Skip to main content

Structural insight into function and regulation of carnitine palmitoyltransferase

Cellular and Molecular Life Sciences volume 66, pages 2489–2501 (2009)Cite this article

Abstract

The control of fatty acid translocation across the mitochondrial membrane is mediated by the carnitine palmitoyltransferase (CPT) system. Modulation of its functionality has simultaneous effects on fatty acid and glucose metabolism. This encourages use of the CPT system as drug target for reduction of gluconeogenesis and restoration of lipid homeostasis, which are beneficial in the treatment of type 2 diabetes mellitus and obesity. Recently, crystal structures of CPT-2 were determined in uninhibited forms and in complexes with inhibitory substrate-analogs with anti-diabetic properties in animal models and in clinical studies. The CPT-2 crystal structures have advanced understanding of CPT structure–function relationships and will facilitate discovery of novel inhibitors by structure-based drug design. However, a number of unresolved questions regarding the biochemistry and pharmacology of CPT enzymes remain and are addressed in this review.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

43,34 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

References

  1. ADA (2003) Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care 26:5–20

    Article  Google Scholar 

  2. Zimmet P, Alberti KG, Shaw J (2001) Global and societal implications of the diabetes epidemic. Nature 414:782–787

    PubMed  CAS  Article  Google Scholar 

  3. Wagman AS, Nuss JM (2001) Current therapies and emerging targets for the treatment of diabetes. Curr Pharm Des 7:417–450

    PubMed  CAS  Article  Google Scholar 

  4. Nathan DM (2007) Rosiglitazone and cardiotoxicity—weighing the evidence. N Engl J Med 357:64–66

    PubMed  CAS  Article  Google Scholar 

  5. Kuhajda FP, Ronnett GV (2007) Modulation of carnitine palmitoyltransferase-1 for the treatment of obesity. Curr Opin Inves Drugs 8:312–317

    CAS  Google Scholar 

  6. Price N, van der Leij F, Jackson V, Corstorphine C, Thomson R, Sorensen A, Zammit V (2002) A novel brain-expressed protein related to carnitine palmitoyltransferase I. Genomics 80:433–442

    PubMed  CAS  Article  Google Scholar 

  7. Wolfgang MJ, Kurama T, Dai Y, Suwa A, Asaumi M, Matsumoto S, Cha SH, Shimokawa T, Lane MD (2006) The brain-specific carnitine palmitoyltransferase-1c regulates energy homeostasis. Proc Natl Acad Sci USA 103:7282–7287

    PubMed  CAS  Article  Google Scholar 

  8. Sierra AY, Gratacós E, Carrasco P, Clotet J, Ureña J, Serra D, Asins G, Hegardt FG, Casals N (2008) CPT1c is localized in endoplasmic reticulum of neurons and has carnitine palmitoyltransferase activity. J Biol Chem 283:6878–6885

    PubMed  CAS  Article  Google Scholar 

  9. Roomets E, Kivelä T, Tyni T (2008) Carnitine palmitoyltransferase I and acyl-CoA dehydrogenase 9 in retina: insights of retinopathy in mitochondrial trifunctional protein defects. Invest Ophthalmol Vis Sci 49:1660–1664

    PubMed  Article  Google Scholar 

  10. Obici S, Feng Z, Arduini A, Conti R, Rossetti L (2003) Inhibition of hyopothalmic carnitine palmitoyltransferase-1 decreases food intake and glucose production. Nat Med 6:756–761

    Article  CAS  Google Scholar 

  11. Kanamaru T, Shinagawa S, Asai M, Okazaki H, Sugiyama Y, Fujita T, Iwatsuka H, Yoneda M (1985) Emeriamine, an antidiabetic beta-aminobetaine derived from a novel fungal metabolite. Life Sci 37:217–223

    PubMed  CAS  Article  Google Scholar 

  12. Shinagawa S, Kanamaru T, Harada S, Asai M, Okazaki H (1987) Chemistry and inhibitory activity of long chain fatty acid oxidation of emeriamine and its analogues. J Med Chem 30:1458–1463

    PubMed  CAS  Article  Google Scholar 

  13. Jenkins DL, Griffith OW (1985) dl-aminocarnitine and acetyl-dl-aminocarnitine. Potent inhibitors of carnitine acyltransferases and hepatic triglyceride catabolism. J Biol Chem 260:14748–14755

