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Substitutions of Three Amino Acids in Human Heart/Muscle Type Carnitine Palmitoyltransferase I Caused by Single Nucleotide Polymorphisms

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Abstract

Heart/muscle type carnitine palmitoyltransferase I (M-CPTI) catalyzes the rate-limiting step of mitochondrial long-chain fatty acid (LCFA) oxidation in muscle and adipose tissue. Three replacements of nucleotides resulting in missense mutations of I66V, S427C, and E531K were observed in the M-CPTI gene of patients showing abnormal fatty acid metabolism. These nucleotide replacements were found to be common single nucleotide polymorphisms (SNPs) of this gene and not specific to patients. The question of whether these missense mutations caused by SNPs alter the functional properties of M-CPTI remains unanswered. Thus, we examined whether these missense mutations are associated with any changes in the enzymatic properties of M-CPTI. None of these mutations was found to cause remarkable alteration of its enzymatic properties. Based on the comparison of amino acid sequences of M-CPTI among different animal species, the roles of these amino acids in the enzyme are discussed.

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References

  • Bonnefont JP, Demaugre F, Prip-Buus C, Saudubray JM, Brivet M, Abadi N, Thuillier L (1999) Carnitine palmitoyltransferase deficiencies. Mol Genet Metab 68:424–440

    Article  PubMed  CAS  Google Scholar 

  • Cox KB, Johnson KR, Wood PA (1998) Chromosomal locations of the mouse fatty acid oxidation genes Cpt1a, Cpt1b, Cpt2, Acadvl, and metabolically related Crat gene. Mamm Genome 9:608–610

    Article  PubMed  CAS  Google Scholar 

  • Dai J, Zhu H, Woldegiorgis G (2003) Leucine-764 near the extreme C-terminal end of carnitine palmitoyltransferase I is important for activity. Biochem Biophys Res Commun 301:758–763

    Article  PubMed  CAS  Google Scholar 

  • Demaugre F, Bonnefont JP, Colonna M, Cepanec C, Leroux JP, Saudubray JM (1991) Infantile form of carnitine palmitoyltransferase II deficiency with hepatomuscular symptoms and sudden death. Physiopathological approach to carnitine palmitoyltransferase II deficiencies. J Clin Invest 87:859–864

    Article  PubMed  CAS  Google Scholar 

  • Haga H, Yamada R, Ohnishi Y, Nakamura Y, Tanaka T (2002) Gene-based SNP discovery as part of the Japanese Millennium Genome Project: Identification of 190,562 genetic variations in the human genome. J Hum Genet 47:605–610

    Article  PubMed  CAS  Google Scholar 

  • Hashimoto M, Shinohara Y, Majima E, Hatanaka T, Yamazaki N, Terada H (1999) Expression of the bovine heart mitochondrial ADP/ATP carrier in yeast mitochondria: Significantly enhanced expression by replacement of the N-terminal region of the bovine carrier by the corresponding regions of the yeast carriers. Biochim Biophys Acta 1409:113–124

    Article  PubMed  CAS  Google Scholar 

  • Hirakawa M, Tanaka T, Hashimoto Y, Kuroda M, Takagi T, Nakamura Y (2002) JSNP: A database of common gene variations in the Japanese population. Nucleic Acids Res 30:158–162

    Article  PubMed  CAS  Google Scholar 

  • Ho SN, Hunt HD, Horton RM, Pullen JK, Pease LR (1989) Site-directed mutagenesis by overlap extension using the polymerase chain reaction. Gene 77:51–59

    Article  PubMed  CAS  Google Scholar 

  • IJlst L, Mandel H, Oostheim W, Ruiter JP, Gutman A, Wanders RJ (1998) Molecular basis of hepatic carnitine palmitoyltransferase I deficiency. J Clin Invest 102:527–531

    PubMed  CAS  Google Scholar 

  • Jackson VN, Zammit VA, Price NT (2000) Identification of positive and negative determinants of malonyl-CoA sensitivity and carnitine affinity within the amino termini of rat liver- and muscle-type carnitine palmitoyltransferase I. J Biol Chem 275:38410–38416

    Article  PubMed  CAS  Google Scholar 

  • McGarry JD, Brown NF (1997) The mitochondrial carnitine palmitoyltransferase system: From concept to molecular analysis. Eur J Biochem 244:1–14

    Article  PubMed  CAS  Google Scholar 

  • Niwa H, Yamamura K, Miyazaki J (1991) Efficient selection for high-expression transfectants with a novel eukaryotic vector. Gene 108:193–199

    Article  PubMed  CAS  Google Scholar 

  • Price NT, van der Leij FR, Jackson VN, Corstorphine CG, Thomson R, Sorensen A, Zammit VA (2002) A novel brain-expressed protein related to carnitine palmitoyltransferase I. Genomics 80:433–442

