Loading Pathway...
Error: Pathway image not found.
Hide
Pathway Description
Sarcosine Oncometabolite Pathway
Rattus norvegicus
Category:
Metabolite Pathway
Sub-Category:
Disease
Created: 2018-08-31
Last Updated: 2019-09-22
Sarcosine is a compound derived from the amino acid glycine and is involved in both its synthesis and degradation, and is an intermediate in the metabolism of choline to glycine. In cases of prostate cancer, the cancer cells seem to produce higher levels of sarcosine. Elevated levels of sarcosine found in the urine of patients with prostate cancer, and it has been suggested that these elevated levels are responsible for the development of the cancer.
This pathway begins with choline’s transport into the mitochondrial matrix via xolute carrier family protein 44 A1 and the choline transporter-like protein 2. Once in the matrix, choline is oxidized to betaine aldehyde by choline dehydrogenase, and in the process reduces an acceptor. Betaine aldehyde is then converted to betaine by the addition of a water molecule by alpha-aminoadipic semialdehyde dehydrogenase. Following this, betaine is transported out of the mitochondria by an unknown transporter, where it then reacts with homocysteine to form dimethylglycine and L-methionine in a reaction catalyzed by betaine-homocysteine S-methyltransferase 1. The dimethylglycine is then transported back into the mitochondrial matrix by another unknown transporter, where it can react with tetrahydrofolate to form sarcosine and 5-methyltetrahydrofolic acid in a reaction catalyzed by dimethylglycine dehydrogenase. In at least some cases of prostate cancer cells, the SARDH gene is mutated, which encodes the sarcosine dehydrogenase protein. This can lead to an increase of sarcosine in the cells, as sarcosine dehydrogenase typically converts sarcosine to glycine, which is then converted to and from L-serine by serine hydroxymethyltransferase. With a non-functional or less functional enzyme, sarcosine levels will be increased, and serine and glycine levels will be reduced.
A separate set of reactions outside of the mitochondria begins with the L-methionine produced by betaine—homocysteine S-methyltransferase 1, which is then converted to S-adenosylmethionine by a complex consisting of S-adenosylmethionine synthase and methionine adenosyltransferase. S-adenosylmethionine then reacts with glycine reversibly to form S-adenosylhomocysteine, as well as sarcosine. The expression of the gene encoding glycine N-methyltransferase, GNMT, can also be elevated in cancer tissues, leading to an increased concentration of sarcosine outside of the mitochondria as well.
References
Sarcosine Oncometabolite Pathway References
Khan AP, Rajendiran TM, Ateeq B, Asangani IA, Athanikar JN, Yocum AK, Mehra R, Siddiqui J, Palapattu G, Wei JT, Michailidis G, Sreekumar A, Chinnaiyan AM: The role of sarcosine metabolism in prostate cancer progression. Neoplasia. 2013 May;15(5):491-501.
Pubmed: 23633921
Huang S, Lin Q: Functional expression and processing of rat choline dehydrogenase precursor. Biochem Biophys Res Commun. 2003 Sep 19;309(2):344-50. doi: 10.1016/j.bbrc.2003.08.010.
Pubmed: 12951056