    PubMed  CAS  Google Scholar 

  14. Jenkins DL, Griffith OW (1986) Antiketogenic and hypoglycemic effects of aminocarnitine and acylaminocarnitines. Proc Natl Acad Sci USA 83:290–294

    PubMed  CAS  Article  Google Scholar 

  15. Giannessi F, Chiodi P, Marzi M, Minetti P, Pessotto P, De Angelis F, Tassoni E, Conti R, Giorgi F, Mabilia M, Dell’Uomo N, Muck S, Tinti MO, Carminati P, Arduini A (2001) Reversible carnitine palmitoyltransferase inhibitors with broad chemical diversity as potential antidiabetic agents. J Med Chem 44:2383–2386

    PubMed  CAS  Article  Google Scholar 

  16. Giannessi F, Pessotto P, Tassoni E, Chiodi P, Conti R, De Angelis F, Dell’Uomo N, Catini R, Deias R, Tinti MO, Carminati P, Arduini A (2003) Discovery of a long-chain carbamoyl aminocarnitine derivative, a reversible carnitine palmitoyltransferase inhibitor with antiketotic and antidiabetic activity. J Med Chem 46:303–309

    PubMed  CAS  Article  Google Scholar 

  17. Chegary M, Te Brinke H, Doolaard M, Ijlst L, Wijburg FA, Wanders RJ, Houten SM (2008) Characterization of l-aminocarnitine, an inhibitor of fatty acid oxidation. Mol Genet Metab 93:403–410

    PubMed  CAS  Article  Google Scholar 

  18. Fritz IB, Yue KT (1963) Long-chain carnitine acyltransferase and the role of acylcarnitine derivatives in the catalytic increase of fatty acid oxidation induced by carnitine. J Lipid Res 4:279–288

    PubMed  CAS  Google Scholar 

  19. Esser V, Kuwajima M, Britton CH, Krishnan K, Foster DW, McGarry JD (1993) Inhibitors of mitochondrial carnitine palmitoyltransferase I limit the action of proteases on the enzyme. Isolation and partial amino acid analysis of a truncated form of the rat liver isozyme. J Biol Chem 268:5810–5816

    PubMed  CAS  Google Scholar 

  20. Esser V, Britton CH, Weis BC, Foster DW, McGarry JD (1993) Cloning, sequencing, and expression of a cDNA encoding rat liver carnitine palmitoyltransferase I. Direct evidence that a single polypeptide is involved in inhibitor interaction and catalytic function. J Biol Chem 268:5817–5822

    PubMed  CAS  Google Scholar 

  21. Yates DW, Garland PB (1970) Carnitine palmitoyltransferase activities (EC 2.3.1.-) of rat liver mitochondria. Biochem J 119:547–552

    PubMed  CAS  Google Scholar 

  22. Kopec B, Fritz IB (1971) Properties of a purified carnitine palmitoyltransferase, and evidence for the existence of other carnitine acyltransferases. Can J Biochem 49:941–948

    PubMed  CAS  Article  Google Scholar 

  23. West DW, Chase JFA, Tubbs PK (1971) The separation and properties of two forms of carnitine palmitoyltransferase from ox liver mitochondria. Biochem Biophys Res Comm 42:912–918

    PubMed  CAS  Article  Google Scholar 

  24. Solberg HE (1972) Different carnitine acyltransferases in calf liver. Biochem Biophys Acta 280:422–433

    PubMed  CAS  Google Scholar 

  25. Kopec B, Fritz IB (1973) Comparison of properties of carnitine palmitoyltransferase I with those of carnitine palmitoyltransferase II, and preparation of antibodies to carnitine palmitoyltransferases. J Biol Chem 248:4069–4074

    PubMed  CAS  Google Scholar 

  26. Brown NF, Sen A, Soltis DA, Jones B, Foster DW, McGarry JD (1993) Expression of precursor and mature carnitine palmitoyltransferase II in Escherichia coli and in vitro: differential behaviour of rat and human isoforms. Biochem J 294:79–86

    PubMed  CAS  Google Scholar 

  27. McGarry JD, Brown NF (2000) Reconstitution of purified, active and malonyl-CoA-sensitive rat liver carnitine palmitoyltransferase I: relationship between membrane environment and malonyl-CoA sensitivity. Biochem J 349:179–187

