If an enzyme name is shown in bold, there is experimental evidence for this enzymatic activity.
Locations of Mapped Genes:
|Superclasses:||Degradation/Utilization/Assimilation → Aldehyde Degradation|
|Detoxification → Methylglyoxal Detoxification|
Methylglyoxal is produced in small amounts during glycolysis (via dihydroxyacetone phosphate), fatty acid metabolism (via acetone) and protein metabolism (via aminoacetone). Methylglyoxal is highly toxic, most likely as a result of its interaction with protein side chains (see [Kalapos99] for a review). There are several pathways for the detoxification of methylglyoxal, based on different enzymes that are able to convert methylglyoxal to less toxic compounds. These enzymes include glyoxalase enzymes, methylglyoxal reductases, aldose reductases, aldehyde reductases and methylglyoxal dehydrogenases.
About This Pathway
In E. coli, the glutathione-dependent glyoxalase system is probably the most common pathway that catalyzes the conversion of methylglyoxal to a less toxic product. In the pathway shown here, methylglyoxal is converted to (R)-lactate via the intermediate (S)-lactoyl-glutathione by two glyoxylase enzymes. glyoxalase I (GloA) isomerizes the hemithioacetal that is formed non-enzymatically from methylglyoxal and glutathione to (S)-lactoyl-glutathione. Glyoxalase II enzymes, mainly GloB with a minor contribution from GloC, hydrolyze the thioester to (R)-lactate, regenerating the glutathione in the process [Reiger15]. In addition, YeiG can catalyze the hydrolysis of S-lactoylglutathione and may also be involved in the detoxification of endogenous methylglyoxal [Gonzalez06].
This system not only involves the enzymes encoded by the unlinked genes gloA, gloB and gloC, but also their integration with the glutathione adduct-gated KefGB K+ efflux system. Studies of a ΔgloB mutant supported a model that includes activation of KefGB by S-lactoylglutathione resulting in K+ efflux and H+ influx. This lowering of cytoplasmic pH also protects against methylglyoxal damage [Ozyamak10].
The fate of (R)-lactate is less well characterized. It can be excreted or further metabolized [Ozyamak10]. In the latter case it may be converted to pyruvate by the action of D-lactate dehydrogenase, a flavoprotein specific to the D-form of lactate [Dym00].
Superpathways: superpathway of methylglyoxal degradation
Gonzalez06: Gonzalez CF, Proudfoot M, Brown G, Korniyenko Y, Mori H, Savchenko AV, Yakunin AF (2006). "Molecular basis of formaldehyde detoxification: Characterization of two s-formylglutathione hydrolases from Escherichia coli, FrmB and YeiG." J Biol Chem 281:14514-14522. PMID: 16567800
Ozyamak10: Ozyamak E, Black SS, Walker CA, Maclean MJ, Bartlett W, Miller S, Booth IR (2010). "The critical role of S-lactoylglutathione formation during methylglyoxal detoxification in Escherichia coli." Mol Microbiol 78(6);1577-90. PMID: 21143325
Barnes70: Barnes EM, Kaback HR (1970). "Beta-galactoside transport in bacterial membrane preparations: energy coupling via membrane-bounded D-lactic dehydrogenase." Proc Natl Acad Sci U S A 66(4);1190-8. PMID: 4394455
Barnes71: Barnes EM, Kaback HR (1971). "Mechanisms of active transport in isolated membrane vesicles. I. The site of energy coupling between D-lactic dehydrogenase and beta-galactoside transport in Escherichia coli membrane vesicles." J Biol Chem 1971;246(17);5518-22. PMID: 4330922
Butland05: Butland G, Peregrin-Alvarez JM, Li J, Yang W, Yang X, Canadien V, Starostine A, Richards D, Beattie B, Krogan N, Davey M, Parkinson J, Greenblatt J, Emili A (2005). "Interaction network containing conserved and essential protein complexes in Escherichia coli." Nature 433(7025);531-7. PMID: 15690043
CamposBermudez10: Campos-Bermudez VA, Gonzalez JM, Tierney DL, Vila AJ (2010). "Spectroscopic signature of a ubiquitous metal binding site in the metallo-β-lactamase superfamily." J Biol Inorg Chem 15(8);1209-18. PMID: 20535505
Clugston04: Clugston SL, Yajima R, Honek JF (2004). "Investigation of metal binding and activation of Escherichia coli glyoxalase I: kinetic, thermodynamic and mutagenesis studies." Biochem J 377(Pt 2);309-16. PMID: 14556652
Clugston98: Clugston SL, Barnard JF, Kinach R, Miedema D, Ruman R, Daub E, Honek JF (1998). "Overproduction and characterization of a dimeric non-zinc glyoxalase I from Escherichia coli: evidence for optimal activation by nickel ions." Biochemistry 1998;37(24);8754-63. PMID: 9628737
Davidson01: Davidson G, Clugston SL, Honek JF, Maroney MJ (2001). "An XAS investigation of product and inhibitor complexes of Ni-containing GlxI from Escherichia coli: mechanistic implications." Biochemistry 40(15);4569-82. PMID: 11294624
DiazMejia09: Diaz-Mejia JJ, Babu M, Emili A (2009). "Computational and experimental approaches to chart the Escherichia coli cell-envelope-associated proteome and interactome." FEMS Microbiol Rev 33(1);66-97. PMID: 19054114
Fung79: Fung LW, Pratt EA, Ho C (1979). "Biochemical and biophysical studies on the interaction of a membrane-bound enzyme, D-lactate dehydrogenase from Escherichia coli, with phospholipids." Biochemistry 1979;18(2);317-24. PMID: 369600
GeorgeNasciment76: George-Nascimento C, Wakil SJ, Short SA, Kaback HR (1976). "Effect of lipids on the reconstitution of D-lactate oxidase in Escherichia coli membrane vesicles." J Biol Chem 251(21);6662-6. PMID: 789373
He00: He MM, Clugston SL, Honek JF, Matthews BW (2000). "Determination of the structure of Escherichia coli glyoxalase I suggests a structural basis for differential metal activation." Biochemistry 39(30);8719-27. PMID: 10913283
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