    Article  PubMed  CAS  Google Scholar 

  • Price NT, Jackson VN, van der Leij FR, Cameron JM, Travers MT, Bartelds B, Huijkman NC, Zammit VA (2003) Cloning and expression of the liver and muscle isoforms of ovine carnitine palmitoyltransferase 1: residues within the N-terminus of the muscle isoform influence the kinetic properties of the enzyme. Biochem J 372:871–879

    Article  PubMed  CAS  Google Scholar 

  • Ramsay RR, Gandour RD, van der Leij FR (2001) Molecular enzymology of carnitine transfer and transport. Biochim Biophys Acta 1546:21–43

    PubMed  CAS  Google Scholar 

  • Shi J, Zhu H, Arvidson DN, Woldegiorgis G (1999) 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. J Biol Chem 274:9421–9426

    Article  PubMed  CAS  Google Scholar 

  • van der Leij FR, Huijkman NC, Boomsma C, Kuipers JR, Bartelds B (2000) Genomics of the human carnitine acyltransferase genes. Mol Genet Metab 71:139–153

    Article  PubMed  CAS  Google Scholar 

  • Yamazaki N, Shinohara Y, Shima A, Terada H (1995) High expression of a novel carnitine palmitoyltransferase I-like protein in rat brown adipose tissue and heart: Isolation and characterization of its cDNA clone. FEBS Lett 363:41–45

    Article  PubMed  CAS  Google Scholar 

  • Yamazaki N, Shinohara Y, Shima A, Yamanaka Y, Terada H (1996) Isolation and characterization of cDNA and genomic clones encoding human muscle type carnitine palmitoyltransferase I. Biochim Biophys Acta 1307:157–161

    PubMed  Google Scholar 

  • Yamazaki N, Yamanaka Y, Hashimoto Y, Shinohara Y, Shima A, Terada H (1997) Structural features of the gene encoding human muscle type carnitine palmitoyltransferase I. FEBS Lett 409:401–406

    Article  PubMed  CAS  Google Scholar 

  • Yamazaki N, Yamanaka Y, Hashimoto Y, Hiramatsu T, Shinohara Y, Terada H (2003) The gene encoding muscle-type carnitine palmitoyltransferase I: Comparison of the 5′-upstream region of human and rodent genes. J Biochem (Tokyo) 133:523–532

    CAS  Google Scholar 

  • Zhu H, Shi J, de Vries Y, Arvidson DN, Cregg JM, Woldegiorgis G (1997) Functional studies of yeast-expressed human heart muscle carnitine palmitoyltransferase I. Arch Biochem Biophys 347:53–61

    Article  PubMed  CAS  Google Scholar 

  • Zhu H, Shi J, Treber M, Dai J, Arvidson DN, Woldegiorgis G (2003) Substitution of glutamate-3, valine-19, leucine-23, and serine-24 with alanine in the N-terminal region of human heart muscle carnitine palmitoyltransferase I abolishes malonyl CoA inhibition and binding. Arch Biochem Biophys 413:67–74

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by a grant-in-aid for scientific research (No. 16790055 to N.Y.) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan. This study was also partly supported by grants to Seiji Yamaguchi from the Ministry of Health, Labor, and Welfare of Japan and the Ministry of Education, Culture, Sports, Science, and Technology, and also by the Program for Promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation (NIBIO).

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Authors and Affiliations

  1. Faculty of Pharmaceutical Sciences, University of Tokushima, Shomachi-1, Tokushima, 770-8505, Japan

    Naoshi Yamazaki, Taisuke Matsuo, Miho Kurata, Makiko Suzuki & Yasuo Shinohara

  2. Institute for Genome Research, University of Tokushima, Kuramotocho-3, Tokushima, 770-8503, Japan

    Taisuke Matsuo & Yasuo Shinohara

  3. Department of Pediatrics, Matsue Red Cross Hospital, Horomachi 200, Matsue, Shimane, 690-8506, Japan

    Takehisa Fujiwaki

  4. Department of Pediatrics, Shimane University Faculty of Medicine, Enyacho 89-1, Izumo, Shimane, 693-8501, Japan

    Takehisa Fujiwaki & Seiji Yamaguchi

  5. Faculty of Pharmaceutical Sciences, Tokyo University of Science, Yamazaki 2641, Noda, 278-8510, Japan

    Hiroshi Terada

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  1. Naoshi Yamazaki
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  2. Taisuke Matsuo
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  3. Miho Kurata
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  4. Makiko Suzuki
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  5. Takehisa Fujiwaki
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  6. Seiji Yamaguchi
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  7. Hiroshi Terada
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  8. Yasuo Shinohara
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Correspondence to Naoshi Yamazaki.

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Yamazaki, N., Matsuo, T., Kurata, M. et al. Substitutions of Three Amino Acids in Human Heart/Muscle Type Carnitine Palmitoyltransferase I Caused by Single Nucleotide Polymorphisms. Biochem Genet 46, 54–63 (2008). https://doi.org/10.1007/s10528-007-9129-3

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  • DOI: https://doi.org/10.1007/s10528-007-9129-3

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