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

药用药物中铅结构最常见的来源是微生物和植物产生的生物活性天然产物。发现新结构的可能性非常小，因为寻找生物活性产物依赖于对活生物体的随机筛选。没有一种实际合理的药物设计适用于铅结构的发现。本课题开发了一种寻找天然产物的合理方法，即基于基因组DNA序列和合成酶的分子进化，通过构建所有可能的代谢途径来预测未知的天然产物。随着基因组计划的进展。整个基因被鉴定为一个有机体。换句话说，天然产物的未知代谢途径可以通过从它们的基因中预测的一组酶来预测。研究者首先整理了1987种已知代谢物和96种主要代谢途径。对于一个给定的化合物。所有产生它作为代谢物的酶都是基于他之前为酶反应构建的配体化学数据库列出的。例如，谷氨酸是87种不同酶的产物或底物。通过将代谢物与这些酶连接起来，可能的途径就产生了。然而，产生的路径太复杂了。实际的生物体只使用有限的途径。未知的代谢途径被呈现为那些构建的和那些已知的差异。

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.