Redox-Linked Coordination Chemistry Directs Vitamin B 12 Trafficking

• Published in: Accounts of chemical research 2021-04, Vol.54 (8), p.2003-2013
• Main Authors: Banerjee, Ruma, Gouda, Harsha, Pillay, Shubhadra
• Format: Article
• Language: English
• Subjects: Cobalt - chemistry; Cobamides - chemistry; Coordination Complexes - chemistry; Humans; Lysosomes - metabolism; Methylmalonyl-CoA Mutase - chemistry; Methylmalonyl-CoA Mutase - metabolism; Methyltransferases - chemistry; Methyltransferases - metabolism; Mitochondria - metabolism; Oxidation-Reduction; Protein Structure, Tertiary; Vitamin B 12 - analogs & derivatives; Vitamin B 12 - chemistry; Vitamin B 12 - metabolism
• ISSN: 0001-4842; 1520-4898
• DOI: 10.1021/acs.accounts.1c00083

Metals are partners for an estimated one-third of the proteome and vary in complexity from mononuclear centers to organometallic cofactors. Vitamin B or cobalamin represents the epitome of this complexity and is the product of an assembly line comprising some 30 enzymes. Unable to biosynthesize cobalamin, mammals rely on dietary provision of this essential cofactor, which is needed by just two enzymes, one each in the cytoplasm (methionine synthase) and the mitochondrion (methylmalonyl-CoA mutase). Brilliant clinical genetics studies on patients with inborn errors of cobalamin metabolism spanning several decades had identified at least seven genetic loci in addition to the two encoding B enzymes. While cells are known to house a cadre of chaperones dedicated to metal trafficking pathways that contain metal reactivity and confer targeting specificity, the seemingly supernumerary chaperones in the B pathway had raised obvious questions as to the rationale for their existence.With the discovery of the genes underlying cobalamin disorders, our laboratory has been at the forefront of ascribing functions to B chaperones and elucidating the intricate redox-linked coordination chemistry and protein-linked cofactor conformational dynamics that orchestrate the processing and translocation of cargo along the trafficking pathway. These studies have uncovered novel chemistry that exploits the innate chemical versatility of alkylcobalamins, i.e., the ability to form and dismantle the cobalt-carbon bond using homolytic or heterolytic chemistry. In addition, they have revealed the practical utility of the dimethylbenzimidazole tail, an appendage unique to cobalamins and absent in the structural cousins, porphyrin, chlorin, and corphin, as an instrument for facilitating cofactor transfer between active sites.In this Account, we navigate the chemistry of the B trafficking pathway from its point of entry into cells, through lysosomes, and into the cytoplasm, where incoming cobalamin derivatives with a diversity of upper ligands are denuded by the β-ligand transferase activity of CblC to the common cob(II)alamin intermediate. The broad reaction and lax substrate specificity of CblC also enables conversion of cyanocobalamin (technically, vitamin B , i.e., the form of the cofactor in one-a-day supplements), to cob(II)alamin. CblD then hitches up with CblC via a unique Co-sulfur bond to cob(II)alamin at a bifurcation point, leading to the cytoplasmic methylcobalamin or mitochond