MetaCyc Pathway: L-carnitine biosynthesis
Inferred from experimentTraceable author statement to experimental support

Enzyme View:

Pathway diagram: L-carnitine biosynthesis

This view shows enzymes only for those organisms listed below, in the list of taxa known to possess the pathway. If an enzyme name is shown in bold, there is experimental evidence for this enzymatic activity.

Synonyms: (R)-carnitine biosynthesis

Superclasses: BiosynthesisMetabolic Regulators Biosynthesis

Some taxa known to possess this pathway include : Homo sapiens, Mus musculus, Neurospora crassa, Rattus norvegicus

Expected Taxonomic Range: Eukaryota

General Background

L-carnitine is a zwitterionic, quaternary amine carboxylate. It has essential roles in intermediary metabolism including energy metabolism, hormonal action and stress adaptation. It is present in animals, plants and microorganisms. Its biosynthetic pathway has been characterized in mammals (reviewed in [Vaz02] and fungi [Kaufman77]. Its physiological role in plants is beginning to be determined [Bourdin07]. Its physiological role in bacteria is unknown, although it serves as a nutrient, or as an osmolyte (in [Govindasamy04]. Several bacterial carnitine degradation pathways have been characterized (see L-carnitine degradation I L-carnitine degradation II and L-carnitine degradation III. L-carnitine is used in pharmaceutical and nutritional preparations and methods have been described for its production and separation from its D-carnitine enantiomer [Freimuller02, Castellar98] and reviewed in [Bernal07].

In mammals carnitine is obtained both by endogenous biosynthesis and in the diet. Its homeostasis is also maintained by re-absorption in the kidney. The best characterized role of carnitine is in aiding the transport of activated, long-chain fatty acids into mitochondria for β-oxidation (see mitochondrial L-carnitine shuttle). It also transfers products of peroxisomal β-oxidation into mitochondria for oxidation in the TCA cycle (see TCA cycle II (plants and fungi)). Other functions include modulation of acyl-CoA/CoA ratios, energy storage as acetylcarnitine, and excretion of poorly metabolized acyl groups as carnitine esters (reviewed in [Vaz02]).

About This Pathway

L-carnitine is biosynthesized from N6,N6,N6-trimethyl-L-lysine, a compound generated post-translationally via methylation of protein L-lysine residues in a S-adenosyl-methionine-dependent reaction. Proteins modified in this way include calmodulin, myosin, actin, cytochrome C and histones. When these proteins are degraded in lysosomes, N6,N6,N6-trimethyl-L-lysine is released. The rate of carnitine biosynthesis depends upon the availability of N6,N6,N6-trimethyl-L-lysine in the mitochondrial matrix at the site of ε-N-trimethyllysine hydroxylase activity. A transport system for this substrate and the product 3-hydroxy-N6,N6,N6-trimethyl-L-lysine has been postulated [vanVlies07]. Reviewed in [Vaz02] and [Steiber].

The pathway involves C3 hydroxylation of N6,N6,N6-trimethyl-L-lysine by an enzyme found in kidney, liver, heart, muscle and brain mitochondria. L-ascorbate (vitamin C) is required to maintain the iron cofactor of this enzyme in the ferrous state. A cytosolic aldolase located in liver and various other tissues then produces 4-trimethylammoniobutanal. It has been suggested that this enzyme is identical to cytosolic serine hydroxymethyltransferase (EC, but this has not been confirmed (reviewed in [Vaz02]. After dehydrogenation to γ-butyrobetaine in the cytosol, this compound enters the circulation and is actively transported primarily into the kidney and liver. In these organs a cytosolic enzyme hydroxylates this compound at C3 to produce L-carnitine. In this reaction, L-ascorbate is again required to maintain the ferrous iron cofactor. L-carnitine enters the circulation and is taken up by other tissues via active, sodium-dependent transporters (reviewed in [Steiber]).

