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MetaCyc Pathway: superpathway of trimethylamine degradation
Inferred from experiment

Enzyme View:

Pathway diagram: superpathway of trimethylamine degradation

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.

Superclasses: Degradation/Utilization/AssimilationAmines and Polyamines Degradation

Some taxa known to possess this pathway include : Aminobacter aminovorans, Methylocella silvestris, Methyloversatilis universalis, Methylovorus mays

Expected Taxonomic Range: Bacteria

General Background

Methylated amines are ubiquitous in the environment, especially in the marine ecosystem. They are produced by the degradation of proteins and of quartenary amines such as glycine betaine, carnitine, choline, and trimethylamine N-oxide, which are common osmolytes of many marine organisms.

The most methylated form, trimethylamine (TMA), can be converted to methane by methanogenic archaea via methanogenesis (see methanogenesis from trimethylamine). In addition, some microorganisms are able to use TMA as the sole source for carbon, nitrogen and energy. TMA is first converted in several steps to methylamine (MMA), which can be oxidized further by multiple mechanisms, depending on the bacteria. Bacteria that possess the enzyme methylamine dehydrogenase ( EC, can oxidize methylamine to formaldehyde and ammonia is a single reaction (see methylamine degradation I). MMA-degrading bacteria that lack that enzyme can achieve the same outcome by a pathway that proceeds via two unusual amino acids - N5-methyl-L-glutamine and N-methyl-L-glutamate, as described here. The microbial oxidation of methylated amines is an important component of environmental cycling of carbon and nitrogen, as well as an essential step in preventing formation of methane, the second most important greenhouse gas following carbon dioxide [Latypova10].

About This Pathway

The intermediates of this pathway were discovered in the 1960s and a preliminary pathway has been proposed [Shaw66]. The original pathway involved two key enzymes, N-methyl-L-glutamate synthase (EC and methylglutamate dehydrogenase (EC The first enzyme was believed to convert methylamine into N-methyl-L-glutamate [Shaw66, Pollock71] and the second to cleave the latter to formaldehyde and glutamate [Hersh71, Hersh72]. In a parallel route, an enzyme that converts methylamine into N5-methyl-L-glutamine ( glutamate--methylamine ligase, EC has also been reported [Kung69]. The relation between these two branches has not been clear. A potential solution has been proposed in a much later study involving the bacterium Methylocella silvestris, according to which the actual in vivo substrate of EC is N5-methyl-L-glutamine rather than methylamine [Chen10a]. This proposal is supported by the observation that N5-methyl-L-glutamine is converted to N-methyl-L-glutamate, as determined by radiotracer work in Hyphomicrobium vulgare [Loginova76]. Based on this proposal, all three enzymes form a linear route, with methylamine first converted to N5-methyl-L-glutamine, which is subsequently converted to N-methyl-L-glutamate and oxidized to formaldehyde and glutamate [Chen10a].

The methyl groups are released in this pathway in the form of formaldehyde, which can be assimilated via the serine pathway or oxidized to CO2. The nitrogen is released in the form of ammonia and can be assimilated via the GS/GOGAT pathway.

Subpathways: trimethylamine degradation, methylamine degradation II

Created 08-Dec-2011 by Caspi R, SRI International


Chen10a: Chen Y, Scanlan J, Song L, Crombie A, Rahman MT, Schafer H, Murrell JC (2010). "{gamma}-Glutamylmethylamide is an essential intermediate in the metabolism of methylamine by Methylocella silvestris." Appl Environ Microbiol 76(13);4530-7. PMID: 20472738

Hersh71: Hersh LB, Peterson JA, Thompson AA (1971). "An N-methyl glutamate dehydrogenase from Pseudomonas M.A." Arch Biochem Biophys 145(1);115-20. PMID: 4399353

Hersh72: Hersh LB, Stark MJ, Worthen S, Fiero MK (1972). "N-methylglutamate dehydrogenase: kinetic studies on the solubilized enzyme." Arch Biochem Biophys 150(1);219-26. PMID: 5028076

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

Kung69: Kung HF, Wagner C (1969). "Gamma-glutamylmethylamide. A new intermediate in the metabolism of methylamine." J Biol Chem 244(15);4136-40. PMID: 5800436

Latypova10: Latypova E, Yang S, Wang YS, Wang T, Chavkin TA, Hackett M, Schafer H, Kalyuzhnaya MG (2010). "Genetics of the glutamate-mediated methylamine utilization pathway in the facultative methylotrophic beta-proteobacterium Methyloversatilis universalis FAM5." Mol Microbiol 75(2);426-39. PMID: 19943898

Loginova76: Loginova NV, Shishkina VN, Trotsenko IU (1976). "[Primary metabolic pathways of methylated amines in Hyphomicrobium vulgare]." Mikrobiologiia 45(1);41-7. PMID: 940497

Pollock71: Pollock RJ, Hersh LB (1971). "N-methylglutamate synthetase. Purification and properties of the enzyme." J Biol Chem 246(15);4737-43. PMID: 5562354

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

Shaw66: Shaw WV, Tsai L, Stadtman ER (1966). "The enzymatic synthesis of N-methylglutamic acid." J Biol Chem 241(4);935-45. PMID: 5905132

