Journal article
Secoisolariciresinol dehydrogenase: mode of catalysis and stereospecificity of hydride transfer in Podophyllum peltatum
Organic & biomolecular chemistry, Vol.4(5), pp.808-816
03/07/2006
Handle:
https://hdl.handle.net/2376/115720
PMID: 16493463
Abstract
Secoisolariciresinol dehydrogenase (SDH) catalyzes the NAD+ dependent enantiospecific conversion of secoisolariciresinol into matairesinol. In Podophyllum species, (-)-matairesinol is metabolized into the antiviral compound, podophyllotoxin, which can be semi-synthetically converted into the anticancer agents, etoposide, teniposide and Etopophos. Matairesinol is also a precursor of the cancer-preventative "mammalian" lignan, enterolactone, formed in the gut following ingestion of, for example, various high fiber dietary foods, as well as being an intermediate to numerous defense compounds in vascular plants. This study investigated the mode of enantiospecific Podophyllum SDH catalysis, the order of binding, and the stereospecificity of hydride abstraction/transfer from secoisolariciresinol to NAD+. SDH contains a highly conserved catalytic triad (Ser153, Tyr167 and Lys171), whose activity was abolished with site-directed mutagenesis of Tyr167Ala and Lys171Ala, whereas mutagenesis of Ser153Ala only resulted in a much reduced catalytic activity. Isothermal titration calorimetry measurements indicated that NAD+ binds first followed by the substrate, (-)-secoisolariciresinol. Additionally, for hydride transfer, the incoming hydride abstracted from the substrate takes up the pro-S position in the NADH formed. Taken together, a catalytic mechanism for the overall enantiospecific conversion of (-)-secoisolariciresinol into (-)-matairesinol is proposed.
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Details
- Title
- Secoisolariciresinol dehydrogenase: mode of catalysis and stereospecificity of hydride transfer in Podophyllum peltatum
- Creators
- Syed G A Moinuddin - Institute of Biological Chemistry, Washington State University, Pullman, WA 99164-6340, USABuhyun YounDiana L BedgarMichael A CostaGregory L HelmsChulHee KangLaurence B DavinNorman G Lewis
- Publication Details
- Organic & biomolecular chemistry, Vol.4(5), pp.808-816
- Academic Unit
- Chemistry, Department of; Biological Chemistry, Institute of; NMR Center
- Publisher
- England
- Grant note
- GM 66173 / NIGMS NIH HHS
- Identifiers
- 99900547803301842
- Language
- English
- Resource Type
- Journal article