    PubMed  CAS  Article  Google Scholar 

  28. Brown NF, Esser V, Foster DW, McGarry JD (1994) Expression of a cDNA for rat liver carnitine palmitoyltransferase I in yeast establishes that catalytic activity and malonyl-CoA sensitivity reside in a single polypeptide. J Biol Chem 269:26438–26442

    PubMed  CAS  Google Scholar 

  29. Prip-Buus C, Cohen I, Kohl C, Esser V, McGarry JD, Girard J (1998) Topological and functional analysis of the rat liver carnitine palmitoyltransferase 1 expressed in Saccharomyces cerevisiae. FEBS Lett 429:173–178

    PubMed  CAS  Article  Google Scholar 

  30. Zammit VA (2008) Carnitine palmitoyltransferase 1: central to cell function. IUBMB Life 60:347–354

    PubMed  CAS  Article  Google Scholar 

  31. Hsiao YS, Jogl G, Esser V, Tong L (2006) Crystal structure of rat carnitine palmitoyltransferase II (CPT-II). Biochem Biophys Res Commun 346:974–980

    PubMed  CAS  Article  Google Scholar 

  32. Rufer AC, Thoma R, Benz J, Stihle M, Gsell B, De Roo E, Banner DW, Mueller F, Chomienne O, Hennig M (2006) The crystal structure of carnitine palmitoyltransferase 2 and implications for diabetes treatment. Structure 14:713–723

    PubMed  CAS  Article  Google Scholar 

  33. Rufer AC, Lomize A, Benz J, Chomienne O, Thoma R, Hennig M (2007) Carnitine palmitoyltransferase 2: analysis of membrane association and complex structure with a substrate analog. FEBS Lett 581:3247–3252

    PubMed  CAS  Article  Google Scholar 

  34. Krissinel E, Henrick K (2007) Inference of macromolecular assemblies from crystalline state. J Mol Biol 372:774–797

    PubMed  CAS  Article  Google Scholar 

  35. Clarke PR, Bieber LL (1981) Isolation and purification of mitochondrial carnitine octanoyltransferase activities from beef heart. J Biol Chem 256:9861–9868

    PubMed  CAS  Google Scholar 

  36. Fiol CJ, Bieber LL (1988) Effects of octylglucoside and triton X-100 on the kinetics and specificity of carnitine palmitoyltransferase. Lipids 23:120–125

    PubMed  CAS  Article  Google Scholar 

  37. Nichols-Smith S, Kuhl T (2005) Electrostatic interactions between model mitochondrial membranes. Colloids Surf B Biointerfaces 41:121–127

    PubMed  CAS  Article  Google Scholar 

  38. Rubio-Gozalbo ME, Bakker JA, Waterham HR, Wanders RJ (2004) Carnitine–acylcarnitine translocase deficiency, clinical, biochemical and genetic aspects. Mol Aspects Med 25:521–532

    PubMed  CAS  Article  Google Scholar 

  39. Palsdottir H, Hunte C (2004) Lipids in membrane protein structures. Biochim Biophys Acta 1666:2–18

    PubMed  CAS  Article  Google Scholar 

  40. Faye A, Esnous C, Price NT, Onfray MA, Girard J, Prip-Buus C (2007) Rat liver carnitine palmitoyltransferase 1 forms an oligomeric complex within the outer mitochondrial membrane. J Biol Chem 282:26908–26916

    PubMed  CAS  Article  Google Scholar 

  41. Cohen I, Kohl C, McGarry JD, Girard J, Prip-Buus C (1998) The N-terminal domain of rat liver carnitine palmitoyltransferase 1 mediates import into the outer mitochondrial membrane and is essential for activity and malonyl-CoA sensitivity. J Biol Chem 273:29896–29904

    PubMed  CAS  Article  Google Scholar 

  42. Cohen I, Guillerault F, Girard J, Prip-Buus C (2001) The N-terminal domain of rat liver carnitine palmitoyltransferase 1 contains an internal mitochondrial import signal and residues essential for folding of its C-terminal catalytic domain. J Biol Chem 276:5403–5411

    PubMed  CAS  Article  Google Scholar 

  43. Faye A, Borthwick K, Esnous C, Price NT, Gobin S, Jackson VN, Zammit VA, Girard J, Prip-Buus C (2005) Demonstration of N- and C-terminal domain intramolecular interactions in rat liver carnitine palmitoyltransferase 1 that determine its degree of malonyl-CoA sensitivity. Biochem J 387:67–76

