Abstract
The Mycobacterium tuberculosis rv3802c gene encodes an essential enzyme with thioesterase and phospholipase A activity. Overexpression of Rv3802 orthologs in Mycobacterium smegmatis and Corynebacterium glutamicum increases mycolate content and decreases glycerophospholipids. Although a role in modulating the lipid composition of the unique mycomembrane has been proposed, the true biological function of Rv3802 remains uncertain. In this study, we present the first M. tuberculosis Rv3802 X-ray crystal structure, solved to 1.7 Å resolution. On the basis of the binding of PEG molecules to Rv3802, we identified its lipid-binding site and the structural basis for phosphatidyl-based substrate binding and phospholipase A activity. We found that movement of the α8-helix affords lipid binding and is required for catalytic turnover through covalent tethering. We gained insights into the mechanism of acyl hydrolysis by observing differing arrangements of PEG and water molecules within the active site. This study provides structural insights into biological function and facilitates future structure-based drug design toward Rv3802.
Highlights
The Mycobacterium tuberculosis rv3802c gene encodes an essential enzyme with thioesterase and phospholipase A activity
The M. tuberculosis cell envelope consists of four major components: an inner cytoplasmic membrane, a periplasmic region composed of the peptidoglycan and arabinogalactan, the
The biological function of rv3802c remains in question; the gene has been determined to be essential for M. tuberculosis viability (10 –12)
Summary
The Mycobacterium tuberculosis rv3802c gene encodes an essential enzyme with thioesterase and phospholipase A activity. Overexpression of Rv3802 orthologs in Mycobacterium smegmatis and Corynebacterium glutamicum increases mycolate content and decreases glycerophospholipids. On the basis of the binding of PEG molecules to Rv3802, we identified its lipid-binding site and the structural basis for phosphatidyl-based substrate binding and phospholipase A activity. The biological function of rv3802c remains in question; the gene has been determined to be essential for M. tuberculosis viability (10 –12). M. tuberculosis Rv3802 structure and lipid binding and MSMEG_6394) in addition to the Corynebacterium glutamicum ortholog NCgl2775 (11). Based on the location of the identified lipid-binding site and previous studies, further insights into a biological function for Rv3802 are gained as well as a basis for future structure-based drug design efforts
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