A1 Vertaisarvioitu alkuperäisartikkeli tieteellisessä lehdessä
Structure-Based Engineering of Angucyclinone 6-Ketoreductases.
Tekijät: Patrikainen, Niiranen, Thapa, Paananen, Tähtinen, Mäntsälä, Niemi, Metsä-Ketelä
Julkaisuvuosi: 2014
Journal: Chemistry and Biology
Tietokannassa oleva lehden nimi: Chemistry & biology
Lehden akronyymi: Chem Biol
Vuosikerta: 21
Numero: 10
Aloitussivu: 1381
Lopetussivu: 1391
Sivujen määrä: 11
ISSN: 1879-1301
DOI: https://doi.org/10.1016/j.chembiol.2014.07.017
Tiivistelmä
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.
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.
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