Chemical Mechanism of Homoisocitrate Dehydrogenase from Saccharomyces cerevisiae.

Chemical Mechanism of Homoisocitrate Dehydrogenase from Saccharomyces cerevisiae. Research Abstract Details 

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Chemical Mechanism of Homoisocitrate Dehydrogenase from Saccharomyces cerevisiae. Abstract Text:

Ying Lin,Jerome Volkman,Kenneth M Nicholas,Takashi Yamamoto,Tadashi Eguchi,Susan L Nimmo,Ann H West,Paul F Cook,

Homoisocitrate dehydrogenase (HIcDH, 3-carboxy-2-hydroxyadipate dehydrogenase) catalyzes the fourth reaction of the alpha-aminoadipate pathway for lysine biosynthesis, the conversion of homoisocitrate to alpha-ketoadipate using NAD as an oxidizing agent. A chemical mechanism for HIcDH is proposed on the basis of the pH dependence of kinetic parameters, dissociation constants for competitive inhibitors, and isotope effects. According to the pH-rate profiles, two enzyme groups act as acid-base catalysts in the reaction. A group with a p K a of ~6.5-7 acts as a general base accepting a proton as the beta-hydroxy acid is oxidized to the beta-keto acid, and this residue participates in all three of the chemical steps, acting to shuttle a proton between the C2 hydroxyl and itself. The second group acts as a general acid with a p K a of 9.5 and likely catalyzes the tautomerization step by donating a proton to the enol to give the final product. The general acid is observed in only the V pH-rate profile with homoisocitrate as a substrate, but not with isocitrate as a substrate, because the oxidative decarboxylation portion of the isocitrate reaction is limiting overall. With isocitrate as the substrate, the observed primary deuterium and (13)C isotope effects indicate that hydride transfer and decarboxylation steps contribute to rate limitation, and that the decarboxylation step is the more rate-limiting of the two. The multiple-substrate deuterium/ (13)C isotope effects suggest a stepwise mechanism with hydride transfer preceding decarboxylation. With homoisocitrate as the substrate, no primary deuterium isotope effect was observed, and a small (13)C kinetic isotope effect (1.0057) indicates that the decarboxylation step contributes only slightly to rate limitation. Thus, the chemical steps do not contribute significantly to rate limitation with the native substrate. On the basis of data from solvent deuterium kinetic isotope effects, viscosity effects, and multiple-solvent deuterium/ (13)C kinetic isotope effects, the proton transfer step(s) is slow and likely reflects a conformational change prior to catalysis.

Chemical Mechanism of Homoisocitrate Dehydrogenase from Saccharomyces cerevisiae. Publishing Authors By Initials

Y Lin,J Volkman,KM Nicholas,T Yamamoto,T Eguchi,SL Nimmo,AH West,PF Cook,

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Chemical Mechanism of Homoisocitrate Dehydrogenase from Saccharomyces cerevisiae. Journal Published:

PUBLICATION TYPE: Journal Article

Journal: Biochemistry

VOLUME: 47

Page Numbers: 4169-80

Journal Abbreviation: Biochemistry

ISSN: 0006-2960

DAY: 6

MONTH: 03

YEAR: 2008

Chemical Mechanism of Homoisocitrate Dehydrogenase from Saccharomyces cerevisiae. Information

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LANGUAGE: eng

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AFFILIATION: Department of Chemistry and Biochemistry, University of Oklahoma, 620 Parrington Oval, Norman, Oklahoma 73019, and Department of Chemistry and Materials Science, Tokyo Institute of Technology, O-okayama, Meguro-ku, Tokyo 152-8551, Japan pcook@ou.edu.

Country: United States

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MEDLINETA: Biochemistry

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