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

受抑制的磷脂酶和犬尿氨酸 AM 的单晶 X 射线衍射

• 批准号: 7601608
• 负责人: WILLIAM H CHURCH
• 金额: $ 0.28万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7601608
• 关键词: Binding; Brain; Cell Death; Complex; Computer Retrieval of Information on Scientific Projects Database; DNA Damage; Data Set; Dinoprostone; Enzymes; Exhibits; Fibroblasts; Funding; Grant; Human; Inflammatory; Institution; Kynurenic Acid; Kynurenine; Lead; Malignant neoplasm of prostate; Mediating; Multienzyme Complexes; Niacinamide; Nicotinamide adenine dinucleotide; Oxidative Stress; Pathway interactions; Patients; Pharmaceutical Preparations; Phospholipase; Phospholipase A2; Production; Rate; Research; Research Personnel; Resolution; Resources; Role; Schizophrenia; Source; Structure; Synovial Cell; Transferase; United States National Institutes of Health; Work; cytokine; enhancing factor; inhibitor/antagonist; kynurenine-pyruvate aminotransferase; novel; prevent; protein folding

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.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 新型分泌型磷脂酶A2（sPLA 2）抑制剂 sPLA 2酶调节精氨酸介导的炎症途径。外源性Ⅱ A族sPLA 2（sPLA 2-IIA）可增强类风湿关节炎患者滑膜成纤维细胞样细胞产生前列腺素E2（PGE 2）。此外，sPLA 2-IIA可以诱导前列腺癌细胞的增殖。sPLA 2-IIA表现出酶和活性独立的行动，我们已经开发出抑制剂，阻止这两个。我们最近收集了抑制剂酶复合物的14-BMC的高达1.6分辨率的高分辨率数据集。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。 作为精神分裂症药物的人犬尿氨酸氨基转移酶-I（hKAT-I）抑制剂 hKAT-I催化由犬尿氨酸形成犬尿烯酸。犬尿烯酸在精神分裂症患者的大脑和CSF中的水平升高。最近的研究表明，这是脑hKAT-I活性显著升高的结果。这作为一个令人信服的证据，这样的抑制剂将是一个有效的抗精神病药物，但目前还没有已知的特异性抑制剂的hKAT-I。我们已经确定了几个先导化合物和初步结果表明，这些化合物表现出很强的结合和有效的抑制hKAT-I。我们试图确定hKAT-I抑制剂复合物的结构。 前B细胞集落增强因子（PBEF） PBEF是烟酰胺磷酸核糖基转移酶（NAmPRTase）。NAmPRTases催化NAD补救途径中的限速步骤，表明PBEF在介导氧化应激、防止DNA损伤和细胞死亡中具有关键作用。 PBEF在结构上与任何已知的蛋白质折叠无关。我们期望确定结构将揭示PBEF的作用机制以及新的蛋白质折叠。