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Origin of starter units for erythromycin biosynthesis
K J Weissman1, M Bycroft, J Staunton
1Cambridge Centre for Molecular Recognition and Department of Organic Chemistry, University of Cambridge, Cambridge, UK.
Biochemistry
|August 7, 1998
Summary
Modular polyketide synthases (PKSs) are key to natural product synthesis. Purified 6-deoxyerythronolide B synthase (DEBS) 1-TE does not catalyze methylmalonyl-CoA decarboxylation, challenging prior findings.
Area of Science:
- Biochemistry and Molecular Biology
- Natural Product Synthesis
- Enzymology
Background:
- Modular polyketide synthases (PKSs) synthesize clinically important natural products.
- Their modular structure enables combinatorial synthesis of novel bioactive polyketides.
- Controlling starter acid supply is crucial for combinatorial PKS strategies.
Purpose of the Study:
- To investigate if the beta-ketosynthase (KS) domain of DEBS 1-TE can prime its own biosynthesis.
- To determine if DEBS 1-TE catalyzes methylmalonyl-CoA decarboxylation to propionyl-CoA.
Main Methods:
- Utilized rigorously purified DEBS 1-TE, a bimodular derivative of 6-deoxyerythronololide B synthase.
- Assayed for the decarboxylation activity of methylmalonyl-CoA to propionyl-CoA.
Main Results:
- Purified DEBS 1-TE did not exhibit methylmalonyl-CoA decarboxylation activity.
- This finding contrasts with previous reports on a similar mini-PKS, DEBS 1+TE.
Conclusions:
- The beta-ketosynthase domain in DEBS 1-TE does not appear to catalyze the priming reaction.
- This suggests limitations in using DEBS 1-TE for combinatorial biosynthesis strategies requiring self-priming activity.