Discovery and characterization of bioactive phosphonic acid biosynthetic pathways

生物活性膦酸生物合成途径的发现和表征

• 批准号: 164477712
• 负责人: Dr. Annette Erb
• 金额: --
• 依托单位: Chemical and Life Sciences Laboratory
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2009
• 资助国家: 德国
• 起止时间: 2008-12-31 至 2010-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/164477712?language=en
• 关键词: Discovery; characterization; bioactive; phosphonic; acid

Phosphonic acids are characterized by stable carbon-phosphorus bonds. A number of naturally produced phosphonates have been discovered which possess antibiotic activity. Fosmidomycin, a phosphonate produced by Streptomyces lavendulae, inhibits the nonmevalonate pathway of isoprenoid biosynthesis at an early stage, blocking the enzyme deoxyxylulose phosphate reductoisomerase (DXR). This pathway has been detected in the Malaria causing parasite Plasmodium falciparum, and fosmidomycin has been demonstrated to be active against this parasite. The aim of this project is to investigate the biosynthetic pathway of fosmidomycin and to elucidate the molecular basis of resistance against this compound. The biosynthetic gene cluster of this secondary metabolite has been cloned and sequenced. The identified open reading frames suggest that the fosmidomycin pathway differs from the recently elucidated pathway of the structurally similar compound FR900098. Knock-out mutants will be generated and analyzed for their production profile. Furthermore, enzymatic reactions will be tested in vitro to prove the proposed pathway and to understand the biochemistry of enzymes acting on C-P compounds. The elucidation of the pathway will help develop novel phosphonate lead compounds via combinatorial biosynthesis.

膦酸的特征在于稳定的碳-磷键。已经发现了许多天然产生的具有抗生素活性的膦酸酯。磷酰胺霉素是一种由链霉菌产生的膦酸盐，在早期阶段抑制类异戊二烯生物合成的非甲羟戊酸途径，阻断脱氧木酮糖磷酸还原异构酶（DXR）。已在引起疟疾的寄生虫恶性疟原虫中检测到该途径，并且已证明磷咪霉素对该寄生虫具有活性。本研究的目的是研究磷司霉素的生物合成途径，并阐明磷司霉素耐药的分子基础。该次级代谢产物的生物合成基因簇已被克隆和测序。鉴定的开放阅读框表明，磷霉素途径不同于最近阐明的结构相似化合物FR 900098的途径。将产生敲除突变体并分析其生产概况。此外，酶促反应将在体外进行测试，以证明所提出的途径，并了解酶作用于C-P化合物的生物化学。该途径的阐明将有助于通过组合生物合成开发新的膦酸酯先导化合物。