Fluorogenic structure activity library pinpoints molecular variations in substrate specificity of structurally homologous esterases

The Journal of Biological Chemistry
Alex WhiteR Jeremy Johnson

Abstract

Cellular esterases catalyze many essential biological functions by performing hydrolysis reactions on diverse substrates. The promiscuity of esterases complicates assignment of their substrate preferences and biological functions. To identify universal factors controlling esterase substrate recognition, we designed a 32-member structure-activity relationship (SAR) library of fluorogenic ester substrates and used this library to systematically interrogate esterase preference for chain length, branching patterns, and polarity to differentiate common classes of esterase substrates. Two structurally homologous bacterial esterases were screened against this library, refining their previously broad overlapping substrate specificity. Vibrio cholerae esterase ybfF displayed a preference for γ-position thioethers and ethers, whereas Rv0045c from Mycobacterium tuberculosis displayed a preference for branched substrates with and without thioethers. We determined that this substrate differentiation was partially controlled by individual substrate selectivity residues Tyr-119 in ybfF and His-187 in Rv0045c; reciprocal substitution of these residues shifted each esterase's substrate preference. This work demonstrates that the selectivity of ...Continue Reading

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Citations

Oct 30, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Jonathan HiraChristian S Lentz
Apr 30, 2021·Protein Science : a Publication of the Protein Society·Isobel E BowlesGeoffrey C Hoops
Jul 20, 2021·ELife·Justin J MillerAudrey R Odom John
Jun 30, 2019·Analytical Chemistry·Kenton J HetrickRonald T Raines

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