Gibbs RA, Weinstock GM, Metzker ML, Muzny DM, Sodergren EJ, Scherer S, Scott G, Steffen D, Worley KC, Burch PE, Okwuonu G, Hines S, Lewis L, DeRamo C, Delgado O, Dugan-Rocha S, Miner G, Morgan M, Hawes A, Gill R, Celera, Holt RA, Adams MD, Amanatides PG, Baden-Tillson H, Barnstead M, Chin S, Evans CA, Ferriera S, Fosler C, Glodek A, Gu Z, Jennings D, Kraft CL, Nguyen T, Pfannkoch CM, Sitter C, Sutton GG, Venter JC, Woodage T, Smith D, Lee HM, Gustafson E, Cahill P, Kana A, Doucette-Stamm L, Weinstock K, Fechtel K, Weiss RB, Dunn DM, Green ED, Blakesley RW, Bouffard GG, De Jong PJ, Osoegawa K, Zhu B, Marra M, Schein J, Bosdet I, Fjell C, Jones S, Krzywinski M, Mathewson C, Siddiqui A, Wye N, McPherson J, Zhao S, Fraser CM, Shetty J, Shatsman S, Geer K, Chen Y, Abramzon S, Nierman WC, Havlak PH, Chen R, Durbin KJ, Egan A, Ren Y, Song XZ, Li B, Liu Y, Qin X, Cawley S, Worley KC, Cooney AJ, D'Souza LM, Martin K, Wu JQ, Gonzalez-Garay ML, Jackson AR, Kalafus KJ, McLeod MP, Milosavljevic A, Virk D, Volkov A, Wheeler DA, Zhang Z, Bailey JA, Eichler EE, Tuzun E, Birney E, Mongin E, Ureta-Vidal A, Woodwark C, Zdobnov E, Bork P, Suyama M, Torrents D, Alexandersson M, Trask BJ, Young JM, Huang H, Wang H, Xing H, Daniels S, Gietzen D, Schmidt J, Stevens K, Vitt U, Wingrove J, Camara F, Mar Alba M, Abril JF, Guigo R, Smit A, Dubchak I, Rubin EM, Couronne O, Poliakov A, Hubner N, Ganten D, Goesele C, Hummel O, Kreitler T, Lee YA, Monti J, Schulz H, Zimdahl H, Himmelbauer H, Lehrach H, Jacob HJ, Bromberg S, Gullings-Handley J, Jensen-Seaman MI, Kwitek AE, Lazar J, Pasko D, Tonellato PJ, Twigger S, Ponting CP, Duarte JM, Rice S, Goodstadt L, Beatson SA, Emes RD, Winter EE, Webber C, Brandt P, Nyakatura G, Adetobi M, Chiaromonte F, Elnitski L, Eswara P, Hardison RC, Hou M, Kolbe D, Makova K, Miller W, Nekrutenko A, Riemer C, Schwartz S, Taylor J, Yang S, Zhang Y, Lindpaintner K, Andrews TD, Caccamo M, Clamp M, Clarke L, Curwen V, Durbin R, Eyras E, Searle SM, Cooper GM, Batzoglou S, Brudno M, Sidow A, Stone EA, Venter JC, Payseur BA, Bourque G, Lopez-Otin C, Puente XS, Chakrabarti K, Chatterji S, Dewey C, Pachter L, Bray N, Yap VB, Caspi A, Tesler G, Pevzner PA, Haussler D, Roskin KM, Baertsch R, Clawson H, Furey TS, Hinrichs AS, Karolchik D, Kent WJ, Rosenbloom KR, Trumbower H, Weirauch M, Cooper DN, Stenson PD, Ma B, Brent M, Arumugam M, Shteynberg D, Copley RR, Taylor MS, Riethman H, Mudunuri U, Peterson J, Guyer M, Felsenfeld A, Old S, Mockrin S, Collins F: Genome sequence of the Brown Norway rat yields insights into mammalian evolution. Nature. 2004 Apr 1;428(6982):493-521. doi: 10.1038/nature02426.
Pubmed: 15057822
Gerhard DS, Wagner L, Feingold EA, Shenmen CM, Grouse LH, Schuler G, Klein SL, Old S, Rasooly R, Good P, Guyer M, Peck AM, Derge JG, Lipman D, Collins FS, Jang W, Sherry S, Feolo M, Misquitta L, Lee E, Rotmistrovsky K, Greenhut SF, Schaefer CF, Buetow K, Bonner TI, Haussler D, Kent J, Kiekhaus M, Furey T, Brent M, Prange C, Schreiber K, Shapiro N, Bhat NK, Hopkins RF, Hsie F, Driscoll T, Soares MB, Casavant TL, Scheetz TE, Brown-stein MJ, Usdin TB, Toshiyuki S, Carninci P, Piao Y, Dudekula DB, Ko MS, Kawakami K, Suzuki Y, Sugano S, Gruber CE, Smith MR, Simmons B, Moore T, Waterman R, Johnson SL, Ruan Y, Wei CL, Mathavan S, Gunaratne PH, Wu J, Garcia AM, Hulyk SW, Fuh E, Yuan Y, Sneed A, Kowis C, Hodgson A, Muzny DM, McPherson J, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madari A, Young AC, Wetherby KD, Granite SJ, Kwong PN, Brinkley CP, Pearson RL, Bouffard GG, Blakesly RW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Griffith M, Griffith OL, Krzywinski MI, Liao N, Morin R, Palmquist D, Petrescu AS, Skalska U, Smailus DE, Stott JM, Schnerch A, Schein JE, Jones SJ, Holt RA, Baross A, Marra MA, Clifton S, Makowski KA, Bosak S, Malek J: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome Res. 2004 Oct;14(10B):2121-7. doi: 10.1101/gr.2596504.
