Tetrapyrroles pp 330-342 | Cite as

Coenzyme B12-Catalyzed Radical Isomerizations

Part of the Molecular Biology Intelligence Unit book series (MBIU)


Cobalamins are complex organometallic cofactors essential for catalysis in three enzyme families, the isomerases, methyltransferases and reductive dehalogenases. This account focuses on the isomerases, which catalyze difficult and unusual 1,2-rearrangement reactions. These enzymes utilize AdoCbl as a radical reservoir. They induce homolytic cleavage of the Co-C bond of the cofactor thus generating a highly reactive 5′-deoxyadenosyl radical that initiates the radical rearrangement process. Over the past decade, structure-function and computational studies of several members of the isomerase family have provided interesting insights into the mechanism of AdoCbl-dependent radical isomerizations. In particular, these studies have revealed the critical role played by the protein in catalyzing the trillion-fold rate enhancement of Co-C bond homolysis, in shielding radical intermediates from adventitious side-reactions and in facilitating the rearrangement process itself.

Cobalamins, or B12-cofactors, are used by three classes of enzymes and have long fascinated bioinorganic chemists because of their complex structure and their stable organometallic bond which is the only known biologically.1 These tetrapyrrolic cofactors contain a central cobalt atom tethered by four equatorial nitrogen ligands from pyrroles A-D of the corrin ring (Fig. 1). One peculiarity of the corrin ring is the degree of flexibility, not enjoyed by the other tetrapyrrole cofactors (e.g., porphyrins), afforded by its fairly reduced state. In solution and at physiological pH, the lower trans-axial ligand of the cobalt atom is a nitrogen atom provided by the bulky base, 5,6-dimethylbenzimidazole (DMB),1 that is appended via a nucleotide loop from the periphery of ring D of the corrin macrocycle. Diversity is thus present at the upper cis-axial ligand where cyano-, hydroxo-, -methyl- and deoxyadenosyl- groups are seen in vitamin B12, hydroxocobalamin, methylcobalamin (MeCbl) and adenosylcobalamin (AdoCbl) respectively. Stricdy speaking, diversity is also present in the trans position; however, technically these are described as cobamides rather than cobalamins.1

A key feature of the enzymes that utilize B12 as cofactors is their ability to control the reactivity of the stable Co-C bond to undergo either heterolytic or homolytic scission. Thus, biological methylation reactions carried out by MeCbl-dependent enzymes, operate through heterolytic cleavage of the Co-C bond generating cob(I)alamin and the methyl cation is transferred to an acceptor molecule.1 On the other hand, biological rearrangement reactions catalyzed by AdoCbl-dependent isomerases, proceed via the homolytic fission of the Co-C bond, producing cob(II)alamin and a highly reactive 5′-deoxyadenosyl radical that initiates radical chemistry.2 In this chapter, we will focus on the B12-dependent isomerases.


Thiyl Radical Bond Homolysis Radical Isomerization Reductive Dehalogenases Corrin Ring 
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Copyright information

© Landes Bioscience and Springer Science+Business Media 2009

Authors and Affiliations

  1. 1.Department of Biological ChemistryUniversity of MichiganAnn ArborUSA

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