NSF Young Investigator: Studies on Oxidosqualene Cyclase and Catalytic Antibiotics

9457703格里芬·斯坦福大学将在美国国家科学基金会青年研究员奖下开展两个主要项目：(1)氧化橙烯环化酶(OSC)的详细分析和(2)对其细胞靶标表现出催化活性的抗菌剂的研制(即催化抗生素)。第一个项目的长期目标将是详细了解OSC酶的机理和结构，OSC酶催化氧化月桂烯转化为甾醇和相关的三萜类化合物。将制备OSCs的抑制剂，其中将包括具有良好的抗真菌活性的抑制剂。在第二个项目中，将检验这样一种假设，即对目标起催化作用的抗菌剂将比那些按化学计量作用的抗菌剂更有效。在这项研究中，杆菌肽，它隔离了细胞壁生物合成的中间体，含有焦磷酸杆菌烯基焦磷酸。这笔来自有机动力学项目的拨款支持斯坦福大学约翰·H·格里芬教授的研究。我们将探讨酶影响分子环化成类固醇的机制，并与酶的结构有关。根据对酶结构的了解，将制备这种酶的抑制剂，包括那些具有抗真菌活性的抑制剂。在另一个项目中，将从分子角度研究抗菌作用的机制。将对一种假设进行检验，以确定以催化方式工作的抗菌剂是否比不以催化方式工作的抗菌剂更有效。

9457703 Griffin Stanford University Two major projects will be pursued under this NSF Young Investigator Award: (1) The detailed analysis of oxidosqualene cyclase (OSC) enzymes and (2) The elaboration of antibacterial agents which exhibit catalytic activity towards their cellular targets (i.e., catalytic antibiotics). A long-term goal in the first project will be to gain a detailed mechanistic and structural understanding of OSC enzymes, which catalyze the transformation of oxidosqualene to sterols and related triterpenoids. Inhibitors of OSCs will be prepared that will include inhibitors with promising anti-fungal activity. In the second project, the hypothesis that antibacterial agents which act catalytically against their targets will be more potent than those which act stoichiometrically will be tested. In this study, bacitracin, which sequesters intermediates in cell wall biosynthesis containing bactoprenyl pyrophosphate will be investigated. This grant from the Organic Dynamics Program supports the research of Professor John H. Griffin at Stanford University. The mechanism by which an enzyme affects the cyclization of a molecule into steroids will be pursued and related to the structure of enzyme. From a knowledge of the structure of the enzyme, inhibitors of this enzyme will be prepared that include those with anti-fungal activity. In another project, the mechanism of antibacterial action will be investigated from a molecular perspective. A hypothesis will be tested to determine if antibacterial agents that operate in a catalytic manner are more potent than those that do not.