Engineering broader specificity into an antibiotic-producing polyketide synthase.
The wide-specificity loading module for the avermectin-producing polyketide synthase was grafted onto the first multienzyme component (DEBS1) of the erythromycin-producing polyketide synthase in place of the normal loading module. Expression of this hybrid enzyme in the erythromycin producer Saccharopolyspora erythraea produced several novel antibiotic erythromycins derived from endogenous branched-chain acid starter units typical of natural avermectins. Because the avermectin polyketide synthase is known to accept more than 40 alternative carboxylic acids as starter units, this approach opens the way to facile production of novel analogs of antibiotic macrolides.
Marsden
A F
AF
Cambridge Centre for Molecular Recognition and Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QW, UK.
Wilkinson
B
B
Cortés
J
J
Dunster
N J
NJ
Staunton
J
J
Leadlay
P F
PF
D000900:Anti-Bacterial Agents / Q000096:biosynthesis*; D002264:Carboxylic Acids / Q000378:metabolism; D003001:Cloning, Molecular; D004917:Erythromycin / Q000031:analogs & derivatives* / Q000096:biosynthesis; D005285:Fermentation; D007559:Ivermectin / Q000031:analogs & derivatives / Q000378:metabolism; D009097:Multienzyme Complexes / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D015202:Protein Engineering; D055503:Protein Multimerization; D016930:Saccharopolyspora / Q000201:enzymology; D013302:Streptomyces / Q000201:enzymology; D013379:Substrate Specificity
D000900:Anti-Bacterial Agents; D002264:Carboxylic Acids; D009097:Multienzyme Complexes; D004917:Erythromycin; D007559:Ivermectin; C019264:avermectin