Non-linear enzymatic logic in natural product modular mega-synthases and -synthetases.
Modular polyketide synthases and nonribosomal peptide synthetases are giant multienzymes that catalyze the assembly of a wide variety of bioactive natural products including several important clinical drugs. In simple mechanical terms, these systems function as molecular assembly lines, where each domain in the multienzyme performs its task once during the assembly process. However, several polyketide synthase and nonribosomal peptide synthetase systems have been discovered with architectures that suggest a deviation from this assembly line mechanistic logic. This article discusses progress toward understanding the mechanistic logic underlying such non-linear systems, identifies areas where further mechanistic insight into these systems is required and reflects on the likely consequences of non-linear enzymatic logic for attempts to genetically engineer modular polyketide synthases and nonribosomal peptide synthetases to produce analogs of bioactive natural products.
Haynes
Stuart W
SW
University of Warwick, Department of Chemistry, Coventry CV4 7AL, UK.
Challis
Gregory L
GL
D000818:Animals; D001688:Biological Products / Q000096:biosynthesis*; D006801:Humans; D008025:Ligases / Q000378:metabolism*; D017711:Nonlinear Dynamics
D001688:Biological Products; D008025:Ligases