ArticleJournal of the American Chemical Society2012
Bifunctionality of the thiamin diphosphate cofactor: assignment of tautomeric/ionization states of the 4'-aminopyrimidine ring when various intermediates occupy the active sites during the catalysis of yeast pyruvate decarboxylase.
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 11 papers.
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Who cites it
11 citing papers in PubMed, 31 citations in OpenAlex.
- Structures of Listeria monocytogenes MenD in ThDP-bound and in-crystallo captured intermediate I-bound forms.Acta crystallographica. Section F, Structural biology communications · 2025Article
- Improving tyrosol production efficiency through shortening the allosteric signal transmission distance of pyruvate decarboxylase.Applied microbiology and biotechnology · 2023Article
- Human 2-Oxoglutarate Dehydrogenase and 2-Oxoadipate Dehydrogenase Both Generate Superoxide/HNeurochemical research · 2019Review
- Constructing a synthetic pathway for acetyl-coenzyme A from one-carbon through enzyme design.Nature communications · 2019Article
- Evidence of Diradicals Involved in the Yeast Transketolase Catalyzed Keto-Transferring Reactions.Chembiochem : a European journal of chemical biology · 2018Article
- Thiamin Diphosphate Activation in 1-Deoxy-d-xylulose 5-Phosphate Synthase: Insights into the Mechanism and Underlying Intermolecular Interactions.The journal of physical chemistry. B · 2016Article
- Identification of charge transfer transitions related to thiamin-bound intermediates on enzymes provides a plethora of signatures useful in mechanistic studies.Biochemistry · 2014Article
- Electron density reactivity indexes of the tautomeric/ionization forms of thiamin diphosphate.Journal of molecular modeling · 2013Article
- Influence of allosteric regulators on individual steps in the reaction catalyzed by Mycobacterium tuberculosis 2-hydroxy-3-oxoadipate synthase.The Journal of biological chemistry · 2013Article
- Article
- Experimental observation of thiamin diphosphate-bound intermediates on enzymes and mechanistic information derived from these observations.Bioorganic chemistry · 2005Review
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Authors and funding
6 authors at 2 institutions in 2 countries.
Funding
Abstract
Thiamin diphosphate (ThDP) dependent enzymes perform crucial C-C bond forming and breaking reactions in sugar and amino acid metabolism and in biosynthetic pathways via a sequence of ThDP-bound covalent intermediates. A member of this superfamily, yeast pyruvate decarboxylase (YPDC) carries out the nonoxidative decarboxylation of pyruvate and is mechanistically a simpler ThDP enzyme. YPDC variants created by substitution at the active center (D28A, E51X, and E477Q) and on the substrate activation pathway (E91D and C221E) display varying activity, suggesting that they stabilize different covalent intermediates. To test the role of both rings of ThDP in YPDC catalysis (the 4'-aminopyrimidine as acid-base, and thiazolium as electrophilic covalent catalyst), we applied a combination of steady state and time-resolved circular dichroism experiments (assessing the state of ionization and tautomerization of enzyme-bound ThDP-related intermediates), and chemical quench of enzymatic reaction mixtures followed by NMR characterization of the ThDP-bound intermediates released from YPDC (assessing occupancy of active centers by these intermediates and rate-limiting steps). Results suggest the following: (1) Pyruvate and analogs induce active site asymmetry in YPDC and variants. (2) The rare 1',4'-iminopyrimidine ThDP tautomer participates in formation of ThDP-bound intermediates. (3) Propionylphosphinate also binds at the regulatory site and its binding is reflected by catalytic events at the active site 20 Å away. (4) YPDC stabilizes an electrostatic model for the 4'-aminopyrimidinium ionization state, an important contribution of the protein to catalysis. The combination of tools used provides time-resolved details about individual events during ThDP catalysis; the methods are transferable to other ThDP superfamily members.
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