Refereed journal article or data article (A1)

Structure-Based Engineering of Angucyclinone 6-Ketoreductases.




List of Authors: Patrikainen, Niiranen, Thapa, Paananen, Tähtinen, Mäntsälä, Niemi, Metsä-Ketelä

Publication year: 2014

Journal: Chemistry and Biology

Journal name in source: Chemistry & biology

Journal acronym: Chem Biol

Volume number: 21

Issue number: 10

Number of pages: 11

ISSN: 1879-1301

DOI: http://dx.doi.org/10.1016/j.chembiol.2014.07.017


Abstract
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.


Last updated on 2021-24-06 at 08:08