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Activation/Inhibition of Cholinesterases by Excess Substrate: Interpretation of the Phenomenological b Factor in Steady-State Rate Equation.
Mukhametgalieva, Aliya R; Nemtarev, Andrey V; Sykaev, Viktor V; Pashirova, Tatiana N; Masson, Patrick.
Afiliación
  • Mukhametgalieva AR; Biochemical Neuropharmacology Laboratory, Kazan Federal University, 18 Ul. Kremlevskaya, 420008 Kazan, Russia.
  • Nemtarev AV; Arbuzov Institute of Organic and Physical Chemistry, Kazan Scientific Center, Russian Academy of Sciences, 8 Ul. Arbuzov, 420088 Kazan, Russia.
  • Sykaev VV; Arbuzov Institute of Organic and Physical Chemistry, Kazan Scientific Center, Russian Academy of Sciences, 8 Ul. Arbuzov, 420088 Kazan, Russia.
  • Pashirova TN; Arbuzov Institute of Organic and Physical Chemistry, Kazan Scientific Center, Russian Academy of Sciences, 8 Ul. Arbuzov, 420088 Kazan, Russia.
  • Masson P; Biochemical Neuropharmacology Laboratory, Kazan Federal University, 18 Ul. Kremlevskaya, 420008 Kazan, Russia.
Int J Mol Sci ; 24(13)2023 Jun 21.
Article en En | MEDLINE | ID: mdl-37445649
Cholinesterases (ChEs) display a non-michaelian behavior with positively charged substrates. In the steady-state rate equation, the b factor describes this behavior: if b > 1 there is substrate activation, if b < 1 there is substrate inhibition. The mechanistic significance of the b factor was investigated to determine whether this behavior depends on acylation, deacylation or on both steps. Kinetics of human acetyl- (AChE) and butyryl-cholinesterase (BChE) were performed under steady-state conditions and using a time-course of complete substrate hydrolysis. For the hydrolysis of short acyl(thio)esters, where acylation and deacylation are partly rate-limiting, steady-state kinetic analysis could not decide which step determines b. However, the study of the hydrolysis of an arylacylamide, 3-(acetamido)-N,N,N-trimethylanilinium (ATMA), where acetylation is rate-limiting, showed that b depends on the acylation step. The magnitude of b and opposite b values between AChE and BChE for the hydrolysis of acetyl(thio)- versus benzoyl-(thio) esters, then indicated that the productive adjustment of substrates in the active center at high concentration depends on motions of both the Ω and the acyl-binding loops. Benzoylcholine was shown to be a poor substrate of AChE, and steady-state kinetics showed a sudden inhibition at high concentration, likely due to the non-dissociation of hydrolysis products. The poor catalytic hydrolysis of this bulky ester by AChE illustrates the importance of the fine adjustment of substrate acyl moiety in the acyl-binding pocket. Molecular modeling and QM/MM simulations should definitively provide evidence for this statement.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Colinesterasas / Ésteres Tipo de estudio: Prognostic_studies / Qualitative_research Límite: Humans Idioma: En Revista: Int J Mol Sci Año: 2023 Tipo del documento: Article País de afiliación: Rusia Pais de publicación: Suiza
Texto completo
Añadir a Mi BVS
Imprimir
XML
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Colinesterasas / Ésteres Tipo de estudio: Prognostic_studies / Qualitative_research Límite: Humans Idioma: En Revista: Int J Mol Sci Año: 2023 Tipo del documento: Article País de afiliación: Rusia Pais de publicación: Suiza