3-Ketoacyl ACP Synthase III: A Novel Antibiotic Target

3-酮脂酰 ACP 合酶 III：新型抗生素靶点

• 批准号: 7026511
• 负责人: KEVIN A REYNOLDS
• 金额: $ 28.22万
• 依托单位: PORTLAND STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-01 至 2008-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7026511
• 关键词: X ray crystallography; acetyl coA; active sites; acyl carrier protein; antibacterial agents; antibiotics; antiinfective agents; antimalarial agents; catalyst; chemical binding; drug design /synthesis /production; drug interactions; drug screening /evaluation; enzyme inhibitors; enzyme structure; enzyme substrate; fatty acid biosynthesis; fatty acid synthase; fluorimetry; nuclear magnetic resonance spectroscopy; polymerase chain reaction; site directed mutagenesis; stop flow technique; X ray crystallography; acetyl coA; active sites; acyl carrier protein; antibacterial agents; antibiotics; antiinfective agents; antimalarial agents; catalyst; chemical binding; drug design /synthesis /production; drug interactions; drug screening /evaluation; enzyme inhibitors; enzyme structure; enzyme substrate; fatty acid biosynthesis; fatty acid synthase; fluorimetry; nuclear magnetic resonance spectroscopy; polymerase chain reaction; site directed mutagenesis; stop flow technique

DESCRIPTION (provided by applicant): Fatty acid biosynthesis by a type II dissociated fatty acid synthase (FAS) is a fundamental and indispensable metabolic pathway in many organisms, including bacteria and parasites. The distinctions between this and the multifunctional type I FAS of higher organisms offer a selective target for the design of novel antibacterial and antiparasitic agents, needed to combat the resurgence of antibiotic-resistant bacteria and multidrug-resistant forms of the malaria-causing plasmodial parasites. In all type II FAS systems, the initial condensation step is carried out by 3-ketoacyl acyl carrier protein (ACP) synthase III (KASIII, FabH), which catalyzes the condensation of an acyl CoA substrate with malonyl ACP to generate a 3-ketoacyl ACP product. FabH also appears to play a key role in regulation of fatty acid biosynthesis and is not targeted by any current drugs, making it a particularly attractive new target for drug design. The long-term objective of our work is to understand the structural and mechanistic bases of FabH that define its physiological roles and to use this information to generate novel potent and selective inhibitors. This grant will extend our study of FabH enzymes from organisms such as Escherichia coil and Staphylococcus aureus, which initiate de novo fatty acid biosynthesis from different short chain acyl CoA substrates, and Mycobacterium tuberculosis, which uses FabH to initiate mycolate biosynthesis from long chain acyl CoA substrates. Mutational analyses and crystallography will be used to investigate the differing substrate and inhibitor specificities of these enzymes. In conjunction with ongoing crystallographic, molecular modeling and kinetic analyses, the mode of binding of 1,2-dithiole-3-one and related compounds which are potent novel active site FabH inhibitors, and a second series of inhibitors that appear to bind in the FabH phosphopantetheine binding channel, will be investigated. The information gathered from these studies will be used to design, synthesize and ultimately test inhibitors, which maximize interactions with both active site residues and those in either the acyl-binding pocket or phosphopantetheine-binding channel. Such compounds should have enhanced activity and selectivity against FabH and be powerful new lead compounds for development of novel antibacterial and antiparastitic/antimalarial drugs.

描述（由申请人提供）：II型解离脂肪酸合酶（FAS）的脂肪酸生物合成是许多生物体中的基本且不可或缺的代谢途径，包括细菌和寄生虫。该高等生物的多功能I FAS之间的区别为设计新型抗菌和抗寄生虫的设计提供了一个选择性的靶标，这些目标是应对抗生素耐药细菌的复兴以及由疟疾引起的疟疾质量质量寄生虫的复兴。在所有II型FAS系统中，最初的冷凝步骤均由3-酮酰基酰基载体蛋白（ACP）合酶III（KASIII，FABH）进行，该酰基蛋白（Kasiii，Fabh）催化了与malonyl ACP的酰基COA底物的缩合，以生成3-酮酰基ACP产品。 Fabh似乎在调节脂肪酸生物合成中也起着关键作用，并且没有任何当前药物的靶向，因此它是药物设计的特别有吸引力的新目标。 我们工作的长期目标是了解FABH定义其生理作用的FABH的结构和机械基础，并使用这些信息来产生新颖的有效和选择性抑制剂。这笔赠款将扩展我们对诸如Escherichia Coil和金黄色葡萄球菌等有机体的Fabh酶的研究，这些生物会从不同的短链酰基COA底物和结核菌的分枝杆菌中启动从头脂肪酸的生物合成，这些结核病使用Fabh从长期的蛋白酶蛋白酶蛋白酶替代。突变分析和晶体学将用于研究这些酶的不同底物和抑制剂特异性。结合持续的晶体学，分子建模和动力学分析，具有有效的新型活性位点FABH抑制剂的1,2-二二唑-3-one和相关化合物的结合模式，以及在FABH磷酸氨基磷酸结合通道中似乎结合的第二系列抑制剂，将被研究。从这些研究中收集的信息将用于设计，合成和最终测试抑制剂，从而最大程度地与活性位点残基和酰基结合袋或磷酸耐乙氨酸结合通道的相互作用最大化。 这样的化合物应具有对FABH的活性和选择性的增强，并且是新型抗菌和抗肉食/抗疟疾药物的有力新铅化合物。