Dealkylation of Coenzyme B₁₂ and Related Organocobalamins:  Ligand Structural Effects on Rates and Mechanisms of Hydrolysis

Abstract

Rates and mechanisms of dealkylations of coenzyme B12, Ado-B12, and of five related organocobalamin compounds, including 2‘,5‘-dideoxyadenosyl, 3‘,5‘-dideoxyadenosyl, 2‘,3‘,5‘-trideoxyadenosyl, 1,5-dideoxyribofuranosyl, and tetrahydrofurfuryl complexes (2‘dAdo-B12, 3‘dAdo-B12, 2‘,3‘ddAdo-B12, 1dRF-B12, and THFF-B12, respectively), were determined in acidic solutions. In each case, competitive homolytic and acid-induced hydrolytic cobalt−carbon bond decomposition pathways were identified. Two mechanisms were observed for Co−C bond hydrolysis: the first, involving initial depurination followed by elimination from an organometallic intermediate, predominates for 2‘dAdo-B12 and 2‘,3‘-ddAdoB12; the second path, involving ring-opening protonation at the ribofuranosyl oxygen, analogous to hydrolyses of simple β-hydroxy and β-alkoxy complexes, predominates for the other four complexes. The rates of both hydrolysis pathways exhibited a marked dependence on the ligand functional groups. Ado-B12, the most substituted and most stable of the complexes, decomposes nearly 10 000-fold more slowly than the least stable, unsubstituted THFF-B12 complex. Systematic variation of the hydroxy and adenine substituents on the furanosyl ring afforded insights into the roles of these substituents in effecting this large stabilization toward hydrolysis. Because of the extreme hydrolytic stability of the coenzyme, biologically relevant homolytic dissociation of 5‘-deoxyadenosyl radical is competitive with hydrolysis over a wide pH range where the unprotonated, base-on form is kinetically dominant. Determination of the pH dependence of the dealkylation rates of Ado-B12, 2‘dAdo-B12, and 3‘dAdo-B12 afforded quantification of the competition between homolytic and hydrolytic paths. In contrast to hydrolysis, the limiting homolytic Co−C bond dissociation rate was found to be insensitive to hydroxy substitution. Finally, broader issues relevant to organocobalamin chemistry and also bearing on earlier observations, are considered, among them protonation equilibria and dealkylation kinetics of organocobalamins, and fitting procedures for axial base dissociation equilibria.

Evaluation of Allergenic Metals and Other Trace Elements in Personal Care Products

“…All four transition metals are essential to humans, even though there is still some debate surrounding chromium. The only known biological function for cobalt is in vitamin B 12 , which is essential for various rearrangement and methylation reactions [16,17] . On the other hand, copper is essential for many processes including electron transfer (azurin and plastocyanin), oxygen atom transfer (e.g.…”

Cobalt:B12Enzymes & Coenzymes

“…More slowly (and under more acidic conditions), the organometallically bound deoxyadenosyl group is cleaved by heterolytic decomposition. 62, 63 The strength of the Co-C bond of coenzyme B 12 (3) has been estimated in the laboratories of Halpern 12 and of Finke 64,65 to be ca. 30 kcal mol −1 from a series of kinetic analyses of its thermal decomposition in aqueous and nonaqueous solutions.…”

Solution structure, enzymatic, and non-enzymatic reactivity of 3-isoadenosylcobalamin, a structural isomer of coenzyme B12 with surprising coenzymic activity

“…(6) can be neglected, and k homo;on can be calculated directly as k homo;obs =a on . Similarly, the heterolytic reactivity of base-off alkylcobalamins is also much smaller than that of the base-on species [71,88,89] so that the k het;off term in Eq. (7) may also be neglected, and k het;on is given by k het;obs =a on .…”