SINGLE CRYSTAL X-RAY DIFFRACTION OF INHIBITED PHOSPHOLIPASE AND KYNURENINE AM

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 分泌型磷脂酶A2(SPLA2)的新抑制剂 SPLA2酶调节细胞因子介导的炎症途径。外源性IIA单链磷脂酶A2(sPLA2-IIA)可促进RA患者成纤维样滑膜细胞产生前列腺素E2(PGE2)。此外，sPLA2-IIA还可以诱导前列腺癌细胞的增殖。sPLA2-IIA表现出酶和活性两种非依赖性作用，我们已经开发出同时阻断这两种作用的抑制剂。我们最近收集了高分辨率数据集，在14-BMC上的分辨率高达1.6&##酶复合体。我们正在开发更有效的抑制剂，我们希望通过类似的机制发挥作用，并寻求用高分辨率的晶体结构来证实这一点。 人犬尿氨酸转氨酶-I(hKAT-I)抑制剂治疗精神分裂症 HKAT-I催化犬尿氨酸生成犬尿酸。精神分裂症患者的大脑和脑脊液中犬尿酸水平升高。最近的研究表明，这是大脑hKAT-I活性显著增加的结果。这是一个令人信服的证据，证明这种抑制剂将是一种有效的抗精神病药物，然而，目前还没有已知的hKAT-I的特定抑制剂。我们已经鉴定了几个先导化合物，初步结果表明，这些化合物对hKAT-I具有很强的结合和有效的抑制作用。我们试图确定hKAT-I抑制剂复合体的结构。 前BCELL集落增强因子(PBEF) PBEF是一种烟酰胺磷酸核糖转移酶(NAMPRTase)。NAMPRTase催化NAD挽救途径中的限速步骤，提示PBEF在介导氧化应激、防止DNA损伤和细胞死亡方面起着关键作用。 PBEF在结构上与任何已知的蛋白质折叠无关。我们期望通过确定结构来揭示PBEF的作用机制以及新的蛋白质折叠。

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.