This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. NEW INHIBITORS OF SECRETED PHOSPHOLIPASE A2 (sPLA2) sPLA2 enzymes regulate cytokine-mediated inflammatory pathways. Exogenous Group IIA sPLA2(sPLA2-IIA)can enhance prostaglandin E2(PGE2)production in fibroblast-like synovial cells from RA patients. Furthermore sPLA2-IIA can induce the proliferation of prostate cancer cells.sPLA2-IIA exhibits both enzymatic and activity independent actions and we have developed inhibitors that block both. We recently collected high resolution datasets up to 1.6 Ǻ resolution on 14-BMC of the inhibitor enzyme complex. We are developing more potent inhibitors that we hope will work via a similar mechanism and seek to confirm this with high resolution crystal structures. HUMAN KYNURENINE AMINOTRANSFERASE-I (hKAT-I) INHIBITORS AS DRUGS FOR SCHIZOPHRENIA hKAT-I catalyses the formation of kynurenic acid from kynurenine. Kynurenic acid is found in elevated levels in the brains and CSF of patients with schizophrenia. Recent studies demonstrate that this is a consequence of significantly higher brain hKAT-I activity. This serves as compelling evidence that such an inhibitor would be an efficacious anti-psychotic agent, however there are currently no known specific inhibitors of hKAT-I.We have identified several lead compounds and preliminary results suggest that these compounds exhibit strong binding and potent inhibition of hKAT-I. We seek to determine the structure of the hKAT-I inhibitor complex. PRE-BCELL COLONY ENHANCING FACTOR (PBEF) PBEF is a nicotinamide phosphoribosyl transferase (NAmPRTase). NAmPRTases catalyse the rate limiting step in the salvage pathway of NAD suggesting that PBEF has a key role in mediating oxidative stress, preventing DNA damage and cell death. PBEF is not structurally related to any known protein fold. We expect that determining the structure will reveal the mechanism of action of PBEF as well as novel protein folds.
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