Publication Abstract from PubMed
Angucyclines are tetracyclic polyketides produced by Streptomyces bacteria that exhibit notable biological activities. The great diversity of angucyclinones is generated in tailoring reactions, which modify the common benz[a]anthraquinone carbon skeleton. In particular, the opposite stereochemistry of landomycins and urdamycins/gaudimycins at C-6 is generated by the short-chain alcohol dehydrogenases/reductases LanV and UrdMred/CabV, respectively. Here we present crystal structures of LanV and UrdMred in complex with NADP+ and the product analog rabelomycin, which enabled us to identify four regions associated with the functional differentiation. The structural analysis was confirmed in chimeragenesis experiments focusing on these regions adjacent to the active site cavity, which led to reversal of the activities of LanV and CabV. The results surprisingly indicated that the conformation of the substrate and the stereochemical outcome of 6-ketoreduction appear to be intimately linked.
Structure-Based Engineering of Angucyclinone 6-Ketoreductases.,Patrikainen P, Niiranen L, Thapa K, Paananen P, Tahtinen P, Mantsala P, Niemi J, Metsa-Ketela M Chem Biol. 2014 Sep 3. pii: S1074-5521(14)00249-X. doi:, 10.1016/j.chembiol.2014.07.017. PMID:25200607[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
