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A Direct, Early Stage Guanidinylation Protocol for the Synthesis of Complex Aminoguanidine-containing Natural Products
Published on: September 9, 2016
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Structure-based engineering of angucyclinone 6-ketoreductases
Pekka Patrikainen1, Laila Niiranen1, Keshav Thapa1
1Department of Biochemistry, University of Turku, 20014 Turku, Finland.
Chemistry & Biology
|September 10, 2014
Summary
Researchers elucidated how angucycline diversity arises from specific enzymes. Structural and chimeragenesis studies revealed key regions in short-chain alcohol dehydrogenases/reductases that control stereochemistry in drug synthesis.
Area of Science:
- Biochemistry
- Molecular Biology
- Natural Product Synthesis
Background:
- Angucyclines are biologically active tetracyclic polyketides from Streptomyces.
- Tailoring reactions diversify angucyclinones by modifying the benz[a]anthraquinone skeleton.
- Specific short-chain alcohol dehydrogenases/reductases (SDRs) like LanV and UrdMred/CabV dictate stereochemistry at C-6.
Purpose of the Study:
- To determine the structural basis for functional differentiation between SDRs involved in angucycline biosynthesis.
- To understand how these enzymes control the stereochemical outcome of 6-ketoreduction.
Main Methods:
- X-ray crystallography of LanV and UrdMred complexed with NADP+ and rabelomycin.
- Chimeragenesis experiments focusing on regions adjacent to the active site.
Main Results:
- Crystal structures revealed four key regions associated with functional differentiation in LanV and UrdMred.
- Chimeragenesis experiments successfully reversed the activities of LanV and CabV.
- Substrate conformation and stereochemical outcome of 6-ketoreduction are intimately linked.
Conclusions:
- Structural insights into SDRs explain the generation of angucyclinone diversity.
- Targeted modifications of SDRs can alter enzymatic activity and stereochemical outcome.
- This work provides a foundation for engineering novel angucycline derivatives.
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