    PubMed  CAS  Article  Google Scholar 

  44. Jackson VN, Cameron JM, Zammit VA, Price NT (1999) Sequencing and functional expression of the malonyl-CoA-sensitive carnitine palmitoyltransferase from Drosophila melanogaster. Biochem J 341:483–489

    PubMed  CAS  Article  Google Scholar 

  45. Fraser F, Zammit VA (1998) Enrichment of carnitine palmitoyltransferases I and II in the contact sites of rat liver mitochondria. Biochem J 329:225–229

    PubMed  CAS  Google Scholar 

  46. Fraser F, Zammit VA (1999) Submitochondrial and subcellular distributions of the carnitine–acylcarnitine carrier. FEBS Lett 445:41–44

    PubMed  CAS  Article  Google Scholar 

  47. Fraser F, Padovese R, Zammit VA (2001) Distinct kinetics of carnitine palmitoyltransferase i in contact sites and outer membranes of rat liver mitochondria. J Biol Chem 276:20182–20185

    PubMed  CAS  Article  Google Scholar 

  48. Jogl G, Tong L (2003) Crystal structure of carnitine acetyltransferase and implications for the catalytic mechanism and fatty acid transport. Cell 112:113–122

    PubMed  CAS  Article  Google Scholar 

  49. Wu D, Govindasamy L, Lian W, Gu Y, Kukar T, Agbandje-McKenna M, McKenna R (2003) Structure of human carnitine acetyltransferase. Molecular basis for fatty acyl transfer. J Biol Chem 278:13159–13165

    PubMed  CAS  Article  Google Scholar 

  50. Hsiao YS, Jogl G, Tong L (2004) Structural and biochemical studies of the substrate selectivity of carnitine acetyltransferase. J Biol Chem 279:31584–31589

    PubMed  CAS  Article  Google Scholar 

  51. Govindasamy L, Kukar T, Lian W, Pedersen B, Gu Y, Agbandje-McKenna M, Jin S, McKenna R, Wu D (2004) Structural and mutational characterization of l-carnitine binding to human carnitine acetyltransferase. J Struct Biol 146:416–424

    PubMed  CAS  Article  Google Scholar 

  52. Hsiao YS, Jogl G, Tong L (2006) Crystal structures of murine carnitine acetyltransferase in ternary complexes with its substrates. J Biol Chem 281:28480–28487

    PubMed  CAS  Article  Google Scholar 

  53. Hsiao YS, Tong L (2004) Crystal structure of mouse carnitine octanoyltransferase and molecular determinants of substrate selectivity. J Biol Chem 280:738–744

    PubMed  Google Scholar 

  54. Cordente AG, López-Viñas E, Vázquez MI, Gómez-Puertas P, Asins G, Serra D, Hegardt FG (2006) Mutagenesis of specific amino acids converts carnitine acetyltransferase into carnitine palmitoyltransferase. Biochemistry 45:6133–6141

    PubMed  CAS  Article  Google Scholar 

  55. Cai Y, Cronin CN, Engel AG, Ohno K, Hersh LB, Rodgers DW (2004) Choline acetyltransferase structure reveals distribution of mutations that cause motor disorders. EMBO J 23:2047–2058

    PubMed  CAS  Article  Google Scholar 

  56. Govindasamy L, Pedersen B, Lian W, Kukar T, Gu Y, Jin S, Agbandje-McKenna M, Wu D, McKenna R (2004) Structural insights and functional implications of choline acetyltransferase. J Struct Biol 148:226–235

    PubMed  CAS  Article  Google Scholar 

  57. Morillas M, Gómez-Puertas P, Roca R, Serra D, Asins G, Valencia A, Hegardt FG (2001) Structural model of the catalytic core of carnitine palmitoyltransferase I and carnitine octanoyltransferase (COT): mutation of CPT I histidine 473 and alanine 381 and COT alanine 238 impairs the catalytic activity. J Biol Chem 276:45001–45008

    PubMed  CAS  Article  Google Scholar 

  58. Morillas M, Gómez-Puertas P, Rubí B, Clotet J, Ariño J, Valencia A, Hegardt FG, Serra D, Asins G (2002) Structural model of a malonyl-CoA-binding site of carnitine octanoyltransferase and carnitine palmitoyltransferase I: mutational analysis of a malonyl-CoA affinity domain. J Biol Chem 277:11473–11480

