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:||Biosynthesis → Metabolic Regulators Biosynthesis|
Expected Taxonomic Range: Eukaryota
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 184.108.40.206), 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]).
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
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
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
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
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
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
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
Showing only 20 references. To show more, press the button "Show all references".
©2014 SRI International, 333 Ravenswood Avenue, Menlo Park, CA 94025-3493