Pubmed: 15489334
Lee P, Kuhl W, Gelbart T, Kamimura T, West C, Beutler E: Homology between a human protein and a protein of the green garden pea. Genomics. 1994 May 15;21(2):371-8. doi: 10.1006/geno.1994.1279.
Pubmed: 8088832
Skvorak AB, Robertson NG, Yin Y, Weremowicz S, Her H, Bieber FR, Beisel KW, Lynch ED, Beier DR, Morton CC: An ancient conserved gene expressed in the human inner ear: identification, expression analysis, and chromosomal mapping of human and mouse antiquitin (ATQ1). Genomics. 1997 Dec 1;46(2):191-9. doi: 10.1006/geno.1997.5026.
Pubmed: 9417906
Forestier M, Reichen J, Solioz M: Application of mRNA differential display to liver cirrhosis: reduced fetuin expression in biliary cirrhosis in the rat. Biochem Biophys Res Commun. 1996 Aug 14;225(2):377-83. doi: 10.1006/bbrc.1996.1183.
Pubmed: 8753772
Sowden MP, Collins HL, Smith HC, Garrow TA, Sparks JD, Sparks CE: Apolipoprotein B mRNA and lipoprotein secretion are increased in McArdle RH-7777 cells by expression of betaine-homocysteine S-methyltransferase. Biochem J. 1999 Aug 1;341 ( Pt 3):639-45.
Pubmed: 10417327
Yamada K, Tobimatsu T, Toraya T: Cloning, sequencing, and heterologous expression of rat methionine synthase cDNA. Biosci Biotechnol Biochem. 1998 Nov;62(11):2155-60.
Pubmed: 9972236
Lundby A, Secher A, Lage K, Nordsborg NB, Dmytriyev A, Lundby C, Olsen JV: Quantitative maps of protein phosphorylation sites across 14 different rat organs and tissues. Nat Commun. 2012 Jun 6;3:876. doi: 10.1038/ncomms1871.
Pubmed: 22673903
Horikawa S, Sasuga J, Shimizu K, Ozasa H, Tsukada K: Molecular cloning and nucleotide sequence of cDNA encoding the rat kidney S-adenosylmethionine synthetase. J Biol Chem. 1990 Aug 15;265(23):13683-6.
Pubmed: 1696256
Hiroki T, Horikawa S, Tsukada K: Structure of the rat methionine adenosyltransferase 2A gene and its promoter. Eur J Biochem. 1997 Dec 15;250(3):653-60. doi: 10.1111/j.1432-1033.1997.00653.x.
Pubmed: 9461287
Kim JS, Coon SL, Blackshaw S, Cepko CL, Moller M, Mukda S, Zhao WQ, Charlton CG, Klein DC: Methionine adenosyltransferase:adrenergic-cAMP mechanism regulates a daily rhythm in pineal expression. J Biol Chem. 2005 Jan 7;280(1):677-84. doi: 10.1074/jbc.M408438200. Epub 2004 Oct 25.
Pubmed: 15504733
Lang H, Polster M, Brandsch R: Rat liver dimethylglycine dehydrogenase. Flavinylation of the enzyme in hepatocytes in primary culture and characterization of a cDNA clone. Eur J Biochem. 1991 Jun 15;198(3):793-9. doi: 10.1111/j.1432-1033.1991.tb16083.x.
Pubmed: 1710985
Cook RJ, Misono KS, Wagner C: The amino acid sequences of the flavin-peptides of dimethylglycine dehydrogenase and sarcosine dehydrogenase from rat liver mitochondria. J Biol Chem. 1985 Oct 25;260(24):12998-3002.
Pubmed: 4055729
Porter DH, Cook RJ, Wagner C: Enzymatic properties of dimethylglycine dehydrogenase and sarcosine dehydrogenase from rat liver. Arch Biochem Biophys. 1985 Dec;243(2):396-407. doi: 10.1016/0003-9861(85)90516-8.
Pubmed: 2417560
This pathway was propagated using PathWhiz -
Pon, A. et al. Pathways with PathWhiz (2015) Nucleic Acids Res. 43(Web Server issue): W552–W559.
Propagated from SMP0002313
Highlighted elements will appear in red.
Highlight Compounds
Highlight Proteins
Enter relative concentration values (without units). Elements will be highlighted in a color gradient where red = lowest concentration and green = highest concentration. For the best results, view the pathway in Black and White.
Visualize Compound Data
Visualize Protein Data
Downloads
Settings