    PubMed  CAS  Article  Google Scholar 

  59. Gobin S, Thuillier L, Jogl G, Faye A, Tong L, Chi M, Bonnefont JP, Girard J, Prip-Buus C (2003) Functional and structural basis of carnitine palmitoyltransferase 1A deficiency. J Biol Chem 278:50428–50434

    PubMed  CAS  Article  Google Scholar 

  60. Woldegiorgis G, Dai J, Arvidson D (2005) Structure–function studies with the mitochondrial carnitine palmitoyltransferase I and II. Chemical Monthly 136:1325–1340

    CAS  Article  Google Scholar 

  61. López-Viñas E, Bentebibel A, Gurunathan C, Morillas M, de Arriaga D, Serra D, Asins G, Hegardt FG, Gómez-Puertas P (2007) Definition by functional and structural analysis of two malonyl-CoA sites in carnitine palmitoyltransferase 1A. J Biol Chem 282:18212–18224

    PubMed  Article  Google Scholar 

  62. Murthy MS, Pande SV (1985) Microcompartmentation of transported carnitine, acetylcarnitine and ADP occurs in the mitochondrial matrix. Implications for transport measurements and metabolism. Biochem J 230:657–663

    PubMed  CAS  Google Scholar 

  63. Ramsay RR, Naismith JH (2003) A snapshot of carnitine acetyltransferase. Trends Biochem Sci 28:343–346

    PubMed  CAS  Article  Google Scholar 

  64. Kerner J, Distler AM, Minkler P, Parland W, Peterman SM, Hoppel CL (2004) Phosphorylation of rat liver mitochondrial carnitine palmitoyltransferase-I: effect on the kinetic properties of the enzyme. J Biol Chem 279:41104–41113

    PubMed  CAS  Article  Google Scholar 

  65. Kerner J, Hoppel CL (2005) Carnitine palmitoyltransferase-I and regulation of mitochondrial fatty acid oxidation. Chemical Monthly 136:1311–1323

    CAS  Article  Google Scholar 

  66. Distler AM, Kerner J, Hoppel CL (2007) Post-translational modifications of rat liver mitochondrial outer membrane proteins identified by mass spectrometry. Biochim Biophys Acta 1774:628–636

    PubMed  CAS  Google Scholar 

  67. Fukumoto K, Pierro A, Spitz L, Eaton S (2002) Differential effects of neonatal endotoxemia on heart and kidney carnitine palmitoyl transferase I. J Pediatr Surg 37:723–726

    PubMed  Article  Google Scholar 

  68. Fukumoto K, Pierro A, Zammit VA, Spitz L, Eaton S (2004) Tyrosine nitration of carnitine palmitoyl transferase I during endotoxaemia in suckling rats. Biochim Biophys Acta 1683:1–6

    PubMed  CAS  Google Scholar 

  69. Eaton S, Fukumoto K, Stefanutti G, Spitz L, Zammit VA, Pierro A (2003) Myocardial carnitine palmitoyltransferase I as a target for oxidative modification in inflammation and sepsis. Biochem Soc Trans 31:1133–1136

    PubMed  CAS  Article  Google Scholar 

  70. Lopaschuk GD, Wall SR, Olley PM, Davies NJ (1988) Etomoxir, a carnitine palmitoyltransferase I inhibitor, protects hearts from fatty acid-induced ischemic injury independent of changes in long chain acylcarnitine. Circ Res 63:1036–1043

    PubMed  CAS  Google Scholar 

  71. Caspary F, Elliott G, Navé BT, Verzaal P, Rohrbach M, Das PK, Nagelkerken L, Nieland JD (2005) A new therapeutic approach to treat psoriasis by inhibition of fatty acid oxidation by etomoxir. Br J Dermatol 153:937–944

    PubMed  CAS  Article  Google Scholar 

  72. Anderson RC, Balestra M, Bell PA, Deems RO, Fillers WS, Foley JE, Fraser JD, Mann WR, Rudin M, Villhauer EB (1995) Antidiabetic agents: a new class of reversible carnitine palmitoyltransferase I inhibitors. J Med Chem 38:3448–3450

