Dissecting and exploiting intermodular communication in polyketide synthases.
Modular polyketide synthases catalyze the biosynthesis of medicinally important natural products through an assembly-line mechanism. Although these megasynthases display very precise overall selectivity, we show that their constituent modules are remarkably tolerant toward diverse incoming acyl chains. By appropriate engineering of linkers, which exist within and between polypeptides, it is possible to exploit this tolerance to facilitate the transfer of biosynthetic intermediates between unnaturally linked modules. This protein engineering strategy also provides insights into the evolution of modular polyketide synthases.
Gokhale
R S
RS
Department of Chemical Engineering, Stanford University, Stanford CA 94305-5025, USA.
Tsuji
S Y
SY
Cane
D E
DE
Khosla
C
C
D000595:Amino Acid Sequence; D002384:Catalysis; D004926:Escherichia coli / Q000201:enzymology / Q000235:genetics; D019143:Evolution, Molecular; D005798:Genes, Bacterial; D007783:Lactones / Q000378:metabolism*; D018942:Macrolides / Q000378:metabolism; D008969:Molecular Sequence Data; D009097:Multienzyme Complexes / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D019906:Nuclear Magnetic Resonance, Biomolecular; D010455:Peptides / Q000378:metabolism; D015202:Protein Engineering; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism; D013302:Streptomyces / Q000201:enzymology
D007783:Lactones; D018942:Macrolides; D009097:Multienzyme Complexes; D010455:Peptides; D011993:Recombinant Fusion Proteins