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Computational Studies: B12 Cofactors and their Interaction with Enzyme Active Sites

  1. Thomas C. Brunold

Published Online: 15 SEP 2009

DOI: 10.1002/0470862106.ia626

Encyclopedia of Inorganic Chemistry

Encyclopedia of Inorganic Chemistry

How to Cite

Brunold, T. C. 2009. Computational Studies: B12 Cofactors and their Interaction with Enzyme Active Sites. Encyclopedia of Inorganic Chemistry. .

Author Information

  1. University of Wisconsin-Madison, Madison, WI, USA

Publication History

  1. Published Online: 15 SEP 2009


Cyanocobalamin, commonly known as vitamin B12, and its biologically active derivatives, 5′-deoxyadenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl), have long fascinated scientists with their elaborate structures and intriguing reactivities in enzymatic systems. While the large size and complex electronic structures of these cofactors have posed a major challenge for theoretical chemists, recent insights gained from kinetic, spectroscopic, and X-ray crystallographic studies have established an excellent foundation for validating computational investigations of the geometric, electronic, and reactivity properties of the isolated cofactors and the molecular details of the catalytic cycles of B12-dependent enzymes. This review—which is by no means exhaustive—summarizes salient information that has been obtained from experimentally validated computational studies of the following: (i) the free B12 cofactors in their Co3+, Co2+, and Co1+ oxidation states; (ii) the mechanism by which enzymes involved in the biosynthesis of AdoCbl overcome the large thermodynamic barrier associated with the Co2+ [RIGHTWARDS ARROW] Co1+ reduction; (iii) plausible strategies by which AdoCbl-dependent enzymes achieve a trillion-fold rate of acceleration for the homolytic cleavage of the cofactor's Co[BOND]C(Ado) bond; and (iv) the means by which MeCbl-dependent methyltransferases regenerate the active MeCbl cofactor and accelerate the rate of methyl transfer via heterolytic Co[BOND]C(Me) bond cleavage by as many as 6 orders of magnitude.


  • adenosylcobalamin;
  • ATP:corrinoid adenosyltransferases;
  • coenzyme B12;
  • density functional theory;
  • isomerases;
  • methylcobalamin;
  • methyltransferases;
  • quantum mechanics/molecular mechanics;
  • time-dependent density functional theory