Disease relevance of Dimedazole

• The B(12) used was quantitatively labeled with (14)C at one particular atom of the dimethylbenzimidazole (DMB) moiety by exploiting idiosyncrasies of Salmonella metabolism [1].
• Sinorhizobium meliloti bluB is necessary for production of 5,6-dimethylbenzimidazole, the lower ligand of B12 [2].
• Binding of Cob(II)alamin to the adenosylcobalamin-dependent ribonucleotide reductase from Lactobacillus leichmannii. Identification of dimethylbenzimidazole as the axial ligand [3].
• Biosynthesis of vitamin B12. Formation of free 5,6-dimethylbenzimidazole and alpha-ribazole from riboflavin by Propionibacterium freudenreichii [4].
• The cob operon of E. coli comprises the cobU gene, encoding the bifunctional cobinamide kinase-guanylyltransferase; the cobS gene, encoding cobalamin synthetase; and the cobT gene, encoding dimethylbenzimidazole phosphoribosyltransferase [5].

High impact information on Dimedazole

• These structures reveal that the B12 cofactor undergoes a major conformational change on binding to the apoenzymes of methionine synthase and methylmalonyl-coenzyme A mutase: The dimethylbenzimidazole ligand to the cobalt is displaced by a histidine residue from the protein [6].
• Two mutants that lead to severe impairment (mut0) are Gly-630 --> Glu and Gly-703 --> Arg, which map to the binding site for the dimethylbenzimidazole nucleotide substituent of adenosylcobalamin [7].
• In vivo data showed that the lack of cobC function blocks the synthesis of cobalamin from its precursors cobinamide and 5,6-dimethylbenzimidazole, i.e. it prevents the assembly of the nucleotide loop of cobalamin [8].
• These measurements can be used to estimate the influence of the dimethylbenzimidazole ligand on both the thermodynamics and kinetics of methyl transfer between methyltetrahydrofolate and cob(I)alamin or cob(I)inamide [9].
• Dimethylbenzimidazole contributes approximately 0.6 kcal/mol of stabilization for the forward reaction and approximately 2.2 kcal/mol of destabilization for the reverse reaction [9].

Chemical compound and disease context of Dimedazole

• Biosynthesis of vitamin B12 in anaerobic bacteria. Mode of incorporation of glycine into the 5,6-dimethylbenzimidazole moiety in Eubacterium limosum [10].
• In anaerobic bacteria 5-hydroxybenzimidazole and 5-hydroxy-6-methylbenzimidazole are precursors of the 5,6-dimethylbenzimidazole moiety of vitamin B12 [11].

Biological context of Dimedazole

• Mutants with lesions in the promoter-distal end of the operon synthesize vitamin B12 only if provided with 5,6-dimethylbenzimidazole (DMB), the lower ligand of vitamin B12 [12].
• The sequence contained the DXHXXG consensus sequence typical for displacement of the dimethylbenzimidazole base of the corrinoid cofactor by a histidine from the protein [13].
• Efficacy of hydroxocobalamin (vitamin B12) as a cyanide antidote is limited by its high molecular weight (1355 g/mol) and by the competitive binding of the cobalamin dimethylbenzimidazole [14].

Anatomical context of Dimedazole

• 1. 70 S ribosomes isolated from strains of Escherichia coli 113-3, K12 and B take part in vitamin B-12 biosynthesis from AdoCbi-GDP, NAD and dimethylbenzimidazole in the presence of enzymes of the cytosol fraction [15].

Associations of Dimedazole with other chemical compounds

• Free dimethylbenzimidazole axial base-on cob(II)alamin was formed by photolysis of the corresponding adenosylcobalamin and cryotrapped in glycerol-aqueous glass [16].
• These experiments reveal that one molecule of glycine is incorporated into 5,6-dimethylbenzimidazole moiety of vitamin B12 in a regiospecific manner [10].
• Spectroscopic data show that the dimethylbenzimidazole group trans to the NO(2)(-) ligand is protonated and partially dechelated at pH 1, by which a reaction with NO is induced [17].
• (15)N superhyperfine splitting in the EPR signals of the low-spin Co(2+) of B(12r), bound in the active site of EAL, indicates that the dimethylbenzimidazole moiety of the cofactor contributes the lower axial ligand consistent with "base-on" binding of coenzyme B(12) to EAL [18].
• Examination of the role of base-off cobalamin species (where the 5,6-dimethylbenzimidazole ligand coordinated to cobalt is detached by protonation of the imidazole nitrogen) in differentiation between homolytic and heterolytic cobalt-carbon bond cleavage mechanisms is a primary step in better understanding B12-dependent enzyme catalysis [19].

Gene context of Dimedazole

• The cobT gene of Salmonella typhimurium encodes the NaMN: 5,6-dimethylbenzimidazole phosphoribosyltransferase responsible for the synthesis of N1-(5-phospho-alpha-D-ribosyl)-5,6-dimethylbenzimidazole, an intermediate in the synthesis of the nucleotide loop of cobalamin [20].
• The end of the cob operon: evidence that the last gene (cobT) catalyzes synthesis of the lower ligand of vitamin B12, dimethylbenzimidazole [12].
• Thus it was found that C-1 of glycine is incorporated into position 7a, C-2 of glycine into position 3a of the 5,6-dimethylbenzimidazole moiety of vitamin B12 [10].

Analytical, diagnostic and therapeutic context of Dimedazole

• From the behaviors in paper electrophoresis and the lability to CH- of cobalt-base bond of 0-2'-succinylated vitamin B12 derivatives, it was suggested that the terminal COOH of the 0-2'-succinyl group forms an inner salt with the imidazole nucleus of 5,6-dimethylbenzimidazole [21].

References