    PubMed  CAS  Article  Google Scholar 

  73. Anderson RC (1998) Carnitine palmitoyltransferase: a viable target for the treatment of NIDDM? Curr Pharm Des 4:1–16

    PubMed  CAS  Google Scholar 

  74. Kurukulasuriya R, Link JT, Madar DJ, Pei Z, Richards SJ, Rohde JJ, Souers AJ, Szczepankiewicz BG (2003) Potential drug targets and progress towards pharmacologic inhibition of hepatic glucose production. Curr Med Chem 10:123–153

    PubMed  CAS  Google Scholar 

  75. Grynberg A (2005) Effectors of fatty acid oxidation reduction: promising new anti-ischaemic agents. Curr Pharm Des 11:489–509

    PubMed  CAS  Article  Google Scholar 

  76. Morillas M, Gómez-Puertas P, Bentebibel A, Sellés E, Casals N, Valencia A, Hegardt FG, Asins G, Serra D (2003) Identification of conserved amino acid residues in rat liver carnitine palmitoyltransferase I critical for malonyl-CoA inhibition. Mutation of methionine 593 abolishes malonyl-CoA inhibition. J Biol Chem 278:9058–9063

    PubMed  CAS  Article  Google Scholar 

  77. Napal L, Dai J, Treber M, Haro D, Marrero PF, Woldegiorgis G (2003) A single amino acid change (substitution of the conserved Glu-590 with alanine) in the C-terminal domain of rat liver carnitine palmitoyltransferase I increases its malonyl-CoA sensitivity close to that observed with the muscle isoform of the enzyme. J Biol Chem 278:34084–34089

    PubMed  CAS  Article  Google Scholar 

  78. Swanson ST, Foster DW, McGarry JD, Brown NF (1998) Roles of the N- and C-terminal domains of carnitine palmitoyltransferase I isoforms in malonyl-CoA sensitivity of the enzymes: insights from expression of chimaeric proteins and mutation of conserved histidine residues. Biochem J 335:513–519

    PubMed  CAS  Google Scholar 

  79. Jackson VN, Cameron JM, Fraser F, Zammit VA, Price NT (2000) Use of six chimeric proteins to investigate the role of intramolecular interactions in determining the kinetics of carnitine palmitoyltransferase I isoforms. J Biol Chem 275:19560–19566

    PubMed  CAS  Article  Google Scholar 

  80. Cook GA, Mynatt RL, Kashfi K (1994) Yonetani–Theorell analysis of hepatic carnitine palmitoyltransferase-I inhibition indicates two distinct inhibitory binding sites. J Biol Chem 269:8803–8807

    PubMed  CAS  Google Scholar 

  81. Yang N, Kays JS, Skillman TR, Burris L, Seng TW, Hammond C (2005) C75 [4-methylene-2-octyl-5-oxo-tetrahydro-furan-3-carboxylic acid] activates carnitine palmitoyltransferase-1 in isolated mitochondria and intact cells without displacement of bound malonyl CoA. J Pharmacol Exp Ther 312:127–133

    PubMed  CAS  Article  Google Scholar 

  82. McGarry JD, Leatherman GF, Foster DW (1978) Carnitine palmitoyltransferase I. The site of inhibition of hepatic fatty acid oxidation by malonyl-CoA. J Biol Chem 253:4128–4136

    PubMed  CAS  Google Scholar 

  83. Traufeller K, Gellerich FN, Zierz S (2004) Different sensitivities of CPT I and CPT II for inhibition by l-aminocarnitine in human skeletal muscle. Biochim Biophys Acta 1608:149–154

    PubMed  CAS  Article  Google Scholar 

  84. Tutwiler GF, Kirsch T, Mohrbacher RJ, Ho W (1978) Pharmacologic profile of methyl 2-tetradecylglycidate (McN-3716)—an orally effective hypoglycemic agent. Metabolism 27:1539–1556

    PubMed  CAS  Article  Google Scholar 

  85. Kiorpes TC, Hoerr D, Ho W, Weaner LE, Inman MG, Tutwiler GF (1884) Identification of 2-tetradecylglycidyl coenzyme A as the active form of methyl 2-tetradecylglycidate (methyl palmoxirate) and its characterization as an irreversible, active site-directed inhibitor of carnitine palmitoyltransferase A in isolated rat liver mitochondria. J Biol Chem 259:9750–9755

    Google Scholar 

  86. Selby PL, Sherratt HS (1989) Substituted 2-oxiranecarboxylic acids: a new group of candidate hypoglycaemic drugs. Trends Pharmacol Sci 10:495–500

    PubMed  CAS  Article  Google Scholar 

  87. Bone AJ, Sherratt HS, Turnbull DM, Osmundsen H (1982) Increased activity of peroxisomal beta-oxidation in rat liver caused by ethyl 2(5(4-chlorophenyl)pentyl)-oxiran-2-carboxylate: an inhibitor of mitochondrial beta-oxidation. Biochem Biophys Res Commun 104:708–712

    PubMed  CAS  Article  Google Scholar 

  88. Koundakjian PP, Turnbull DM, Bone AJ, Rogers MP, Younan SI, Sherratt HS (1984) Metabolic changes in fed rats caused by chronic administration of ethyl 2[5(4-chlorophenyl)pentyl]oxirane-2-carboxylate, a new hypoglycaemic compound. Biochem Pharmacol 33:465–473

    PubMed  CAS  Article  Google Scholar 

  89. Wolf HP, Engel DW (1985) Decrease of fatty acid oxidation, ketogenesis and gluconeogenesis in isolated perfused rat liver by phenylalkyl oxirane carboxylate (B 807–27) due to inhibition of CPT I (EC 2.3.1.21). Eur J Biochem 146:359–363

    PubMed  CAS  Article  Google Scholar 

  90. Weis BC, Esser V, Foster DW, McGarry JD (1994) Rat heart expresses two forms of mitochondrial carnitine palmitoyltransferase I. The minor component is identical to the liver enzyme. J Biol Chem 269:18712–18715

    PubMed  CAS  Google Scholar 

  91. Weis BC, Cowan AT, Brown N, Foster DW, McGarry JD (1994) Use of a selective inhibitor of liver carnitine palmitoyltransferase I (CPT I) allows quantification of its contribution to total CPT I activity in rat heart. Evidence that the dominant cardiac CPT I isoform is identical to the skeletal muscle enzyme. J Biol Chem 269:26443–26448

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Article  Google Scholar 

  93. Merrill CL, Ni H, Yoon LW, Tirmenstein MA, Narayanan P, Benavides GR, Easton MJ, Creech DR, Hu CX, McFarland DC, Hahn LM, Thomas HC, Morgan KT (2002) Etomoxir-induced oxidative stress in HepG2 cells detected by differential gene expression is confirmed biochemically. Toxicol Sci 68:93–101

    PubMed  CAS  Article  Google Scholar 

  94. Vickers AE, Bentley P, Fisher RL (2006) Consequences of mitochondrial injury induced by pharmaceutical fatty acid oxidation inhibitors is characterized in human and rat liver slices. Toxicol In Vitro 20:1173–1182

    PubMed  CAS  Article  Google Scholar 

  95. Randle PJ (1963) Endocrine control of metabolism. Annu Rev Physiol 25:291–324

    PubMed  CAS  Article  Google Scholar 

  96. Randle PJ (1998) Regulatory interactions between lipids and carbohydrates: the glucose fatty acid cycle after 35 years. Diabetes Metab Rev 14:263–283

    PubMed  CAS  Article  Google Scholar 

  97. Ashrafian H, Horowitz JD, Frenneaux MP (2007) Perhexiline. Cardiovasc Drug Rev 25:76–97

    PubMed  CAS  Google Scholar 

  98. Inglis S, Stewart S (2006) Metabolic therapeutics in angina pectoris: history revisited with perhexiline. Eur J Cardiovasc Nurs 5:175–184

    PubMed  Article  Google Scholar 

  99. Stephens TW, Higgins AJ, Cook GA, Harris RA (1985) Two mechanisms produce tissue-specific inhibition of fatty acid oxidation by oxfenicine. Biochem J 227:651–660

    PubMed  CAS  Google Scholar 

  100. Dai Y, Wolfgang MJ, Cha SH, Lane MD (2007) Localization and effect of ectopic expression of CPT1c in CNS feeding centers. Biochem Biophys Res Commun 359:469–474

    PubMed  CAS  Article  Google Scholar 

  101. Aja S, Landree LE, Kleman AM, Medghalchi SM, Vadlamudi A, McFadden JM, Aplasca A, Hyun J, Plummer E, Daniels K, Kemm M, Townsend CA, Thupari JN, Kuhajda FP, Moran TH, Ronnett GV (2008) Pharmacological stimulation of brain carnitine palmitoyl-transferase-1 decreases food intake and body weight. Am J Physiol Regul Integr Comp Physiol 294:R352–R361

