8DYL

Crystal structure of human methylmalonyl-CoA mutase bound to aquocobalamin

Summary for 8DYL

• Entry DOI: 10.2210/pdb8dyl/pdb
• Descriptor: Methylmalonyl-CoA mutase, mitochondrial, COBALAMIN, GLYCEROL, ... (4 entities in total)
• Functional Keywords: cobalamin, mutase, vitamin b12, isomerase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 86718.74

Authors

Mascarenhas, R.N.,Gouda, H.,Banerjee, R. (deposition date: 2022-08-04, release date: 2023-07-12, Last modification date: 2023-10-25)

Primary citation

Gouda, H.,Mascarenhas, R.,Ruetz, M.,Yaw, M.,Banerjee, R.
Bivalent molecular mimicry by ADP protects metal redox state and promotes coenzyme B 12 repair.
Proc.Natl.Acad.Sci.USA, 120:e2220677120-e2220677120, 2023

PubMed Abstract: Control over transition metal redox state is essential for metalloprotein function and can be achieved via coordination chemistry and/or sequestration from bulk solvent. Human methylmalonyl-Coenzyme A (CoA) mutase (MCM) catalyzes the isomerization of methylmalonyl-CoA to succinyl-CoA using 5'-deoxyadenosylcobalamin (AdoCbl) as a metallocofactor. During catalysis, the occasional escape of the 5'-deoxyadenosine (dAdo) moiety leaves the cob(II)alamin intermediate stranded and prone to hyperoxidation to hydroxocobalamin, which is recalcitrant to repair. In this study, we have identified the use of bivalent molecular mimicry by ADP, coopting the 5'-deoxyadenosine and diphosphate moieties in the cofactor and substrate, respectively, to protect against cob(II)alamin overoxidation on MCM. Crystallographic and electron paramagnetic resonance (EPR) data reveal that ADP exerts control over the metal oxidation state by inducing a conformational change that seals off solvent access, rather than by switching five-coordinate cob(II)alamin to the more air stable four-coordinate state. Subsequent binding of methylmalonyl-CoA (or CoA) promotes cob(II)alamin off-loading from MCM to adenosyltransferase for repair. This study identifies an unconventional strategy for controlling metal redox state by an abundant metabolite to plug active site access, which is key to preserving and recycling a rare, but essential, metal cofactor.

PubMed: 36888659
DOI: 10.1073/pnas.2220677120

Experimental method

X-RAY DIFFRACTION (1.9 Å)