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Carnitine biosynthesis
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Carnitine biosynthesis : ウィキペディア英語版
Carnitine biosynthesis
Carnitine biosynthesis is a method for the endogenous production of L-carnitine, a molecule that is essential for energy metabolism.〔(Activation and Transportation of Fatty Acids for Metabolism via Carnitine Shuttle Pathway (with Animation) )〕〔Fraenkel, G.; Friedman, S. Carnitine. ''Vitam. Horm.'' 1957, ''15'', 73–118.〕〔Bremer, J. Carnitine – metabolism and functions. ''Physiol. Rev.'' 1983, ''63'', 1420–1480.〕〔Steiber, A.; Kerner, J.; Hoppel, C. L. Carnitine: a nutritional, biosynthetic, and functional perspective. ''Mol. Aspects Med.'' 2004, ''25'', 455–473.〕 In humans and many other animals, L-carnitine is obtained from both diet and by biosynthesis.〔Rebouche, C. J. Carnitine function and requirements during the life cycle. ''FASEB J.'' 1992, ''6'', 3379–3386.〕〔Lennon, D. L.; Shrago, E. R.; Madden, M.; Nagle, F. J.; Hanson, P. Dietary carnitine intake related to skeletal muscle and plasma carnitine concentrations in adult men and women. ''Am. J. Clin. Nutr.'' 1986, ''43'', 234–238.〕 The carnitine biosynthesis pathway is highly conserved among many eukaryotes and some prokaryotes.〔Lindstedt, G.; Lindstedt, S.; Midtvedt, T.; Tofft, M. The formation and degradation of carnitine in Pseudomonas. ''Biochemistry'' 1967, ''6'', 1262–1270.〕〔Vaz, F. M.; Wanders, R. J. A. Carnitine biosynthesis in mammals. ''Biochem. J.'' 2002, ''361'', 417–429.〕〔Strijbis, K.; Vaz, F, M.; Distel, B. Enzymology of the carnitine biosynthesis pathway. ''IUBMB Life'' 2010, ''62'', 357–362.〕
L-Carnitine is biosynthesized from ''N''ε-trimethyllysine.〔Hulse, J. D.; Ellis, S. R.; Henderson, L. M. Carnitine biosynthesis. β-Hydroxylation of trimethyllysine by an α-ketoglutarate-dependent mitochondrial dioxygenase. ''J. Biol. Chem.'' 1978, ''253'', 1654–1659.〕 At least four enzymes are involved in the overall biosynthetic pathway. They are ''N''ε-trimethyllysine hydroxylase, 3-hydroxy-''N''ε-trimethyllysine aldolase, 4-''N''-trimethylaminobutyraldehyde dehydrogenase and γ-butyrobetaine hydroxylase.
== ''N''ε-Trimethyllysine hydroxylase ==
(詳細はbiosynthetic pathway is ''N''ε-trimethyllysine hydroxylase. ''N''ε-trimethyllysine hydroxylase is an iron(II) and 2-oxoglutarate (2OG) dependent oxygenase.〔Vaz, F. M.; Ofman, R.; Westinga, K.; Back, J. W.; Wanders, R. J. A. Molecular and biochemical characterization of rat ε-''N''-trimethyllysine hydroxylase, the first enzyme of carnitine biosynthesis. ''J. Biol. Chem.'' 2001, ''276'', 33512–33517.〕 ''N''ε-trimethyllysine hydroxylase catalyses the hydroxylation reaction of ''N''ε-trimethyllysine to 3-hydroxy-''N''ε-trimethyllysine.
The current consensus theory about the origin of ''N''ε-trimethyllysine in mammals is that mammals utilise lysosomal or proteasomal degradation of proteins containing ''N''ε-trimethyllysine residues as starting point for carnitine biosynthesis.〔Bremer, J. Biosynthesis of carnitine ''in vivo''. ''Biochim. Biophys. Acta'' 1961, ''48'', 622–624.〕〔Wolf, G.; Berger, C. R. A. Studies on the biosynthesis and turnover of carnitine. ''Arch. Biochem. Biophys. 1961, 92'', 360–365.〕〔Paik, W. K.; Nochumson, S.; Kim, S. Carnitine biosynthesis via protein methylation. ''Trends Biochem. Sci.'' 1977, ''2'', 159–161.〕 An alternative theory involving endogenous non-peptidyl biosynthesis was also proposed, based on evidence gathered from a study involving feeding normal and undernourished human subjects with the amino acid lysine.〔Khan-Siddiqui, L.; Bamji, M. S. Lysine-carnitine conversion in normal and undernourished adult man – suggestion of a nonpeptidyl pathway. ''Am. J. Clin. Nutr.'' 1983, ''37'', 93–98.〕 Although ''N''ε-trimethyllysine biosynthetic pathway involving ''N''ε-trimethyllysine methyltransferase has been fully characterised in fungi including ''Neurospora crassa'', such biosynthetic pathway has never been properly characterised in mammals or humans.〔Rebouche, C. J.; Broquist, H. P. Carnitine biosynthesis in ''Neurospora crassa'': enzymatic conversion of lysine to ε-''N''-trimethyllysine. ''J. Bacteriol.'' 1976, ''126'', 1207–1214.〕 A third theory about the origin of ''N''ε-trimethyllysine in mammals involves dietary intake from vegetable foods, as high-performance liquid chromatography (HPLC) analysis confirmed that vegetables contained a significant amount of ''N''ε-trimethyllysine.〔Servillo, L.; Giovane, A.; Cautela, D.; Castaldo, D.; Balestrieri, M. L. Where Does Nε-Trimethyllysine for the Carnitine Biosynthesis in Mammals Come from? ''PLoS ONE'' 2014, ''9'', e84589.〕

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