Goins_2018_Biochemistry_57_2383

Reference

Title : Characterization of Tetrahydrolipstatin and Stereoderivatives on the Inhibition of Essential Mycobacterium tuberculosis Lipid Esterases - Goins_2018_Biochemistry_57_2383
Author(s) : Goins CM , Sudasinghe TD , Liu X , Wang Y , O'Doherty GA , Ronning DR
Ref : Biochemistry , 57 :2383 , 2018
Abstract :

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 beta-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 beta-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.

PubMedSearch : Goins_2018_Biochemistry_57_2383
PubMedID: 29601187
Gene_locus related to this paper: myctu-a85c , myctu-PKS13 , myctu-Rv3802c

Related information

Inhibitor Orlistat
Gene_locus Orlistat    myctu-a85c    myctu-PKS13    myctu-Rv3802c

Citations formats

Goins CM, Sudasinghe TD, Liu X, Wang Y, O'Doherty GA, Ronning DR (2018)
Characterization of Tetrahydrolipstatin and Stereoderivatives on the Inhibition of Essential Mycobacterium tuberculosis Lipid Esterases
Biochemistry 57 :2383

Goins CM, Sudasinghe TD, Liu X, Wang Y, O'Doherty GA, Ronning DR (2018)
Biochemistry 57 :2383