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Apo and holo structures of an NADP(H)-dependent cinnamyl alcohol dehydrogenase from Saccharomyces cerevisiae

Autor Valencia, Eva; Larroy, Carolina; Ochoa, Wendy F.; Parés, Xavier; Fita, Ignacio ; Biosca, Josep Antoni
Palabras clave yeast ADH
YADH, tetrameric alcohol dehydrogenases
PDH, polyol dehydrogenases
MDR, medium-chain dehydrogenases/reductases
half-of-the-sites reactivity
ADH, dimeric alcohol dehydrogenases
cinnamyl alcohol dehydrogenase
crystal structure
Fecha de publicación 20-ago-2004
EditorAcademic Press
Citación Journal of Molecular Biology 341(4): 1049-1062 (2004)
ResumenThe crystal structure of Saccharomyces cerevisiae ScAdh6p has been solved using the anomalous signal from the two zinc atoms found per subunit, and it constitutes the first structure determined from a member of the cinnamyl alcohol dehydrogenase family. ScAdh6p subunits exhibit the general fold of the medium-chain dehydrogenases/reductases (MDR) but with distinct specific characteristics. In the three crystal structures solved (two trigonal and one monoclinic), ScAdh6p molecules appear to be structural heterodimers composed of one subunit in the apo and the second subunit in the holo conformation. Between the two conformations, the relative disposition of domains remains unchanged, while two loops, Cys250-Asn260 and Ile277-Lys292, experience large movements. The apo-apo structure is disfavoured because of steric impairment involving the loop Ile277-Lys292, while in the holo-holo conformation some of the hydrogen bonds between subunits would break apart. These suggest that the first NADP(H) molecule would bind to the enzyme much more tightly than the second. In addition, fluorimetric analysis of NADPH binding demonstrates that only one cofactor molecule binds per dimer. Therefore, ScAdh6p appears to function according to a half-of-the-sites reactivity mechanism, resulting from a pre-existing (prior to cofactor binding) tendency for the structural asymmetry in the dimer. The specificity of ScAdh6p towards NADP(H) is mainly due to the tripod-like interactions of the terminal phosphate group with Ser210, Arg211 and Lys215. The size and the shape of the substrate-binding pocket correlate well with the substrate specificity of ScAdh6p towards cinnamaldehyde and other aromatic compounds. The structural relationships of ScAdh6p with other MDR structures are analysed. © 2004 Elsevier Ltd. All rights reserved.
Versión del editorhttp://dx.doi.org/10.1016/j.jmb.2004.06.037
URI http://hdl.handle.net/10261/111018
Identificadoresdoi: 10.1016/j.jmb.2004.06.037
issn: 0022-2836
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