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Characterization of Tetrahydrolipstatin and Stereoderivatives on the Inhibition of Essential Mycobacterium tuberculosis Lipid Esterases.
Goins, Christopher M; Sudasinghe, Thanuja D; Liu, Xiaofan; Wang, Yanping; O'Doherty, George A; Ronning, Donald R.
Afiliación
  • Goins CM; Department of Chemistry and Biochemistry , University of Toledo , Toledo , Ohio 43606 , United States.
  • Sudasinghe TD; Department of Chemistry and Biochemistry , University of Toledo , Toledo , Ohio 43606 , United States.
  • Liu X; Department of Chemistry and Chemical Biology , Northeastern University , Boston , Massachusetts 02115 , United States.
  • Wang Y; Department of Chemistry and Chemical Biology , Northeastern University , Boston , Massachusetts 02115 , United States.
  • O'Doherty GA; Department of Chemistry and Chemical Biology , Northeastern University , Boston , Massachusetts 02115 , United States.
  • Ronning DR; Department of Chemistry and Biochemistry , University of Toledo , Toledo , Ohio 43606 , United States.
Biochemistry ; 57(16): 2383-2393, 2018 04 24.
Article en En | MEDLINE | ID: mdl-29601187
Tetrahydrolipstatin (THL) is a covalent inhibitor of many serine esterases. In mycobacteria, THL has been found to covalently react with 261 lipid esterases upon treatment of Mycobacterium bovis cell lysate. However, the covalent adduct is considered unstable in some cases because of the hydrolysis of the enzyme-linked THL adduct resulting in catalytic turnover. In this study, a library of THL stereoderivatives was tested against three essential Mycobacterium tuberculosis lipid esterases of interest for drug development to assess how the stereochemistry of THL affects respective enzyme inhibition and allows for cross enzyme inhibition. The mycolyltransferase Antigen 85C (Ag85C) was found to be stereospecific with regard to THL; covalent inhibition occurs within minutes and was previously shown to be irreversible. Conversely, the Rv3802 phospholipase A/thioesterase was more accepting of a variety of THL configurations and uses these compounds as alternative substrates. The reaction of the THL stereoderivatives with the thioesterase domain of polyketide synthase 13 (Pks13-TE) also leads to hydrolytic turnover and is nonstereospecific but occurs on a slower, multihour time scale. Our findings suggest the stereochemistry of the ß-lactone ring of THL is important for cross enzyme reactivity, while the two stereocenters of the peptidyl arm can affect enzyme specificity and the catalytic hydrolysis of the ß-lactone ring. The observed kinetic data for all three target enzymes are supported by recently published X-ray crystal structures of Ag85C, Rv3802, and Pks13-TE. Insights from this study provide a molecular basis for the kinetic modulation of three essential M. tuberculosis lipid esterases by THL and can be applied to increase potency and enzyme residence times and enhance the specificity of the THL scaffold.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Tuberculosis / Esterasas / Lactonas / Mycobacterium tuberculosis Límite: Humans Idioma: En Revista: Biochemistry Año: 2018 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Tuberculosis / Esterasas / Lactonas / Mycobacterium tuberculosis Límite: Humans Idioma: En Revista: Biochemistry Año: 2018 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos