Enzymology
Patient mutations in human ATP:cob(I)alamin adenosyltransferase differentially affect its catalytic versus chaperone functions
Human ATP:cob(I)alamin adenosyltransferase (ATR) is a mitochondrial enzyme that catalyzes an adenosyl transfer to cob(I)alamin, synthesizing 5′-deoxyadenosylcobalamin (AdoCbl) or coenzyme B12. ATR is also a chaperone that escorts AdoCbl, transferring it to methylmalonyl-CoA mutase, which is important in propionate metabolism. Mutations in ATR lead to methylmalonic aciduria type B, an inborn error of B12 metabolism. Our previous studies have furnished insights into how ATR protein dynamics influence redox-linked cobalt coordination chemistry, controlling its catalytic versus chaperone functions.Surprise! A hidden B12 cofactor catalyzes a radical methylation
Radical S-adenosylmethionine (SAM) (RS) methylases perform methylation reactions at unactivated carbon and phosphorus atoms. RS enzymes typically abstract a hydrogen from their substrates, generating a substrate-centered radical; class B RS methylases catalyze methyl transfer from SAM to cobalamin and then to a substrate-centered carbon or phosphorus radical. Radle et al. now show that Mmp10, an RS enzyme implicated in the methylation of Arg-285 in methyl coenzyme M reductase, binds a methylcobalamin cofactor required for methyl transfer from SAM to a peptide substrate.Methanogenesis marker protein 10 (Mmp10) from Methanosarcina acetivorans is a radical S-adenosylmethionine methylase that unexpectedly requires cobalamin
Methyl coenzyme M reductase (MCR) catalyzes the last step in the biological production of methane by methanogenic archaea, as well as the first step in the anaerobic oxidation of methane to methanol by methanotrophic archaea. MCR contains a number of unique post-translational modifications in its α subunit, including thioglycine, 1-N-methylhistidine, S-methylcysteine, 5-C-(S)-methylarginine, and 2-C-(S)-methylglutamine. Recently, genes responsible for the thioglycine and methylarginine modifications have been identified in bioinformatics studies and in vivo complementation of select mutants; however, none of these reactions has been verified in vitro.Efficient methylation of C2 in l-tryptophan by the cobalamin-dependent radical S-adenosylmethionine methylase TsrM requires an unmodified N1 amine
TsrM catalyzes the methylation of C2 in l-tryptophan (Trp). This reaction is the first step in the biosynthesis of the quinaldic acid moiety of the thiopeptide antibiotic thiostrepton, which exhibits potent activity against Gram-positive pathogens. TsrM is a member of the radical S-adenosylmethionine (SAM) superfamily of enzymes, but it does not catalyze the formation of 5′-deoxyadenosin-5′-yl or any other SAM-derived radical. In addition to a [4Fe–4S] cluster, TsrM contains a cobalamin cofactor that serves as an intermediate methyl carrier in its reaction.
