparus aurata) which encodes a protein with high identity to vertebrate CPT1. This sea bream CPT1 mRNA is predominantly expressed in skeletal and cardiac muscle, with little expression in other tissues. Phylogenetic analysis of other vertebrate CPT1 sequences show that fish genomes contain a single gene related to mammalian CPT1B, and a further two multi-gene families related to mammalian CPT1A. Genes related to mammalian CPT1C are absent in fish. Therefore, based on both functional and evolutionary orthology to mammalian CPT1B, the sea bream CPT1 reported here is a CPT1B isoform. Sea bream CPT1B mRNA expression progressively decreases in heart and muscle up to 12 hours after last feeding, but returns to initial, non-fasted levels after 72 hours. In contrast, in liver non-fasted expression is low, but strongly increases at 24 and 72 hours after last feeding. In white muscle and liver, CPT1B mRNA expression is highly correlated with the expression of peroxisomal proliferator-activated receptor (PPAR ).Thus fatty acid metabolism by CPT1B and its control by PPARs is similar in fish and mammals, but multiple genes for CPT1A-like proteins in fish also suggest different and more complex pathways of lipid utilisation than in mammals.

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Section: Introductionmentioning

confidence: 99%

Molecular characterization of a gilthead sea bream (Sparus aurata) muscle tissue cDNA for carnitine palmitoyltransferase 1B (CPT1B)

Boukouvala

Leaver

Favre-Krey

et al. 2010

Comparative Biochemistry and Physiology Part B: Biochemistry an

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“…In the small number of cases reported to date the affected enzyme is clearly the liver isoform. This is evidenced by the fact that the defect is easily identifiable in homogenates of fibroblasts (which we now know to express the liver-type enzyme essentially exclusively [48]) when appropriate assays are employed to discriminate between the activities of CPT I and CPT 11 [97]. Moreover, the clinical symptomatology, which is usually seen in infancy, displays classical liver involvement ; the hallmark feature is hypoketotic hypoglycemia which, if not treated, can be fatal [98].…”

Section: Structurementioning

confidence: 99%

“…. [38], human L-CPT I [48], rat L-CPT I [45], human M-CPT I 152, 531, rat M-CPT I [51]. Residue numbering is shown at the right of each line.…”

Section: K T D P S L G I I a K I N R T L E L A N C M S 98 K V D Pmentioning

confidence: 99%

The Mitochondrial Carnitine Palmitoyltransferase System — From Concept to Molecular Analysis

McGarry

Brown

1997

European Journal of Biochemistry

1,460

1,220

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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 11, 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 isofornis, the chromosomal localization of their respective genes, and the identification of mutations in the human population.

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“…There is 82% and 88% identity between the human and the rat L-CPT I nucleotide sequence and the predicted protein primary structure, respectively. The human M-CPT I gene has been mapped to chromosome 22q13.3, and the L-CPT I gene is located on chromosome 11q13 (Britton et al, 1995(Britton et al, , 1997.In the second step of the carnitine shuttle, acylcarnitines enter the mitochondrial matrix in exchange for free carnitine, using CACT, an integral inner mitochondrial membrane protein (Fig. 1).…”

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confidence: 99%

Carnitine Palmitoyltransferase II Deficiency: A Clinical, Biochemical, and Molecular Review

Sigauke

Rakheja

Kitson

et al. 2003

Laboratory Investigation

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SUMMARY:Congenital deficiency of carnitine palmitoyltransferase (CPT) II has been known for at least 30 years now, and its phenotypic variability remains fascinating. Three distinct clinical entities have been described, the adult, the infantile, and the perinatal, all with an autosomal recessive inheritance pattern. The adult CPT II clinical phenotype is somewhat benign and requires additional external triggers such as high-intensity exercise before the predominantly myopathic symptoms are elicited. The perinatal and infantile forms involve multiple organ systems. The perinatal disease is the most severe form and is invariably fatal. The introduction of mass spectrometry to analyze blood acylcarnitine profiles has revolutionized the diagnosis of fatty acid oxidation disorders including CPT II deficiency. Its use in expanded neonatal screening programs has made presymptomatic diagnosis a reality. An increasing number of mutations are being identified in the CPT II gene with a distinct genotype-phenotype correlation in most cases. However, clinical variability in some patients suggests additional genetic or environmental modifiers. Herein, we present a new case of lethal perinatal CPT II deficiency with a rare missense mutation, R296Q (907GϾA) associated with a previously described 25-bp deletion on the second allele. We review the clinical features, the diagnostic protocol including expanded neonatal screening, the treatment, and the biochemical and molecular basis of CPT II deficiency. (Lab Invest 2003, 83:1543-1554.T he carnitine palmitoyltransferase (CPT) enzyme system, in association with acyl-coenzyme A (CoA) synthetase and the carnitine-acylcarnitine translocase (CACT), plays an important role in the transfer of long chain fatty acids (LCFA) from the cytosolic compartment to the mitochondrial matrix, where ␤-oxidation occurs (Bieber, 1988). Two genetically distinct mitochondrial membrane-bound enzymes make up the CPT system. CPT I is located on the inner aspect of the outer mitochondrial membrane. This enzyme is physiologically inhibited by the high levels of malonyl-CoA that occur postprandially and thus regulates the entry of LCFA into the mitochondria (McGarry and Brown, 1997). CPT II, which is not inhibited by malonyl-CoA, is situated on the inner aspect of the inner mitochondrial membrane (Murthy and Pande, 1987).CPT II deficiency was first reported by DiMauro and DiMauro (1973) in adults with exercise-induced rhabdomyolysis. It is an autosomal recessive disorder (Angelini et al, 1981;Meola et al, 1987) and is now regarded as one of the most common inherited disorders of lipid metabolism . Isolated presentation in two successive generations has been reported, indicating a possible dominant inheritance (Mongini et al, 1991). Partial CPT II deficiency with an autosomal dominant inheritance pattern has also been reported (Ionasescu et al, 1980). The molecular basis for this presentation was not elucidated.To date, three distinct CPT II-deficient phenotypes have been described in the literature, for wh...

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Human liver mitochondrial carnitine palmitoyltransferase I: characterization of its cDNA and chromosomal localization and partial analysis of the gene.

Cited by 135 publications

References 34 publications

Molecular characterization of a gilthead sea bream (Sparus aurata) muscle tissue cDNA for carnitine palmitoyltransferase 1B (CPT1B)

Molecular characterization of a gilthead sea bream (Sparus aurata) muscle tissue cDNA for carnitine palmitoyltransferase 1B (CPT1B)

The Mitochondrial Carnitine Palmitoyltransferase System — From Concept to Molecular Analysis

Carnitine Palmitoyltransferase II Deficiency: A Clinical, Biochemical, and Molecular Review

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