November 19, 2021

The Banerjee lab publishes a paper in the Journal of Biological Chemistry

Patient mutations in human ATP:cob(I)alamin adenosyltransferase differentially affect its catalytic versus chaperone functions

Human ATP:cob(I)alamin adenosyltransferase (ATR) is a mitochondrial enzyme that catalyzes adenosyl transfer to cob(I)alamin, synthesizing 5´-deoxyadenosylcobalamin (AdoCbl) or coenzyme B12. ATR is also a chaperone that escorts AdoCbl to methylmalonyl-CoA mutase (MCM), which is important in propionate metabolism. Mutations in ATR lead to the metabolic disease methylmalonic aciduria type B. In this study, primary authors Harsha Gouda and Romila Mascarenhas and their colleagues characterized three patient mutations at two conserved active site residues in human ATR, R190C/H and E193K, and obtained crystal structures of R190C and E193K variants. Their combined kinetic, spectroscopic and structural studies reveal that while E193K ATR is likely to be catalytically active at physiologically relevant ATP concentrations, the mutation weakens affinity for the product, promoting AdoCbl release into solution versus transfer to MCM. In contrast, the R190C/H mutations significantly impair catalytic activity, while also diminishing product affinity, compromising both enzymatic and escort functions of ATR. On the basis of their biochemical data the authors predict that patients carrying the E193K mutation are more likely to be responsive to B12 therapy.

Read the JBC paper HERE.