Coα-(1H-Imidazolyl)-Coβ-methylcob(III)amide: Model for Protein-Bound Corrinoid Cofactors

Abstract

Dedicated to Prof. Albert Eschenmoser on the occasion of his 75 th birthdayCoa-(1H-Imidazol-1-yl)-Cob-methylcob(III)amide (4) was synthesized by methylation with methyl iodide of (1H-imidazol-1-yl)cob(I)amide, obtained by electrochemical reduction of Coa-(1H-imidazol-1-yl)-Cobcyanocob(III)amide (5). The spectroscopic data and a single-crystal X-ray structure analysis indicated 4 to exhibit a base-on constitution in solution and in the crystal. The crucial lengths of the axial CoÀN and CoÀCH 3 bonds also emerged from the crystallographic data and were found to be smaller by 0.1 and 0.02 , respectively, than those in methylcob(III)alamin (2). The data of 4 support the view, that the long axial CoÀN bonds as determined by X-ray crystallography for the B 12 -dependent methionine synthase, for methylmalonyl-CoA mutase, and for glutamate mutase represent stretched CoÀN bonds. The thermodynamic effect (the trans influence) of the 1H-imidazole base in 4 on the organometallic reactivity of this model for protein-bound organometallic B 12 cofactors was examined by studying Me-group-transfer equilibria in aqueous solution and using (5',6'-dimethyl-1H-benzimidazol-1-yl)cobamides (cobalamins) as reaction partners (Schemes 2 ± 5, Table). In comparison with methylcob(III)alamin (2), 4 was found to be destabilized for an abstraction of the Co-bound Me group by a Co III electrophile. In contrast, the abstraction of the Co-bound Me group by a radical(oid) Co II species was not significantly influenced thermodynamically by the exchange of the nucleotide base. Likewise, exploratory Me-group-transfer experiments with MeÀCo III and nucleophilic Co I corrinoids at pH 6.8 provided an apparent equilibrium constant near unity. However, this finding also was consistent with partial protonation of the imidazolylcob(I)amide at pH 6.8, suggesting an interesting pH dependence of the Megroup-transfer equilibrium near neutral pH. Therefore, the replacement of the 5',6'-dimethyl-1H-benzimidazole base by an 1H-imidazole moiety, as observed in methyl transferases and in C-skeleton mutases, does not by itself strongly alter the inherent reactivity of the B 12 cofactors in the crucial homolytic and nucleophilic-heterolytic reactions involving the organometallic bond, but may help to enhance the control of the organometallic reactivity by protonation/deprotonation of the axial base.

Electronic structure of the S1 state in methylcobalamin: Insight from CASSCF/MC‐XQDPT2, EOM‐CCSD, and TD‐DFT calculations

“…Using the X-ray crystallographic data for the full MeCbl structure [81] as a starting point for designing the Im-[Co III (corrin)]-CH 3 þ model, we replaced all amide side chains of the corrin ring with the hydrogen atoms while truncating the nucleotide loop at C 17 , leaving the resulting structure positively charged. [82] CASSCF/MC-XQDPT2 calculations Thus, the lower axial DBI fragment was substituted by imidazole (Im).…”

Catalysis of Methyl Group Transfers Involving Tetrahydrofolate and B12

“…Kinetic and thermodynamic studies of alkylated corrinoids have shown that the nature of the lower ligand strongly influences the rate and mode of Co-C bond breaking (Hogenkamp et al, 1965;Kräutler, 1987;Pratt, 1999). Since most of the methyltransferase "C" components contain a Co-N-His bond replacing the Co-N-dmb ligation in the free cofactor, enzymatic (Dorweiler et al, 2003) and model (Fasching et al, 2000) studies have been conducted to determine if this ligand switch conferred a special mechanistic advantage. On the basis of studies of methyl transfer from MTHF to Co(I) in methionine synthase, it was concluded that the replacement of 5,6-dimethylbenzimidazole by imidazole has little effect on the kinetics of the methyl transfer reaction.…”

Crystallography of vitamin B12 proteins

“…12. The axial Co-N distances are 2.28 Å in the cyano cofactor and 2.34 Å in the methyl cofactor bound in the base-off/his-on mode [39,40], and should be compared to the corresponding distances in the Me-(2.09 Å [41]) and the CN-(1.968(9) Å [42]) imidazolylcobamides. Since the protein crystals contain the cofactor to 50% in hexacoordinated and to 50% in pentacoordinated form, the values of 2.28 Å and 2.34 Å in the CN and methyl cofactors were interpreted as the average of the very long distance (assumed to be 2.5 Å ) of the pentacoordinated Co(II) species and the shorter distance of the hexacoordinated Co(III) species.…”