Structural highlights
Function
KGD_MYCS2 Shows three enzymatic activities that share a first common step, the attack of thiamine-PP on 2-oxoglutarate (alpha-ketoglutarate, KG), leading to the formation of an enamine-thiamine-PP intermediate upon decarboxylation. Thus, displays KGD activity, catalyzing the decarboxylation from five-carbon 2-oxoglutarate to four-carbon succinate semialdehyde (SSA). Also catalyzes C-C bond formation between the activated aldehyde formed after decarboxylation of alpha-ketoglutarate and the carbonyl of glyoxylate (GLX), to yield 2-hydroxy-3-oxoadipate (HOA), which spontaneously decarboxylates to form 5-hydroxylevulinate (HLA). And is also a component of the 2-oxoglutarate dehydrogenase (ODH) complex, that catalyzes the overall conversion of 2-oxoglutarate to succinyl-CoA and CO(2). The KG decarboxylase and KG dehydrogenase reactions provide two alternative, tightly regulated, pathways connecting the oxidative and reductive branches of the TCA cycle.[1] [2]
Publication Abstract from PubMed
alpha-ketoacid dehydrogenases are large multi-enzyme machineries that orchestrate the oxidative decarboxylation of alpha-ketoacids with the concomitant production of acyl-CoA and NADH. The first reaction, catalysed by alpha-ketoacid decarboxylases (E1 enzymes), needs a thiamine diphosphate cofactor and represents the overall rate-limiting step. Although the catalytic cycles of E1 from the pyruvate dehydrogenase (E1p) and branched chain alpha-ketoacid dehydrogenase (E1b) complexes have been elucidated, little structural information is available on E1o, the first component of the alpha-ketoglutarate dehydrogenase complex, despite the central role of this complex at the branching point between the TCA cycle and glutamate metabolism. Here, we provide structural evidence that MsKGD, the E1o from Mycobacterium smegmatis, shows two conformations of the post-decarboxylation intermediate, each one associated with a distinct enzyme state. We also report an overall picture of the catalytic cycle, reconstructed by either crystallographic snapshots or modelling. Our results show that the conformational change leading the enzyme from the initial (early) to the late state, although not required for decarboxylation, plays an essential role in catalysis, and possibly in the regulation of mycobacterial E1o.
A dual conformation of the post-decarboxylation intermediate is associated with distinct enzyme states in mycobacterial alpha-ketoglutarate decarboxylase (KGD).,Wagner T, Barilone N, Alzari PM, Bellinzoni M Biochem J. 2013 Oct 31. PMID:24171907[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ O'Hare HM, Duran R, Cervenansky C, Bellinzoni M, Wehenkel AM, Pritsch O, Obal G, Baumgartner J, Vialaret J, Johnsson K, Alzari PM. Regulation of glutamate metabolism by protein kinases in mycobacteria. Mol Microbiol. 2008 Dec;70(6):1408-23. doi: 10.1111/j.1365-2958.2008.06489.x., Epub 2008 Oct 17. PMID:19019160 doi:http://dx.doi.org/10.1111/j.1365-2958.2008.06489.x
- ↑ Wagner T, Bellinzoni M, Wehenkel A, O'Hare HM, Alzari PM. Functional plasticity and allosteric regulation of alpha-ketoglutarate decarboxylase in central mycobacterial metabolism. Chem Biol. 2011 Aug 26;18(8):1011-20. PMID:21867916 doi:10.1016/j.chembiol.2011.06.004
- ↑ Wagner T, Barilone N, Alzari PM, Bellinzoni M. A dual conformation of the post-decarboxylation intermediate is associated with distinct enzyme states in mycobacterial alpha-ketoglutarate decarboxylase (KGD). Biochem J. 2013 Oct 31. PMID:24171907 doi:http://dx.doi.org/10.1042/BJ20131142
