Bioinformatics Approach in Natural Products Discovery: A Cautionary Tale

摘要

In the past decade, the focus of drug discovery has shifted from the traditional natural product research to synthetic medicinalchemistry approach. However, many are reverting back to using natural products resources, but this time taking advantage ofthe booming area of genome sequencing. Using bioinformatics, many novel compounds have been isolated, even from the“unculturable” microbes. However, not all genes can be translated into proteins, and not all proteins are active. Two polyketidesynthase genes, MgPKS2 and MgPKS8, from the plant pathogen fungus Mycosphaerella graminicola were selected usingbioinformatics approach, and were cloned and transformed into a heterologous host, Aspergillus oryzae M-2-3. The genes werelinked with the enhanced green fluorescent protein (eGFP) to detect formation of protein. The transformed MgPKS2 did notshow the formation of the polyketide synthase enzyme but MgPKS8 did. The most possible reason for the negative result ofMgPKS2 is incorrect intron splicing in Aspergillus oryzae M-2-3. MgPKS8 transformants were extracted and checked forproduction of new metabolites using LC-MS. However, none was detected. Some of the possible reasons for these results arethe productions of new metabolites were below the detection level or, the polyketide need a special starter unit for biosynthesisor, incorrect protein folding. These results showed that this emerging method of natural product research has many hiddendifficulties that should be shared amongst the natural product community.