Structure-based perspectives on B12-dependent enzymes

Annu Rev Biochem. 1997;66:269-313. doi: 10.1146/annurev.biochem.66.1.269.

Abstract

Two X-ray structures of cobalamin (B12) bound to proteins have now been determined. These structures reveal that the B12 cofactor undergoes a major conformational change on binding to the apoenzymes of methionine synthase and methylmalonyl-coenzyme A mutase: The dimethylbenzimidazole ligand to the cobalt is displaced by a histidine residue from the protein. Two methyltransferases from archaebacteria that catalyze methylation of mercaptoethanesulfonate (coenzyme M) during methanogenesis have also been shown to contain histidine-ligated cobamides. In corrinoid iron-sulfur methyltransferases from acetogenic and methanogenic organisms, benzimidazole is dissociated from cobalt, but without replacement by histidine. Thus, dimethylbenzimidazole displacement appears to be an emerging theme in cobamide-containing methyltransferases. In methionine synthase, the best studied of the methyltransferases, the histidine ligand appears to be required for competent methyl transfer between methyl-tetrahydrofolate and homocysteine but dissociates for reductive reactivation of the inactive oxidized enzyme. Replacement of dimethylbenzimidazole by histidine may allow switching between the catalytic and activation cycles. The best-characterized B12-dependent mutases that catalyze carbon skeleton rearrangement, for which methylmalonyl-coenzyme A mutase is the prototype, also bind cobalamin cofactors with histidine as the cobalt ligand, although other cobalamin-dependent mutases do not appear to utilize histidine ligation. It is intriguing to find that mutases, which catalyze homolytic rather than heterolytic cleavage of the carbon-cobalt bond, can use this structural motif. In methylmalonylCoA mutase a significant feature, which may be important in facilitating homolytic cleavage, is the long cobalt-nitrogen bond linking histidine to the co-factor. The intermediate radical species generated in catalysis are sequestered in the relatively hydrophilic core of an alpha/beta barrel domain of the mutase.

Publication types

  • Research Support, U.S. Gov't, P.H.S.
  • Review

MeSH terms

  • 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase / chemistry*
  • Animals
  • Cobamides / chemistry
  • Humans
  • Methylmalonyl-CoA Mutase / chemistry*
  • Molecular Sequence Data
  • Protein Conformation
  • Vitamin B 12 / chemistry*

Substances

  • Cobamides
  • 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase
  • Methylmalonyl-CoA Mutase
  • cobamamide
  • Vitamin B 12

Associated data

  • GENBANK/D64002
  • GENBANK/H11042
  • GENBANK/J04774
  • GENBANK/J04975
  • GENBANK/L07099
  • GENBANK/L10064
  • GENBANK/L30136
  • GENBANK/M22990
  • GENBANK/M37508
  • GENBANK/M65022
  • GENBANK/M65131
  • GENBANK/U00017
  • GENBANK/U30484
  • GENBANK/U36337
  • GENBANK/W33307
  • GENBANK/X14965
  • GENBANK/X57941
  • GENBANK/X75890
  • GENBANK/X77484
  • GENBANK/X80997
  • GENBANK/Z46828