Polyketide biosynthesis: understanding and exploiting modularity.
Polyketide-based pharmaceuticals are some of our most important medicines. They are constructed in micro-organisms (typically bacteria and fungi) by gigantic enzyme catalysts called polyketide synthases (PKSs). The organization of PKSs into molecular assembly lines makes them particularly appealing targets for genetic engineering because, in principle, an alteration in the enzyme organization might translate into a predictable change in polyketide structure. Excitingly, this has been shown repeatedly to work in practice, but the efficiency of the engineered PKSs is frequently too low to be useful for large-scale drug synthesis. To reach this goal, researchers need a deeper understanding of the structure and function of these proteins, which are among the most complex in nature. This review highlights some recent experiments which are providing key information about the molecular organization, mechanism and orchestration of these magnificent catalysts, and opening up fresh prospects of truly combinatorial biosynthesis of novel polyketides as leads in drug discovery.
Weissman
Kira J
KJ
Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, UK. kjw21@cus.cam.ac.uk
D000890:Anti-Infective Agents / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use; D001419:Bacteria / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites; D015195:Drug Design; D005658:Fungi / Q000235:genetics / Q000378:metabolism*; D005818:Genetic Engineering / Q000379:methods*; D018942:Macrolides / Q000737:chemistry* / Q000378:metabolism* / Q000627:therapeutic use; D008968:Molecular Conformation; D011994:Recombinant Proteins / Q000378:metabolism; D013329:Structure-Activity Relationship
D000890:Anti-Infective Agents; D000970:Antineoplastic Agents; D018942:Macrolides; D011994:Recombinant Proteins