Computational study of substrate isotope effect probes of transition state structure for acetylcholinesterase catalysis

• Autorzy: Sikorski R. , Malany S. , Seravalli J. , Quinn D.
• Konferencja: Proceedings of the International Conference “2001 an Isotope Odyssey: New Application for a New Millenium", June 24-29, 2001, Zakopane, Poland
• Języki publikacji: EN

Abstrakty

EN

Secondary isotope effects for carbonyl addition reactions of methyl thioacetate, acetone and acetaldehyde have been calculated by ab initio quantum mechanical methods in an effort to interpret measured beta-deuterium isotope effects on acetylcholinesterase- catalyzed hydrolysis of acetylthiocholine. The calculated beta-deuterium isotope effect for equilibrium addition of methanol to methyl thioacetate is D3Keq = 0.965, and the corresponding effect for addition of methoxide ion to methyl thioacetate wherein three waters are hydrogen bonded to the carbonyl oxyanion is D3Keq = 1.086. Neither of these calculated isotope effects is as inverse as the experimental beta-deuterium isotope effect for acetylcholinesterase-catalyzed hydrolysis of acetylthiocholine, D3kE = 0.90š0.03. Structural comparisons show that the water-solvated methoxide adduct of methyl thioacetate is more expanded than is the neutral methanol addition adduct, and suggest that the degree to which the isotope effect is inverse (i.e. less than) is inversely correlated to the degree of expansion of the adduct. A similar correlation of beta-deuterium and beta-deuterium secondary isotope effects with the degree of expansion of the adducts is found for equilibrium additions of methanol and methoxide ion to acetaldehyde. These computational results suggest that the markedly inverse beta-deuterium isotope effect for the acetylcholinesterase reaction arises from enzymic compression of the transition state.

Słowa kluczowe

EN

acetylcholinesterase; carbonyl addition reactions; enzyme mechanisms; quantum mechanical calculation; transition state structure

• Wydawca: Institute of Nuclear Chemistry and Technology
• Czasopismo: Nukleonika
• Rocznik: 2002
• Tom: Vol. 47,suppl.1
• Strony: 9--12
• Opis fizyczny: Bibliogr. 20 poz., rys.

Twórcy

autor

Sikorski R.

• The University of Iowa, Department of Chemistry, 315 CB, Iowa City, IA 52242, USA, Tel.: [phone], Fax: [phone]

autor

Malany S.

• The University of Iowa, Department of Chemistry, Iowa City, IA 52242, USA Current address: Neurochemie, Max-Planck-Institut für Hirnforschung, 46 Deutschordenstr., Frankfurt, Germany

autor

Seravalli J.

• The University of Iowa, Department of Chemistry, Iowa City, IA 52242, USA Current address: Department of Biochemistry, University of Nebraska, The Beadle Center N113, Lincoln, NE 68588, USA

autor

Quinn D.

• The University of Iowa, Department of Chemistry, 315 CB, Iowa City, IA 52242, USA, Tel.: [phone], Fax: [phone]

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