Loading Pathway...
Error: Pathway image not found.
Hide
Pathway Description
Threonine and 2-Oxobutanoate Degradation
Mus musculus
Category:
Metabolite Pathway
Sub-Category:
Metabolic
Created: 2018-01-21
Last Updated: 2019-08-16
2-oxobutanoate, also known as 2-Ketobutyric acid, is a 2-keto acid that is commonly produced in the metabolism of amino acids such as methionine and threonine. Like other 2-keto acids, degradation of 2-oxobutanoate occurs in the mitochondrial matrix and begins with oxidative decarboxylation to its acyl coenzyme A derivative, propionyl-CoA. This reaction is mediated by a class of large, multienzyme complexes called 2-oxo acid dehydrogenase complexes. While no 2-oxo acid dehydrogenase complex is specific to 2-oxobutanoate, numerous complexes can catalyze its reaction. In this pathway the branched-chain alpha-keto acid dehydrogenase complex is depicted. All 2-oxo acid dehydrogenase complexes consist of three main components: a 2-oxo acid dehydrogenase (E1) with a thiamine pyrophosphate cofactor, a dihydrolipoamide acyltransferase (E2) with a lipoate cofactor, and a dihydrolipoamide dehydrogenase (E3) with a flavin cofactor. E1 binds the 2-oxobutanoate to the lipoate on E2, which then transfers the propionyl group to coenzyme A, producing propionyl-CoA and reducing the lipoate. E3 then transfers protons to NAD in order to restore the lipoate. Propionyl-CoA carboxylase transforms the propionyl-CoA to S-methylmalonyl-CoA, which is then converted to R-methylmalonyl-CoA via methylmalonyl-CoA epimerase. In the final step, methylmalonyl-CoA mutase acts on the R-methylmalonyl-CoA to produce succinyl-CoA.
References
Threonine and 2-Oxobutanoate Degradation References
Bobik TA, Rasche ME: Identification of the human methylmalonyl-CoA racemase gene based on the analysis of prokaryotic gene arrangements. Implications for decoding the human genome. J Biol Chem. 2001 Oct 5;276(40):37194-8. doi: 10.1074/jbc.M107232200. Epub 2001 Jul 31.
Pubmed: 11481338
de Kok A, Hengeveld AF, Martin A, Westphal AH: The pyruvate dehydrogenase multi-enzyme complex from Gram-negative bacteria. Biochim Biophys Acta. 1998 Jun 29;1385(2):353-66.
Pubmed: 9655933
Fries M, Jung HI, Perham RN: Reaction mechanism of the heterotetrameric (alpha2beta2) E1 component of 2-oxo acid dehydrogenase multienzyme complexes. Biochemistry. 2003 Jun 17;42(23):6996-7002. doi: 10.1021/bi027397z.
Pubmed: 12795594
Jansen R, Kalousek F, Fenton WA, Rosenberg LE, Ledley FD: Cloning of full-length methylmalonyl-CoA mutase from a cDNA library using the polymerase chain reaction. Genomics. 1989 Feb;4(2):198-205.
Pubmed: 2567699
Paxton R, Scislowski PW, Davis EJ, Harris RA: Role of branched-chain 2-oxo acid dehydrogenase and pyruvate dehydrogenase in 2-oxobutyrate metabolism. Biochem J. 1986 Mar 1;234(2):295-303.
Pubmed: 3718468
Zhou ZH, McCarthy DB, O'Connor CM, Reed LJ, Stoops JK: The remarkable structural and functional organization of the eukaryotic pyruvate dehydrogenase complexes. Proc Natl Acad Sci U S A. 2001 Dec 18;98(26):14802-7. doi: 10.1073/pnas.011597698.
Pubmed: 11752427
Edgar AJ: The human L-threonine 3-dehydrogenase gene is an expressed pseudogene. BMC Genet. 2002 Oct 2;3:18. Epub 2002 Oct 2.
Pubmed: 12361482
Wolosker H, Blackshaw S, Snyder SH: Serine racemase: a glial enzyme synthesizing D-serine to regulate glutamate-N-methyl-D-aspartate neurotransmission. Proc Natl Acad Sci U S A. 1999 Nov 9;96(23):13409-14. doi: 10.1073/pnas.96.23.13409.
Pubmed: 10557334
Foltyn VN, Bendikov I, De Miranda J, Panizzutti R, Dumin E, Shleper M, Li P, Toney MD, Kartvelishvily E, Wolosker H: Serine racemase modulates intracellular D-serine levels through an alpha,beta-elimination activity. J Biol Chem. 2005 Jan 21;280(3):1754-63. doi: 10.1074/jbc.M405726200. Epub 2004 Nov 9.
