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ACS Infect Dis. 2018 Jun 8;4(6):904-911. doi: 10.1021/acsinfecdis.7b00263. Epub 2018 Apr 16.

Measuring the Global Substrate Specificity of Mycobacterial Serine Hydrolases Using a Library of Fluorogenic Ester Substrates.

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Department of Chemistry and Biochemistry , Butler University , 4600 Sunset Avenue , Indianapolis , Indiana 46208-3443 , United States.
Howard Hughes Medical Institute , Janelia Research Campus, 19700 Helix Drive , Ashburn , Virginia 20147-2439 , United States.


Among the proteins required for lipid metabolism in Mycobacterium tuberculosis are a significant number of uncharacterized serine hydrolases, especially lipases and esterases. Using a streamlined synthetic method, a library of immolative fluorogenic ester substrates was expanded to better represent the natural lipidomic diversity of Mycobacterium. This expanded fluorogenic library was then used to rapidly characterize the global structure activity relationship (SAR) of mycobacterial serine hydrolases in M. smegmatis under different growth conditions. Confirmation of fluorogenic substrate activation by mycobacterial serine hydrolases was performed using nonspecific serine hydrolase inhibitors and reinforced the biological significance of the SAR. The hydrolases responsible for the global SAR were then assigned using gel-resolved activity measurements, and these assignments were used to rapidly identify the relative substrate specificity of previously uncharacterized mycobacterial hydrolases. These measurements provide a global SAR of mycobacterial hydrolase activity, a picture of cycling hydrolase activity, and a detailed substrate specificity profile for previously uncharacterized hydrolases.


Mycobacterium tuberculosis; fluorogenic substrates; serine hydrolases; structure activity relationship; substrate specificity; tuberculosis

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