Journal
SCIENCE
Volume 320, Issue 5873, Pages 243-246Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.1154711
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Funding
- NIAID NIH HHS [R37 AI014937, R37 AI014937-30] Funding Source: Medline
- NIEHS NIH HHS [ES001670, R01 ES001670] Funding Source: Medline
- NIGMS NIH HHS [F32 GM079408-02, T32 GM080189, R01 GM067725, GM079408, F32 GM079408-01, GM067725, GM070421, R01 GM067725-05] Funding Source: Medline
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PksA, which initiates biosynthesis of the environmental carcinogen aflatoxin B1, is one of the multidomain iterative polyketide synthases (IPKSs), a large, poorly understood family of biosynthetic enzymes. We found that dissection of PksA and its reconstitution from selected sets of domains allows the accumulation and characterization of advanced octaketide intermediates bound to the enzyme, permitting the reactions controlled by individual catalytic domains to be identified. A product template (PT) domain unites with the ketosynthase and thioesterase in this IPKS system to assemble precisely seven malonyl-derived building blocks to a hexanoyl starter unit and mediate a specific cyclization cascade. Because the PT domain is common among nonreducing IPKSs, these mechanistic features should prove to be general for IPKS-catalyzed production of aromatic polyketides.
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