ArticleJournal of the American Chemical Society2012
Proton transfer from C-6 of uridine 5'-monophosphate catalyzed by orotidine 5'-monophosphate decarboxylase: formation and stability of a vinyl carbanion intermediate and the effect of a 5-fluoro substituent.
Article in Journal of the American Chemical Society, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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Who cites it
30 citing papers in PubMed, 42 citations in OpenAlex.
- The Role of Protein Side Chains in Enzyme-Activating Conformational Changes: Lessons from Studies on Variant Enzymes.Chemical reviews · 2025Review
- Dynamically Interacting Protein Networks Provide a Mechanism to Overcome the Enormous Intrinsic Barrier to Orotidine 5'-Monophosphate Decarboxylation.ACS central science · 2025Article
- Identification of Scaffold Specific Energy Transfer Networks in the Enthalpic Activation of Orotidine 5'-Monophosphate Decarboxylase.bioRxiv : the preprint server for biology · 2025Article
- Enabling Role of Ligand-Driven Conformational Changes in Enzyme Evolution.Biochemistry · 2022Review
- An Enzyme with High Catalytic Proficiency Utilizes Distal Site Substrate Binding Energy to Stabilize the Closed State but at the Expense of Substrate Inhibition.ACS catalysis · 2022Article
- Protein-Ribofuranosyl Interactions Activate Orotidine 5'-Monophosphate Decarboxylase for Catalysis.Biochemistry · 2021Article
- Implications for an imidazol-2-yl carbene intermediate in the rhodanase-catalyzed C-S bond formation reaction of anaerobic ergothioneine biosynthesis.ACS catalysis · 2021Article
- Study of intracellular anabolism of 5-fluorouracil and incorporation in nucleic acids based on an LC-HRMS method.Journal of pharmaceutical analysis · 2021Article
- Orotidine 5'-Monophosphate Decarboxylase: The Operation of Active Site Chains Within and Across Protein Subunits.Biochemistry · 2020Article
- Uncovering the Role of Key Active-Site Side Chains in Catalysis: An Extended Brønsted Relationship for Substrate Deprotonation Catalyzed by Wild-Type and Variants of Triosephosphate Isomerase.Journal of the American Chemical Society · 2019Article
- Role of the Carboxylate in Enzyme-Catalyzed Decarboxylation of Orotidine 5'-Monophosphate: Transition State Stabilization Dominates Over Ground State Destabilization.Journal of the American Chemical Society · 2019Article
- Enzyme Architecture: Breaking Down the Catalytic Cage that Activates Orotidine 5'-Monophosphate Decarboxylase for Catalysis.Journal of the American Chemical Society · 2018Article
- Primary Deuterium Kinetic Isotope Effects: A Probe for the Origin of the Rate Acceleration for Hydride Transfer Catalyzed by Glycerol-3-Phosphate Dehydrogenase.Biochemistry · 2018Article
- Orotidine 5'-Monophosphate Decarboxylase: Probing the Limits of the Possible for Enzyme Catalysis.Accounts of chemical research · 2018Review
- Enzyme Architecture: Erection of Active Orotidine 5'-Monophosphate Decarboxylase by Substrate-Induced Conformational Changes.Journal of the American Chemical Society · 2017Article
- A reevaluation of the origin of the rate acceleration for enzyme-catalyzed hydride transfer.Organic & biomolecular chemistry · 2017Review
- Substituent Effects on Carbon Acidity in Aqueous Solution and at Enzyme Active Sites.Synlett : accounts and rapid communications in synthetic organic chemistry · 2017Article
- Enzyme activation through the utilization of intrinsic dianion binding energy.Protein engineering, design & selection : PEDS · 2017Review
- Primary Deuterium Kinetic Isotope Effects From Product Yields: Rationale, Implementation, and Interpretation.Methods in enzymology · 2017Article
- Rate and Equilibrium Constants for an Enzyme Conformational Change during Catalysis by Orotidine 5'-Monophosphate Decarboxylase.Biochemistry · 2015Article
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7 authors at 3 institutions in 1 country.
Funding
Abstract
The exchange for deuterium of the C-6 protons of uridine 5'-monophosphate (UMP) and 5-fluorouridine 5'-monophosphate (F-UMP) catalyzed by yeast orotidine 5'-monophosphate decarboxylase (ScOMPDC) at pD 6.5-9.3 and 25 °C was monitored by (1)H NMR spectroscopy. Deuterium exchange proceeds by proton transfer from C-6 of the bound nucleotide to the deprotonated side chain of Lys-93 to give the enzyme-bound vinyl carbanion. The pD-rate profiles for k(cat) give turnover numbers for deuterium exchange into enzyme-bound UMP and F-UMP of 1.2 × 10(-5) and 0.041 s(-1), respectively, so that the 5-fluoro substituent results in a 3400-fold increase in the first-order rate constant for deuterium exchange. The binding of UMP and F-UMP to ScOMPDC results in 0.5 and 1.4 unit decreases, respectively, in the pK(a) of the side chain of the catalytic base Lys-93, showing that these nucleotides bind preferentially to the deprotonated enzyme. We also report the first carbon acid pK(a) values for proton transfer from C-6 of uridine (pK(CH) = 28.8) and 5-fluorouridine (pK(CH) = 25.1) in aqueous solution. The stabilizing effects of the 5-fluoro substituent on C-6 carbanion formation in solution (5 kcal/mol) and at ScOMPDC (6 kcal/mol) are similar. The binding of UMP and F-UMP to ScOMPDC results in a greater than 5 × 10(9)-fold increase in the equilibrium constant for proton transfer from C-6, so that ScOMPDC stabilizes the bound vinyl carbanions, relative to the bound nucleotides, by at least 13 kcal/mol. The pD-rate profile for k(cat)/K(m) for deuterium exchange into F-UMP gives the intrinsic second-order rate constant for exchange catalyzed by the deprotonated enzyme as 2300 M(-1) s(-1). This was used to calculate a total rate acceleration for ScOMPDC-catalyzed deuterium exchange of 3 × 10(10) M(-1), which corresponds to a transition-state stabilization for deuterium exchange of 14 kcal/mol. We conclude that a large portion of the total transition-state stabilization for the decarboxylation of orotidine 5'-monophosphate can be accounted for by stabilization of the enzyme-bound vinyl carbanion intermediate of the stepwise reaction.
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