Shikimate Pathway Variants

莽草通路变异体

• 批准号: 6623429
• 负责人: JOHN W FROST
• 金额: $ 25.1万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6623429
• 关键词: Bacteroides; Escherichia coli; antiviral agents; biological products; directed evolution; drug design /synthesis /production; enzyme substrate; fructose phosphate; genetic manipulation; gram negative bacteria; mass spectrometry; peptide chemical synthesis; pyruvates; shikimate

DESCRIPTION (provided by applicant): Some of the more interesting aspects of natural product biosynthesis are the variations on common themes. A case in point is the shikimate pathway. Starting with the condensation of phosphoenolpyruvate with D-erythrose 4-phosphate, the shikimate pathway has been the focus of intense scrutiny. One variant of the shikimate pathway is found in Amycolatopsis mediterranei where 1-imino-1-deoxy-D-erythrose 4-phosphate replaces D-erythrose 4-phosphate as the likely starting point of what has been named the aminoshikimate pathway. The hypothesis that 3-amino-3-deoxy-D-fructose 6-phosphate is the source of 1-imino-1-deoxy-D-erythrose 4-phosphate will be explored. In turn, the biosynthesis of 3-amino-3-deoxy-D-fructose 6-phosphate is to be elaborated. Beyond answering fundamental biosynthetic questions associated with the source of the nitrogen atom utilized by the aminoshikimate pathway, proposed research could ultimately lead to a biocatalytic route to aminoshikimic acid suitable for use in the synthesis of anti-influenza agents. A second variant of the shikimate pathway is to be created in Escherichia coli where phosphoenolpyruvate will be replaced by pyruvate as the three-carbon metabolite condensed with D-erythrose 4-phosphate. This will require recruitment of native and evolved 2-keto-3-deoxy-6-phosphogalactonate aldolase to catalyze the condensation of pyruvate with D-erythrose 4-phosphate. Initiating the shikimate pathway with the condensation of pyruvate with D-erythrose 4-phosphate could substantially improve the yields of pharmaceutically important molecules microbially synthesized by way of this pathway and may serve as a paradigm of shikimate pathway variants employed by microbes under anaerobic growth conditions.

描述（由申请人提供）： 天然产物生物合成是共同主题的变体。的情况 点是莽草酸途径。从凝结开始 磷酸烯醇丙酮酸与D-赤藓糖4-磷酸，莽草酸途径具有 成为了严格审查的焦点 在地中海拟无枝酸菌中发现了莽草酸途径的一种变体 其中1-亚氨基-1-脱氧-D-赤藓糖4-磷酸替代D-赤藓糖4-磷酸 作为氨基莽草酸途径的可能起点。 假设3-氨基-3-脱氧-D-果糖6-磷酸是 将探索1-亚氨基-1-脱氧-D-赤藓糖4-磷酸。符合要求的细粉则随 3-氨基-3-脱氧-D-果糖6-磷酸的生物合成有待详细阐述。 除了回答与源头相关的基本生物合成问题之外 氨基莽草酸途径利用的氮原子，建议研究 可以最终导致一种生物催化途径，以氨基莽草酸适合 用于合成抗流感剂。 莽草酸途径的第二种变体将在大肠杆菌中产生 其中磷酸烯醇丙酮酸将被丙酮酸取代， 与D-赤藓糖4-磷酸缩合的代谢产物。这将需要 天然和进化的2-酮-3-脱氧-6-磷酸半乳糖酸醛缩酶的募集 催化丙酮酸与D-赤藓糖4-磷酸缩合。 通过丙酮酸与丙酮酸的缩合引发莽草酸途径， D-赤藓糖4-磷酸可显著提高 通过这种方式微生物合成的药物重要分子 途径，并可作为莽草酸途径变体的范例， 厌氧生长条件下的微生物。