Figure 1: Structures of Cobalamins found in Humans:
X = H2O aquacobalamin (H2OCbl+)
X = CH3 methylcobalamin (MeCbl)
X = 5′-deoxyadenosine adenosylcobalamin (AdoCbl, “coenzyme B12“)
X = SO3 sulphitocobalamin (SO3Cbl)
X = CN cyanocobalamin (CNCbl, “vitamin B12“)
Figure 1 shows the structures of the various forms of vitamin B12 (cobalamins) which are found in the human body. Vitamin B12 derivatives are cofactors in approximately 15 enzyme reactions. Two of these reactions, involving methionine synthase (1) and methylmalonyl-CoA mutase (2), occur in humans and utilize the vitamin B12 derivatives methylcobalamin (MeCbl) and 5′-deoxyadenosylcobalamin (AdoCbl), respectively.
In the former reaction, a methyl group is transferred from methyltetrahydrofolate to homocysteine (Hcy) via MeCbl to generate methionine and tetrahydrofolate, and this reaction has received much attention in the medical literature in recent years. It has been shown that patients with high levels of Hcy have a greatly increased risk of suffering a stroke or a heart attack, and there is also increasing evidence that high levels of Hcy are prevalent in sufferers of Alzheimer’s disease and other neurological disorders.
We are especially interested in the thiol derivatives of vitamin B12, thiolatocobalamins, where X = a thiol group (Figure 1). In 2003 we initiated a collaboration with Dr Donald Jacobsen at the Cleveland Clinic Foundation aimed at studying cobalamin processing in endothelial cells. Thus far we have obtained evidence that glutathionylcopbalamin, GSCbl (X = GS, Fig. 1) is present in aortic endothelial cells, and that GSCbl is decomposed during the typical procedures used to extract and purify vitamin B12 derivatives from cells. We have also found that beta-axial ligand exchange occurs during the extraction and purification of other cobalamins from cells, and have modified the extraction procedure to prevent these side reactions from occurring.
We are also interested in the reactions between cobalamins and nitrogen oxide species such as nitric oxide. Recently we characterized the nitric oxide derivative of B12, nitrosylcobalamin, by X-ray diffraction. In collaboration with other labs we are currently investigating the potential of cobalamins to protect against oxidative stress.