Skulachev00: Skulachev VP (2000). "Biological role of carnosine in the functioning of excitable tissues.Centenary of Gulewitsch's discovery." Biochemistry (Mosc) 65(7);749-50. PMID: 11183736

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

Akerman99: Akerman BR, Lemass H, Chow LM, Lambert DM, Greenberg C, Bibeau C, Mamer OA, Treacy EP (1999). "Trimethylaminuria is caused by mutations of the FMO3 gene in a North American cohort." Mol Genet Metab 68(1);24-31. PMID: 10479479

Bamforth77: Bamforth CW, Large PJ (1977). "Solubilization, partial purification and properties of N-methylglutamate dehydrogenase from Pseudomonas aminovorans." Biochem J 161(2);357-70. PMID: 15545

Bennett13: Bennett BJ, de Aguiar Vallim TQ, Wang Z, Shih DM, Meng Y, Gregory J, Allayee H, Lee R, Graham M, Crooke R, Edwards PA, Hazen SL, Lusis AJ (2013). "Trimethylamine-N-oxide, a metabolite associated with atherosclerosis, exhibits complex genetic and dietary regulation." Cell Metab 17(1);49-60. PMID: 23312283

Chen11a: Chen Y, Patel NA, Crombie A, Scrivens JH, Murrell JC (2011). "Bacterial flavin-containing monooxygenase is trimethylamine monooxygenase." Proc Natl Acad Sci U S A 108(43);17791-6. PMID: 22006322

Halsey12: Halsey KH, Carter AE, Giovannoni SJ (2012). "Synergistic metabolism of a broad range of C1 compounds in the marine methylotrophic bacterium HTCC2181." Environ Microbiol 14(3);630-40. PMID: 21981742

Kalyuzhnaya06: Kalyuzhnaya MG, De Marco P, Bowerman S, Pacheco CC, Lara JC, Lidstrom ME, Chistoserdova L (2006). "Methyloversatilis universalis gen. nov., sp. nov., a novel taxon within the Betaproteobacteria represented by three methylotrophic isolates." Int J Syst Evol Microbiol 56(Pt 11);2517-22. PMID: 17082383

Koeth13: Koeth RA, Wang Z, Levison BS, Buffa JA, Org E, Sheehy BT, Britt EB, Fu X, Wu Y, Li L, Smith JD, DiDonato JA, Chen J, Li H, Wu GD, Lewis JD, Warrier M, Brown JM, Krauss RM, Tang WH, Bushman FD, Lusis AJ, Hazen SL (2013). "Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis." Nat Med 19(5);576-85. PMID: 23563705

Large71: Large PJ (1971). "Non-oxidative demethylation of trimethylamine N-oxide by Pseudomonas aminovorans." FEBS Lett 18(2);297-300. PMID: 11946146

Large72: Large PJ, Boulton CA, Crabbe MJ (1972). "The reduced nicotinamide-adenine dinucleotide phosphate- and oxygen-dependent N-oxygenation of trimethylamine by Pseudomonas aminovorans." Biochem J 128(4);137P-138P. PMID: 4404764

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

Lidbury14: Lidbury I, Murrell JC, Chen Y (2014). "Trimethylamine N-oxide metabolism by abundant marine heterotrophic bacteria." Proc Natl Acad Sci U S A 111(7);2710-5. PMID: 24550299

Myers71: Myers PA, Zatman LJ (1971). "The metabolism of trimethylamine N-oxide by Bacillus PM6." Biochem J 121(1);10P. PMID: 5116524

Sun11a: Sun J, Steindler L, Thrash JC, Halsey KH, Smith DP, Carter AE, Landry ZC, Giovannoni SJ (2011). "One carbon metabolism in SAR11 pelagic marine bacteria." PLoS One 6(8);e23973. PMID: 21886845

Tang13a: Tang WH, Wang Z, Levison BS, Koeth RA, Britt EB, Fu X, Wu Y, Hazen SL (2013). "Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk." N Engl J Med 368(17);1575-84. PMID: 23614584

Wang11d: Wang Z, Klipfell E, Bennett BJ, Koeth R, Levison BS, Dugar B, Feldstein AE, Britt EB, Fu X, Chung YM, Wu Y, Schauer P, Smith JD, Allayee H, Tang WH, DiDonato JA, Lusis AJ, Hazen SL (2011). "Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease." Nature 472(7341);57-63. PMID: 21475195

Yamamoto07: Yamamoto S, Wakayama M, Tachiki T (2007). "Characterization of theanine-forming enzyme from Methylovorus mays no. 9 in respect to utilization of theanine production." Biosci Biotechnol Biochem 71(2);545-52. PMID: 17284842

Yamamoto08a: Yamamoto S, Wakayama M, Tachiki T (2008). "Cloning and expression of Methylovorus mays No. 9 gene encoding gamma-glutamylmethylamide synthetase: an enzyme usable in theanine formation by coupling with the alcoholic fermentation system of baker's yeast." Biosci Biotechnol Biochem 72(1);101-9. PMID: 18175924

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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
Page generated by Pathway Tools version 19.5 (software by SRI International) on Mon May 2, 2016, biocyc13.