Unification Links: KEGG:map00310, Reactome:REACT_2125

Created 17-Nov-2008 by Fulcher CA, SRI International


Bernal07: Bernal V, Sevilla A, Canovas M, Iborra JL (2007). "Production of L-carnitine by secondary metabolism of bacteria." Microb Cell Fact 6;31. PMID: 17910757

Bourdin07: Bourdin B, Adenier H, Perrin Y (2007). "Carnitine is associated with fatty acid metabolism in plants." Plant Physiol Biochem 45(12);926-31. PMID: 17988884

Castellar98: Castellar MR, Canovas M, Kleber HP, Iborra JL (1998). "Biotransformation of D(+)-carnitine into L(-)-carnitine by resting cells of Escherichia coli O44 K74." J Appl Microbiol 85(5);883-90. PMID: 9830124

Freimuller02: Freimuller S, Altorfer H (2002). "A chiral HPLC method for the determination of low amounts of D-carnitine in L-carnitine after derivatization with (+)-FLEC." J Pharm Biomed Anal 30(2);209-218. PMID: 12191705

Govindasamy04: 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(3);416-24. PMID: 15099582

Hulse78: Hulse JD, Ellis SR, Henderson LM (1978). "Carnitine biosynthesis. beta-Hydroxylation of trimethyllysine by an alpha-ketoglutarate-dependent mitochondrial dioxygenase." J Biol Chem 253(5);1654-9. PMID: 627563

Kaufman77: Kaufman RA, Broquist HP (1977). "Biosynthesis of carnitine in Neurospora crassa." J Biol Chem 252(21);7437-9. PMID: 144128

Steiber: Steiber A, Kerner J, Hoppel CL "Carnitine: a nutritional, biosynthetic, and functional perspective." Mol Aspects Med 25(5-6);455-73. PMID: 15363636

vanVlies06: van Vlies N, Wanders RJ, Vaz FM (2006). "Measurement of carnitine biosynthesis enzyme activities by tandem mass spectrometry: differences between the mouse and the rat." Anal Biochem 354(1);132-9. PMID: 16707092

vanVlies07: van Vlies N, Ofman R, Wanders RJ, Vaz FM (2007). "Submitochondrial localization of 6-N-trimethyllysine dioxygenase - implications for carnitine biosynthesis." FEBS J 274(22);5845-51. PMID: 17944936

Vaz02: Vaz FM, Wanders RJ (2002). "Carnitine biosynthesis in mammals." Biochem J 361(Pt 3);417-29. PMID: 11802770

Other References Related to Enzymes, Genes, Subpathways, and Substrates of this Pathway

CelestinoSoper11: Celestino-Soper PB, Shaw CA, Sanders SJ, Li J, Murtha MT, Ercan-Sencicek AG, Davis L, Thomson S, Gambin T, Chinault AC, Ou Z, German JR, Milosavljevic A, Sutcliffe JS, Cook EH, Stankiewicz P, State MW, Beaudet AL (2011). "Use of array CGH to detect exonic copy number variants throughout the genome in autism families detects a novel deletion in TMLHE." Hum Mol Genet 20(22);4360-70. PMID: 21865298

Galland98: Galland S, Le Borgne F, Guyonnet D, Clouet P, Demarquoy J (1998). "Purification and characterization of the rat liver gamma-butyrobetaine hydroxylase." Mol Cell Biochem 178(1-2);163-8. PMID: 9546596

Galland99: Galland S, Le Borgne F, Bouchard F, Georges B, Clouet P, Grand-Jean F, Demarquoy J (1999). "Molecular cloning and characterization of the cDNA encoding the rat liver gamma-butyrobetaine hydroxylase." Biochim Biophys Acta 1441(1);85-92. PMID: 10526231

Kikonyogo96: Kikonyogo A, Pietruszko R (1996). "Aldehyde dehydrogenase from adult human brain that dehydrogenates gamma-aminobutyraldehyde: purification, characterization, cloning and distribution." Biochem J 316 ( Pt 1);317-24. PMID: 8645224

