When a spectator turns killer: suicidal electron transfer from cobalamin in methylmalonyl-CoA mutase

Biochemistry
Monica D Vlasie, Ruma Banerjee

Abstract

Methylmalonyl-CoA mutase belongs to the class of adenosylcobalamin (AdoCbl)-dependent carbon skeleton isomerases and catalyzes the rearrangement of methylmalonyl-CoA to succinyl-CoA. In this study, we have evaluated the contribution of the active site residue, R207, in the methylmalonyl-CoA mutase-catalyzed reaction. The R207Q mutation results in a 10(4)-fold decrease in k(cat) and >30-fold increase in the K(M) for the substrate, methylmalonyl-CoA. R207 and the active site residue, Y89, are within hydrogen bonding distance to the carboxylate of the substrate. In the closely related isomerase, isobutyryl-CoA mutase the homologous residues are F80 and Q198, respectively. We therefore characterized the ability of the double mutant (Y89F/R207Q) of methylmalonyl-CoA mutase as well as of the single mutants (Y89F and R207Q) to catalyze the rearrangement of n-butyryl-CoA to isobutyryl-CoA. While none of the mutant enzymes is capable of isomerizing these substrates, the R207Q (single and double) mutants exhibited irreversible inactivation upon incubation with either n-butyryl-CoA or isobutyryl-CoA. The two products observed during inactivation under both aerobic and strictly anaerobic conditions were 5'-deoxyadenosine and hydroxocobalam...Continue Reading

Citations

Oct 1, 2010·Applied Microbiology and Biotechnology·Birgit E Alber
Jul 19, 2012·Biochemistry·Valentin Cracan, Ruma Banerjee
Feb 27, 2010·Microbial Cell Factories·Thore Rohwerder, Roland H Müller
Oct 19, 2004·Archives of Biochemistry and Biophysics·Vittorio CalabreseD Allan Butterfield
Jun 5, 2012·Journal of Zhejiang University. Science. B·Tóshiko Takahashi-IñiguezMaría Elena Flores
Jan 14, 2005·The Journal of Biological Chemistry·Amanpreet KamboGerry R Boss
Oct 30, 2009·The Journal of Biological Chemistry·Valentin CracanRuma Banerjee
Feb 28, 2015·The Journal of Biological Chemistry·Nadya Kurteva-YanevaThore Rohwerder
Jul 3, 2015·The Journal of Biological Chemistry·Kenichi KitanishiRuma Banerjee
May 16, 2017·Nature Chemical Biology·Raoul G RosenthalTobias J Erb
Oct 24, 2017·Cell·Hongying ShenVamsi K Mootha

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