Biology subjects

Kachhap, S.

Publications and source records attributed to Kachhap, S..

2 recordsLinked to original sources

bioRxiv2021

Allosteric cooperation in β-lactam binding to a non-classical transpeptidase

Mycobacterium tuberculosis peptidoglycan (PG) is atypical as its synthesis involves a new enzyme class, L,D-transpeptidases. Prior studies of L,D-transpeptidases have identified only the catalytic site that binds to peptide moiety of the PG substrate or {beta}-lactam antibiotics. This insight was leveraged to develop mechanism of its activity and inhibition by {beta}-lactams. Here we report identification of an allosteric site at a distance of 21 [A] from the catalytic site that binds the sugar moiety of PG substrates (hereafter referred to as the S-pocket). This site also binds a second {beta}-lactam molecule and influences binding at the catalytic site. We provide evidence that two {beta}-lactam molecules bind co-operatively to this enzyme, one non-covalently at the S-site and one covalently at the catalytic site. This dual {beta}-lactam binding phenomenon is previously unknown and is an observation that may offer novel approaches for the structure-based design of new {beta}-lactam antibiotics for M. tuberculosis.

biochemistry↗

bioRxiv2020

Supraphysiological testosterone induces ferroptosis and activates NF-kappaB mediated immune pathways in prostate cancer through nucleophagy

The discovery that androgens play an important role in the progression of prostate cancer (PCa) has led to the development of androgen deprivation therapy as a first line of treatment against PCa. However, paradoxical growth inhibition has been observed, both experimentally and clinically, in a subset of PCa upon administration of supraphysiological levels of testosterone (SupraT). Here we report that SupraT activates cytoplasmic nucleic acid sensors and induces growth inhibition of SupraT-sensitive PCa cells. This is initiated by induction of two parallel autophagy-mediated processes, namely, ferritinophagy and nucleophagy. Consequently, autophagosomal DNA activates nucleic acid sensors that converge on NF-kappaB to drive immune signaling pathways. Chemokines and cytokines secreted by the tumor cells in response to SupraT results in increased migration of cytotoxic immune cells to tumor beds of animal xenografts and patient tumors. Collectively, our findings indicate that SupraT may inhibit a subset of PCa by activating nucleic acid sensors and downstream immune signaling.

cancer biology↗