Bioinformatic perspectives on NRPS/PKS megasynthases: advances and challenges.
The increased understanding of both fundamental principles and mechanistic variations of NRPS/PKS megasynthases along with the unprecedented availability of microbial sequences has inspired a number of in silico studies of both enzyme families. The insights that can be extracted from these analyses go far beyond a rough classification of data and have turned bioinformatics into a frontier field of natural products research. As databases are flooded with NRPS/PKS gene sequence of microbial genomes and metagenomes, increasingly reliable structural prediction methods can help to uncover hidden treasures. Already, phylogenetic analyses have revealed that NRPS/PKS pathways should not simply be regarded as enzyme complexes, specifically evolved to product a selected natural product. Rather, they represent a collection of genetic opinions, allowing biosynthetic pathways to be shuffled in a process of perpetual chemical innovations and pathways diversification in nature can give impulses for specificities, protein interactions and genetic engineering of libraries of novel peptides and polyketides. The successful translation of the knowledge obtained from bioinformatic dissection of NRPS/PKS megasynthases into new techniques for drug discovery and design remain challenges for the future.
Jenke-Kodama
Holger
H
Humboldt-University, Institute of Biology, Department of Molecular Ecology, Chausseestr. 117, 10115 Berlin, Germany.
Dittmann
Elke
E
D001688:Biological Products; D015195:Drug Design; D055808:Drug Discovery; D005827:Genetics, Microbial; D010453:Peptide Synthases; D048630:Polyketide Synthases
D001688:Biological Products; D048630:Polyketide Synthases; D010453:Peptide Synthases; C104385:non-ribosomal peptide synthase