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SEARCH OF NOVEL BIOACTIVE NATURAL PRODUCTS BASED ON MOLECULAR EVOLUTION OF SYNTHETASES

基于合成酶分子进化的新型生物活性天然产物研究

基本信息

批准号：
06660134
负责人：
NISHIOKA Takaaki
金额：
$ 1.34万
依托单位：
KYOTO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (C)
财政年份：
1994
资助国家：
日本
起止时间：
1994 至 1995
项目状态：
已结题

项目摘要

MOST COMMON SOURCES OF LEAD STRUCTURES OF DRUGS FOR MEDICINAL USES ARE BIOACTIVE NATURAL PRODUCTS PRODUCED BY MICROORGANISMS AND PLANTS.THE PROBABILITY OF FINDING NOVEL STRUCTURE IS VERY SCARCE BECAUSE THE SEARCH OF BIOACTIVE PRODUCTS DEPENDS ON RANDOM SCREENING OF LIVING ORGANISMS.NO PRACTICAL RATIONAL DRUG DESIGN IS APPLICABLE TO LEAD STRUCTURE DISCOVERY.THE PRESENT RESEARCH PROJECT HAVE DEVELOPED A RATIONAL METHOD OF FINDING NATURAL PRODUCTS : THAT IS,IT PREDICTS UNKNOWN NATURAL PRODUCTS BY CONSTRUCTING ALL POSSIBLE METABOLIC PATHWAYS BASED ON GENOME DNA SEQUENCES AND MOLECULAR EVOLUTION OF SYNTHETIC ENZYMES.WITH THE PROGRESS OF GENOME PROJECTS.THE WHOLE GENES BECOME IDENTIFIED FOR AN ORGANISM.IN OTHER WORDS,UNKNOWN METABOLIC PATHWAYS TO NATURAL PRODUCTS COULD BE PREDICTED FROM A SET OF ENZYMES PREDICTED FROM THEIR GENES.THE INVESTIGATOR FIRST COMPILED 1987 KNOWN METABOLITES AND 96 MAIN METABOLIC PATHWAYS.FOR A GIVEN COMPOUND.ALL OF THE ENZYMES PRODUCING IT AS A METABOLITE ARE LISTED BASED ON THE LIGAND CHEMICAL DATABASE WHICH HE PREVIOUSLY CONSTRUCTED DATABASE FOR ENZYMATIC REACTIONS.FOR EXAMPLE,L-GLUTAMATE IS A PRODUCT OR SUBSTRATE OF 87 DIFFERENT ENZYMES.BY CONNECTING THE METABOLITES WITH THESE ENZYMES, POSSIBLE PATHWAYS ARE GENERATED.THE PATHWAYS GENERATED,HOWEVER,ARE TOO COMPLICATED.ACTUAL LIVING ORGANISMS USE ONLY A LIMITED NUMBER OF PATHWAYS.UNKNOWN METABOLIC PATHWAYS ARE PRESENTED AS THE DIFFERENCE OF THOSE CONSTRUCTED AND THOSE KNOWN.

药物先导结构的主要来源是微生物和植物产生的具有生物活性的天然产物。由于生物活性产物的筛选依赖于生物体的随机筛选，因此发现新结构的可能性很小。没有实用的合理药物设计适用于先导结构的发现。本研究项目提供了一种合理的天然产物发现方法：也就是说，它预测未知的天然产物，通过构建所有可能的代谢途径，基于基因组DNA序列和蛋白酶的分子进化。随着基因组计划的进展。整个基因被识别为一个有机体。换句话说，天然产物未知的代谢途径可以从一组从其基因预测的酶来预测。已知的代谢物和96个主要代谢途径。对于一个给定的化合物。所有的酶产生它作为一个代谢物是基于配体化学数据库，他以前建立的数据库酶反应。例如，L-谷氨酸是一个产品或87个不同的酶底物。通过连接代谢物与这些酶，可能的途径产生。然而，太复杂了。实际的生物体只使用有限数量的途径。未知的代谢途径以构建的和已知的代谢途径的差异表示。