7ruv

Structure of Human ATP:Cobalamin Adenosyltransferase E193K bound to adenosylcobalamin

spinqualitylabelsall models 7ruv, resolution 2.10Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7ruv is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.1Å Ligands: 5AD, B12, GOL, K, MG Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease MMAB_HUMAN Defects in MMAB are the cause of methylmalonic aciduria type cblB (MMAB) [MIM:251110; also known as methylmalonic aciduria type B or vitamin B12-responsive methylmalonicaciduria of cblB complementation type. MMAB is a disorder of methylmalonate and cobalamin metabolism due to defective synthesis of adenosylcobalamin. Inheritance is autosomal recessive. Function MMAB_HUMAN Publication Abstract from PubMed Human ATP:cob(I)alamin adenosyltransferase (ATR) is a mitochondrial enzyme that catalyzes an adenosyl transfer to cob(I)alamin, synthesizing 5 -deoxyadenosylcobalamin (AdoCbl) or coenzyme B12. ATR is also a chaperone that escorts AdoCbl, transferring it to methylmalonyl-CoA mutase, which is important in propionate metabolism. Mutations in ATR lead to methylmalonic aciduria type B (or MMAB), an inborn error of B12metabolism. Our previous studies have furnished insights into how ATR protein dynamics influence redox-linked cobalt coordination chemistry, controlling its catalytic versus chaperone functions. In this study, we have 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, which display only subtle structural changes. All three mutations were found to weaken affinities for the cob(II)alamin substrate and the AdoCbl product and increase KM(ATP). (31) P NMR studies show that binding of the triphosphate product, formed during the adenosylation reaction, is also weakened. However, while the kcatof this reaction is significantly diminished for the R190C/H mutants, it is comparable to wild-type enzyme for the E193K variant, revealing the catalytic importance of Arg-190. Furthermore, while the E193K mutation selectively impairs the chaperone function by promoting product release into solution, its catalytic function might be unaffected at physiological ATP concentrations. In contrast, the R190C/H mutations affect both the catalytic and chaperoning activities of ATR. Since the E193K mutation spares the catalytic activity of ATR, our data suggest that patients carrying this mutation are more likely to be responsive to cobalamin therapy. Patient mutations in human ATP:cob(I)alamin adenosyltransferase differentially affect its catalytic versus chaperone functions.,Gouda H, Mascarenhas R, Pillay S, Ruetz M, Koutmos M, Banerjee R J Biol Chem. 2021 Oct 29:101373. doi: 10.1016/j.jbc.2021.101373. PMID:34757128 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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