Spectroscopic Evidence for the Formation of a Four-Coordinate Co~(2+)Cobalamin Species upon Binding to the Human ATP:Cobalamin Adenosyltransferase

摘要

The adenosylated derivative of vitamin B_(12),known as adeno-sylcobalamin (AdoCbl),is essential to all mammals,as it serves as the cofactor for the enzyme methylmalonyl-CoA mutase (MMCM) that detoxifies the cell of methylmalonyl-CoA,a harmful catabolite if allowed to accumulate.Humans are unable to synthesize AdoCbl de novo;rather,they assimilate exogenous cobalamin and convert it to AdoCbl using an enzyme that transfers the adenosyl group from ATP to the cobalamin cosubstrate (Figure 1).Malfunction of this human adenosyltransferase (hATR) can lead to the potentially fatal disease methylmalonic aciduria.Hence,elucidation of the molecular mechanism of cobalamin adenosylation catalyzed by hATR is of considerable interest.Probably the most fascinating,yet still poorly understood,aspect of this process is how hATR activates the cobalamin substrate for Co~(2+)Cbl->Co~(1+)Cbl reduction,as the corresponding reduction midpoint potential of -610 mV versus SHE is below that of in vivo reducing agents (step iii,Figure 1).