Protein–Ribofuranosyl Interactions Activate Orotidine 5′-Monophosphate Decarboxylase for Catalysis

脱羧 化学 立体化学 基质(水族馆) 裂解酶 活动站点 催化作用 生物化学 海洋学 地质学
作者
Judith R. Cristobal,Tiago A. S. Brandão,Archie C. Reyes,John P. Richard
出处
期刊:Biochemistry [American Chemical Society]
卷期号:60 (45): 3362-3373 被引量:6
标识
DOI:10.1021/acs.biochem.1c00589
摘要

The role of a global, substrate-driven, enzyme conformational change in enabling the extraordinarily large rate acceleration for orotidine 5′-monophosphate decarboxylase (OMPDC)-catalyzed decarboxylation of orotidine 5′-monophosphate (OMP) is examined in experiments that focus on the interactions between OMPDC and the ribosyl hydroxyl groups of OMP. The D37 and T100′ side chains of OMPDC interact, respectively, with the C-3′ and C-2′ hydroxyl groups of enzyme-bound OMP. D37G and T100′A substitutions result in 1.4 kcal/mol increases in the activation barrier ΔG⧧ for catalysis of decarboxylation of the phosphodianion-truncated substrate 1-(β-d-erythrofuranosyl)orotic acid (EO) but result in larger 2.1–2.9 kcal/mol increases in ΔG⧧ for decarboxylation of OMP and for phosphite dianion-activated decarboxylation of EO. This shows that these substitutions reduce transition-state stabilization by the Q215, Y217, and R235 side chains at the dianion binding site. The D37G and T100′A substitutions result in <1.0 kcal/mol increases in ΔG⧧ for activation of OMPDC-catalyzed decarboxylation of the phosphoribofuranosyl-truncated substrate FO by phosphite dianions. Experiments to probe the effect of D37 and T100′ substitutions on the kinetic parameters for d-glycerol 3-phosphate and d-erythritol 4-phosphate activators of OMPDC-catalyzed decarboxylation of FO show that ΔG⧧ for sugar phosphate-activated reactions is increased by ca. 2.5 kcal/mol for each −OH interaction eliminated by D37G or T100′A substitutions. We conclude that the interactions between the D37 and T100′ side chains and ribosyl or ribosyl-like hydroxyl groups are utilized to activate OMPDC for catalysis of decarboxylation of OMP, EO, and FO.
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