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A Chemoenzymatic Approach to Accessing Novel Isoprenoid Scaffolds

获取新型类异戊二烯支架的化学酶方法

基本信息

批准号：
10582364
负责人：
Shanteri Singh
金额：
$ 14.06万
依托单位：
UNIVERSITY OF OKLAHOMA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-01 至 2026-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10582364
关键词：
Acids Active Sites Address Alcohols Award Cannabinoids Cells Collaborations Coupled Coupling Diphosphates Engineering Environment Enzymes Escherichia coli Farnesol Funding Generations Geranyltranstransferase Goals Human In Situ In Vitro Industry Isoprene Kinetics Knowledge Libraries Medicine Metabolic Metabolic Pathway Methionine Methodology Methods Methyltransferase Minnesota Modernization Monitor Mutagenesis Natural Products Nature North Carolina Parents Pathway interactions Phosphotransferases Process Production Reaction S-Adenosylmethionine Source Squalene Squalene Synthetase Structure Structure-Activity Relationship System Technology Therapeutic Universities Variant Work analog analytical method base catalyst chemical synthesis combinatorial farnesyl pyrophosphate high throughput screening in vivo inorganic phosphate isopentenyl pyrophosphate isoprenoid metabolic engineering methionine adenosyltransferase non-Native novel prenyl scaffold synthetic biology

项目摘要

Summary of the funded parent award (1R01GM138800-01A1). Isoprenoids represent a diverse class of compounds with a broad range of applications in medicine and industry. Their extraction from natural sources is both challenging and potentially harmful to the environment, while the enormous structural complexity of many isoprenoids makes traditional chemical synthesis nontrivial. Modern metabolic engineering and synthetic biology approaches have overcome some of these difficulties, but issues related to metabolic flux and the limited availability of the universal isoprenoid precursors complicate their widespread implementation. The artificial pathways developed thus far have been solely focused on synthesizing dimethylallyl and isopentenyl diphosphates and require additional enzymes for the generation of polyprenyl-diphosphates (polyprenyl-PPs). Thus, the primary objective of this proposal is to develop an efficient strategy for the synthesis of both natural and unnatural (poly)prenyl-PPs for downstream applications. This will be achieved using two complementary methods: i) employing undecaprenol kinases and isopentenyl phosphate kinases; and ii) employing hydroxyethylthiazole kinase, isopentenyl phosphate kinases, and farnesyl diphosphate synthase. Additionally, the two methods will work in conjunction with isoprenoid methylatransferases to incorporate additional diversity into the polyprenyl- PPs. The proposed studies include: i) structural and functional assessment of selected enzymes, ii) catalyst engineering, and iii) optimization of coupled in vitro and in vivo platforms for the generation of diversified libraries of select natural products. We expect these studies to generate: i) rules and concepts to advance knowledge on structure-activity relationships in selected classes of enzymes; ii) an optimized, enzyme-coupled platform to generate diversified substrates and isoprenoids; and iii) novel isoprenoid analogs with potential therapeutic applications. Thus, the proposed work will offer unprecedented access to uniquely bioactive isoprenoid libraries not readily accessible via traditional methods, and it stands to deepen our fundamental understanding of four enzyme classes while also developing them into useful biocatalysts.

资助父母奖总结（1R01GM138800-01A1）。类异戊二烯代表了不同种类的