    PubMed  CAS  Google Scholar 

  102. López M, Lage R, Saha AK, Pérez-Tilve D, Vázquez MJ, Varela L, Sangiao-Alvarellos S, Tovar S, Raghay K, Rodríguez-Cuenca S, Deoliveira RM, Castañeda T, Datta R, Dong JZ, Culler M, Sleeman MW, Alvarez CV, Gallego R, Lelliott CJ, Carling D, Tschöp MH, Diéguez C, Vidal-Puig A (2008) Hypothalamic fatty acid metabolism mediates the orexigenic action of ghrelin. Cell Metab 7:389–399

    PubMed  Article  CAS  Google Scholar 

  103. Vladutiu GD, Simmons Z, Isackson PJ, Tarnopolsky M, Peltier WL, Barboi AC, Sripathi N, Wortmann RL, Phillips PS (2006) Genetic risk factors associated with lipid-lowering drug-induced myopathies. Muscle Nerve 34:153–162

    PubMed  CAS  Article  Google Scholar 

  104. Wilke RA, Lin DW, Roden DM, Watkins PB, Flockhart D, Zineh I, Giacomini KM, Krauss RM (2007) Identifying genetic risk factors for serious adverse drug reactions: current progress and challenges. Nat Rev Drug Discov 6:904–916 (Erratum in: Nat Rev Drug Discov 7:185)

    PubMed  CAS  Article  Google Scholar 

  105. Antons KA, Williams CD, Baker SK, Phillips PS (2006) Clinical perspectives of statin-induced rhabdomyolysis. Am J Med 119:400–409

    PubMed  CAS  Article  Google Scholar 

  106. Bergstrom JD, Reitz RC (1980) Studies on carnitine palmitoyl transferase: the similar nature of CPTi (inner form) and CPTo (outer form). Arch Biochem Biophys 204:71–79

    PubMed  CAS  Article  Google Scholar 

  107. Miyazawa S, Ozasa H, Osumi T, Hashimoto T (1983) Purification and properties of carnitine octanoyltransferase and carnitine palmitoyltransferase from rat liver. J Biochem 94:529–542

    PubMed  CAS  Google Scholar 

  108. Ramsay RR, Derrick JP, Friend AS, Tubbs PK (1987) Purification and properties of the soluble carnitine palmitoyltransferase from bovine liver mitochondria. Biochem J 244:271–278

    PubMed  CAS  Google Scholar 

  109. Finocchiaro G, Colombo I, DiDonato S (1990) Purification, characterization and partial amino acid sequences of carnitine palmitoyl-transferase from human liver. FEBS Lett 274:163–166

    PubMed  CAS  Article  Google Scholar 

  110. Woeltje KF, Kuwajima M, Foster DW, McGarry JD (1987) Characterization of the mitochondrial carnitine palmitoyltransferase enzyme system. II. Use of detergents and antibodies. J Biol Chem 262:9822–9827

    PubMed  CAS  Google Scholar 

  111. Dobbins RL, Szczepaniak LS, Bentley B, Esser V, Myhill J, McGarry JD (2001) Prolonged inhibition of muscle carnitine palmitoyltransferase-1 promotes intramyocellular lipid accumulation and insulin resistance in rats. Diabetes 50:123–130

    PubMed  CAS  Article  Google Scholar 

Download references

Acknowledgments

We thank Simona Ceccarelli-Grenz and Odile Chomienne for critical reading of the manuscript.

Author information

Affiliations

  1. F. Hoffmann-La Roche AG, Pharma Research Discovery Technologies, 4070, Basel, Switzerland

    Arne C. Rufer, Ralf Thoma & Michael Hennig

Authors
  1. Arne C. Rufer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ralf Thoma
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Michael Hennig
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michael Hennig.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Rufer, A.C., Thoma, R. & Hennig, M. Structural insight into function and regulation of carnitine palmitoyltransferase. Cell. Mol. Life Sci. 66, 2489–2501 (2009). https://doi.org/10.1007/s00018-009-0035-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00018-009-0035-1

Keywords

  • Type 2 diabetes mellitus
  • Carnitine palmitoyltransferase
  • Enzyme isoforms
  • Malonyl-CoA
  • Drug discovery