Pubmed: 15536068
Carninci P, Kasukawa T, Katayama S, Gough J, Frith MC, Maeda N, Oyama R, Ravasi T, Lenhard B, Wells C, Kodzius R, Shimokawa K, Bajic VB, Brenner SE, Batalov S, Forrest AR, Zavolan M, Davis MJ, Wilming LG, Aidinis V, Allen JE, Ambesi-Impiombato A, Apweiler R, Aturaliya RN, Bailey TL, Bansal M, Baxter L, Beisel KW, Bersano T, Bono H, Chalk AM, Chiu KP, Choudhary V, Christoffels A, Clutterbuck DR, Crowe ML, Dalla E, Dalrymple BP, de Bono B, Della Gatta G, di Bernardo D, Down T, Engstrom P, Fagiolini M, Faulkner G, Fletcher CF, Fukushima T, Furuno M, Futaki S, Gariboldi M, Georgii-Hemming P, Gingeras TR, Gojobori T, Green RE, Gustincich S, Harbers M, Hayashi Y, Hensch TK, Hirokawa N, Hill D, Huminiecki L, Iacono M, Ikeo K, Iwama A, Ishikawa T, Jakt M, Kanapin A, Katoh M, Kawasawa Y, Kelso J, Kitamura H, Kitano H, Kollias G, Krishnan SP, Kruger A, Kummerfeld SK, Kurochkin IV, Lareau LF, Lazarevic D, Lipovich L, Liu J, Liuni S, McWilliam S, Madan Babu M, Madera M, Marchionni L, Matsuda H, Matsuzawa S, Miki H, Mignone F, Miyake S, Morris K, Mottagui-Tabar S, Mulder N, Nakano N, Nakauchi H, Ng P, Nilsson R, Nishiguchi S, Nishikawa S, Nori F, Ohara O, Okazaki Y, Orlando V, Pang KC, Pavan WJ, Pavesi G, Pesole G, Petrovsky N, Piazza S, Reed J, Reid JF, Ring BZ, Ringwald M, Rost B, Ruan Y, Salzberg SL, Sandelin A, Schneider C, Schonbach C, Sekiguchi K, Semple CA, Seno S, Sessa L, Sheng Y, Shibata Y, Shimada H, Shimada K, Silva D, Sinclair B, Sperling S, Stupka E, Sugiura K, Sultana R, Takenaka Y, Taki K, Tammoja K, Tan SL, Tang S, Taylor MS, Tegner J, Teichmann SA, Ueda HR, van Nimwegen E, Verardo R, Wei CL, Yagi K, Yamanishi H, Zabarovsky E, Zhu S, Zimmer A, Hide W, Bult C, Grimmond SM, Teasdale RD, Liu ET, Brusic V, Quackenbush J, Wahlestedt C, Mattick JS, Hume DA, Kai C, Sasaki D, Tomaru Y, Fukuda S, Kanamori-Katayama M, Suzuki M, Aoki J, Arakawa T, Iida J, Imamura K, Itoh M, Kato T, Kawaji H, Kawagashira N, Kawashima T, Kojima M, Kondo S, Konno H, Nakano K, Ninomiya N, Nishio T, Okada M, Plessy C, Shibata K, Shiraki T, Suzuki S, Tagami M, Waki K, Watahiki A, Okamura-Oho Y, Suzuki H, Kawai J, Hayashizaki Y: The transcriptional landscape of the mammalian genome. Science. 2005 Sep 2;309(5740):1559-63. doi: 10.1126/science.1112014.
Pubmed: 16141072
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
Huttlin EL, Jedrychowski MP, Elias JE, Goswami T, Rad R, Beausoleil SA, Villen J, Haas W, Sowa ME, Gygi SP: A tissue-specific atlas of mouse protein phosphorylation and expression. Cell. 2010 Dec 23;143(7):1174-89. doi: 10.1016/j.cell.2010.12.001.
Pubmed: 21183079
Tamura T, McMicken HW, Smith CV, Hansen TN: Gene structure for mouse glutathione reductase, including a putative mitochondrial targeting signal. Biochem Biophys Res Commun. 1997 Aug 18;237(2):419-22. doi: 10.1006/bbrc.1997.7153.
Pubmed: 9268726
Tutic M, Lu XA, Schirmer RH, Werner D: Cloning and sequencing of mammalian glutathione reductase cDNA. Eur J Biochem. 1990 Mar 30;188(3):523-8. doi: 10.1111/j.1432-1033.1990.tb15431.x.
Pubmed: 2185014
Ballif BA, Carey GR, Sunyaev SR, Gygi SP: Large-scale identification and evolution indexing of tyrosine phosphorylation sites from murine brain. J Proteome Res. 2008 Jan;7(1):311-8. doi: 10.1021/pr0701254. Epub 2007 Nov 23.
Pubmed: 18034455
Fitzgerald J, Hutchison WM, Dahl HH: Isolation and characterisation of the mouse pyruvate dehydrogenase E1 alpha genes. Biochim Biophys Acta. 1992 May 7;1131(1):83-90. doi: 10.1016/0167-4781(92)90102-6.
Pubmed: 1581363
Zhang J, Xia WL, Brew K, Ahmad F: Adipose pyruvate carboxylase: amino acid sequence and domain structure deduced from cDNA sequencing. Proc Natl Acad Sci U S A. 1993 Mar 1;90(5):1766-70. doi: 10.1073/pnas.90.5.1766.
Pubmed: 8446588
Villen J, Beausoleil SA, Gerber SA, Gygi SP: Large-scale phosphorylation analysis of mouse liver. Proc Natl Acad Sci U S A. 2007 Jan 30;104(5):1488-93. doi: 10.1073/pnas.0609836104. Epub 2007 Jan 22.
Pubmed: 17242355
Schrick JJ, Lingrel JB: cDNA cloning, mapping and expression of the mouse propionyl CoA carboxylase beta (pccb), the gene for human type II propionic acidaemia. Gene. 2001 Feb 7;264(1):147-52. doi: 10.1016/s0378-1119(00)00586-2.
Pubmed: 11245989
Wilkemeyer MF, Crane AM, Ledley FD: Primary structure and activity of mouse methylmalonyl-CoA mutase. Biochem J. 1990 Oct 15;271(2):449-55. doi: 10.1042/bj2710449.
Pubmed: 1978672
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 SMP0000452
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