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The biosynthesis of N-N bond-containing natural products

含N-N键天然产物的生物合成

基本信息

批准号：
9886650
负责人：
Emily Patricia Balskus
金额：
$ 37.24万
依托单位：
HARVARD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-01-01 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9886650
关键词：
Address Anabolism Architecture Attention Biochemical Biochemistry Biological Biology Breathing Chemical Structure Chemicals Chemistry Chemotherapy-Oncologic Procedure Clinical Clinical Trials Complex Drug Compounding Drug usage Enzymes Future Gene Cluster Genes Genome Genomics Goals Health Human Knowledge Life Logic Malignant Neoplasms Malignant neoplasm of pancreas Mediating Molecular Natural Products Nature Nitrogen Outcome Pathway interactions Pharmaceutical Preparations Pharmacologic Substance Proteins Reagent Research Savings Source Streptozocin Structure Synthesis Chemistry Work base bioactive natural products catalyst chemical reaction clinical candidate diazo compound enzyme pathway functional group guided inquiry improved interest microbial microorganism novel pharmacophore programs scaffold small molecule synthetic biology

项目摘要

PROJECT SUMMARY Microbial natural products possess complex chemical structures as well as potent biological activity and are an important source of drugs. While these molecules have captivated synthetic and medicinal chemists for decades, more recently the underlying biosynthetic pathways that construct natural product scaffolds have been recognized as important reservoirs of novel enzymes. Uncovering new enzymatic chemistry and biosynthetic strategies expands our basic understanding of Nature’s synthetic capabilities. It is also a critical first step toward applications of this fundamental knowledge and can serve as an inspiration for synthetic chemists. The long- term goal of the proposed research is to identify microbial enzymes that catalyze previously unappreciated chemical transformations. We envision discovering such enzymes by studying the biosynthesis of natural products containing important molecular architecture and functional groups of unknown biosynthetic origin. An important class of such structural motifs are functional groups containing a nitrogen-nitrogen (N–N) bond, a chemical linkage found in 9% of the 200 best-selling drugs. Reactive N–N bond-containing functional groups, including diazo and N-nitroso groups, are a critical part of biologically active small molecules including streptozotocin (Zanosar®), a clinically used treatment for metastatic pancreatic cancer. They are also uniquely enabling chemical reagents, with diazo compounds mediating many important and powerful chemical transformations in synthetic chemistry, biocatalysis, and biorthogonal chemistry. Though reactive N–N bonds are present in microbial natural products, their biosynthetic origins are poorly understood. Thus, the overall objective of this application is to discover and characterize enzymes that construct diazo- and N-nitroso- containing metabolites. Preliminary results from our lab and others have uncovered biosynthetic gene clusters responsible for constructing multiple diazo- and N-nitroso-containing natural products, including streptozotocin and other molecules that have been in clinical trials. These findings set the stage for our three complementary specific aims: 1) identify and characterize the biosynthetic enzymes responsible for constructing the diazo groups of the natural products cremeomycin and kinamycin; 2) identify and characterize the biosynthetic enzymes responsible for constructing the N-nitroso groups of the natural products streptozotocin and alanosine; 3) access additional diazo and N-nitroso biosynthetic enzymes and natural products by characterizing cryptic gene clusters. By leveraging the tremendous structural diversity of microbial natural products in the genomic era, we will rapidly discover and characterize biosynthetic transformations that fill critical gaps in our current knowledge of enzymatic chemistry capabilities. Finally, the workflow we have formulated for investigating the biosynthesis of reactive N– N bond-containing functional groups will also be readily generalizable to additional structural motifs found in microbial natural products.

项目总结