Kleber97: Kleber HP (1997). "Bacterial carnitine metabolism." FEMS Microbiol Lett 147(1);1-9. PMID: 9037756

Kurys89: Kurys G, Ambroziak W, Pietruszko R (1989). "Human aldehyde dehydrogenase. Purification and characterization of a third isozyme with low Km for gamma-aminobutyraldehyde." J Biol Chem 264(8);4715-21. PMID: 2925663

Kurys93: Kurys G, Shah PC, Kikonygo A, Reed D, Ambroziak W, Pietruszko R (1993). "Human aldehyde dehydrogenase. cDNA cloning and primary structure of the enzyme that catalyzes dehydrogenation of 4-aminobutyraldehyde." Eur J Biochem 218(2);311-20. PMID: 8269919

Latendresse13: Latendresse M. (2013). "Computing Gibbs Free Energy of Compounds and Reactions in MetaCyc."

Lin96: Lin SW, Chen JC, Hsu LC, Hsieh CL, Yoshida A (1996). "Human gamma-aminobutyraldehyde dehydrogenase (ALDH9): cDNA sequence, genomic organization, polymorphism, chromosomal localization, and tissue expression." Genomics 34(3);376-80. PMID: 8786138

Lindstedt70: Lindstedt G, Lindstedt S (1970). "Cofactor requirements of gamma-butyrobetaine hydroxylase from rat liver." J Biol Chem 245(16);4178-86. PMID: 4396068

Lindstedt77: Lindstedt G, Lindstedt S, Nordin I (1977). "Purification and properties of γ-butyrobetaine hydroxylase from Pseudomonas sp AK 1." Biochemistry 16(10);2181-8. PMID: 861203

Lindstedt84: Lindstedt S, Nordin I (1984). "Multiple forms of gamma-butyrobetaine hydroxylase (EC" Biochem J 223(1);119-27. PMID: 6497835

McPherson94: McPherson JD, Wasmuth JJ, Kurys G, Pietruszko R (1994). "Human aldehyde dehydrogenase: chromosomal assignment of the gene for the isozyme that metabolizes gamma-aminobutyraldehyde." Hum Genet 93(2);211-2. PMID: 8112751

Monfregola05: Monfregola J, Cevenini A, Terracciano A, van Vlies N, Arbucci S, Wanders RJ, D'Urso M, Vaz FM, Ursini MV (2005). "Functional analysis of TMLH variants and definition of domains required for catalytic activity and mitochondrial targeting." J Cell Physiol 204(3);839-47. PMID: 15754339

Olson87: Olson AL, Rebouche CJ (1987). "gamma-Butyrobetaine hydroxylase activity is not rate limiting for carnitine biosynthesis in the human infant." J Nutr 117(6);1024-31. PMID: 3110383

Rebouche80: Rebouche CJ, Engel AG (1980). "Tissue distribution of carnitine biosynthetic enzymes in man." Biochim Biophys Acta 630(1);22-9. PMID: 6770910

Rebouche91: Rebouche CJ (1991). "Ascorbic acid and carnitine biosynthesis." Am J Clin Nutr 54(6 Suppl);1147S-1152S. PMID: 1962562

Rebouche98: Rebouche CJ, Seim H (1998). "Carnitine metabolism and its regulation in microorganisms and mammals." Annu Rev Nutr 18;39-61. PMID: 9706218

Ruetschi93: Ruetschi U, Nordin I, Odelhog B, Jornvall H, Lindstedt S (1993). "γ-butyrobetaine hydroxylase. Structural characterization of the Pseudomonas enzyme." Eur J Biochem 213(3);1075-80. PMID: 8504802

Sachan80: Sachan DS, Hoppel CL (1980). "Carnitine biosynthesis. Hydroxylation of N6-trimethyl-lysine to 3-hydroxy-N6-trimethyl-lysine." Biochem J 188(2);529-34. PMID: 6772170

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Please cite the following article in publications resulting from the use of MetaCyc: Caspi et al, Nucleic Acids Research 42:D459-D471 2014
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