Structure adenosylcobalamin

The structure of the E. coli enzyme (Fig. 16-24) shows methylcobalamin bound in a base-off conformation, with histidine 759 of the protein replacing dimethylbenzimidazole in the distal coordination position on the cobalt. This histidine is part of a sequence Asp-X-His-X-X-Gly that is found not only in methionine synthase but also in methylmalonyl-CoA mutase, glutamate mutase, and 2-methyleneglutarate mutase. However, diol dehydratase lacks this sequence and binds adenosylcobalamin with the dimethylbenz-imidazole-cobalt bond intact.417... 

The Bj2 vitamers consist of a group of organometallic compounds that have a common cor-rinoid structure and vary in the substituent bound to the central cobalt atom (Fig. 7) (167,168). The principal naturally occurring Bl2 vitamers are hydroxocobalamin (HOCbl), methylcobal-amin (MeCbl), and adenosylcobalamin (AdoCbl). Cyanocobalamin (CNCbl) is the form commonly used for clinical, pharmaceutical, and food fortification purposes, due to its greater relative stability. 

Structure-Function Relationship of Vitamin Bi2 Coenzyme (Adenosylcobalamin) in the Diol-Dehydrase System... 

Studies of the Structure-Function Relationship of Adenosylcobalamin through the Use of Coenzyme Analogs... 

FIGURE 2. Structure of adenosylcobalamin (coenzyme B12 ). Carbons ln20 of the corrin ring are labeled, as are the four pyrroles (AiiD) and the corrin side chains (ang). The a-face lies below the plane of the corrin ring and the p-face above. 

Figure 1 In the above structure, R = CN denotes cyanocobalamin (CN-Cbl), whilst R = OH is hydroxocobalamin (OH-Cbl) R = 5 -deoxyadenosyl is coenzyme B12 (adenosylcobalamin, AdoCbl) and R = Me is methylcobalamin (MeCbl). By definition all cobalamins contain 5,6-dimethylbenzimidazole, which is the so-called 6th ligand to cobalt in the above structure. Substances containing the corrin ligand, i.e. the planar 14 electron p-system embracing cobalt in the above structure, are also called corrinoids.

Structure of the cobalamin family of compounds. A through D are the four rings in the corrinoid ring system. The B ring is important for cobalamin binding to intrinsic factor. If R = -CN, the molecule is cyanocobalamin (vitamin B12) if R = 5 -deoxyadenosine, the molecule is adenosylcobalamin if R = -CH3, the molecule is methylcobalamin. Arrows pointing toward the cobalt ion represent coordinate-covalent bonds. 

A separate pathway has evolved to build a-ribazole 84, unusual both in its base, 5,6-dimethylbenzimidazole, and in the a-linkage to ribose. Either a-ribazole 84 or its 5 -phosphate 85 is able to accept the adenosylcobinamide phosphate residue from adenosyl-GDP-cobinamide 83, a transfer catalysed by CobV, to form adenosylcobalamin (coenzyme B12, 4) or its 5 -phosphate, respectively. Dephosphorylation of the 5 -phosphate then leads to 4. Thus the end product from nature s marathon, coenzyme 4, has been reached, a structure of marvellous architecture and amazing biological activity. 

Before the crystal structure of adenosylcobalamin became known, coenzyme Bj2 had been described as an adenine derivative of vitamin Bi2- Taking into consideration the cobaltic nature of coenzyme B12, the mechanism in Figure 2(a) for the reaction of MCM was put forward in 1960. This was a proton-coupled electron transfer and free radical mechanism, in which the Co of coenzyme Bj2 was postulated to potentiate the removal of an electron and proton from the substrate to form a carbon-centered substrate radical and Co. The substrate radical would undergo rearrangement to the product-related radical, which would then accept an... 

The first coenzyme Bi2-dependent isomerase to be crystallized and structurally analyzed by X-ray crystallography is MCM. Several crystal structures of MCM are available, and one is illustrated in Figure 23. Like GM and 5,6-LAM, the larger subunit is a TIM barrel. Also like GM, MCM, and methionine synthase, adenosylcobalamin is bound in a base-ofF mode. 

The observation of a kinetically competent cysteinyl-thiyl free radical intermediate implicated Cys408 in a critical mechanistic role. As in other coenzyme Bi2-dependent enzymes, the unpaired electron of the radical was spin coupled to Co of cob(II)alamin. The structure of the thiyl radical was rigorously proven by isotope-edited EPR analysis, and spectral simulations showed that the thiyl radical resided at 5—7 A from Co of cob(II)alamin. The emergence of the radical triplet signal required adenosylcobalamin and dGTP in addition to RTPR. 

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