(-)-
Matairesinol is a central biosynthetic intermediate to numerous 8-8'-lignans, including the
antiviral agent podophyllotoxin in Podophyllum species and its semi-synthetic anticancer derivatives
teniposide,
etoposide, and
Etopophos. It is formed by action of an enantiospecific
secoisolariciresinol dehydrogenase, an
NAD(H)-dependent
oxidoreductase that catalyzes the conversion of (-)-
secoisolariciresinol.
Matairesinol is also a plant-derived precursor of the
cancer-preventative "mammalian"
lignan or "
phytoestrogen"
enterolactone, formed in the gut following ingestion of high
fiber dietary foodstuffs, for example. Additionally,
secoisolariciresinol dehydrogenase is involved in pathways to important plant defense molecules, such as
plicatic acid in the western red cedar (Thuja plicata) heartwood. To understand the molecular and enantiospecific basis of Podophyllum
secoisolariciresinol dehydrogenase, crystal structures of the apo-form and binary/ternary complexes were determined at 1.6, 2.8, and 2.0 angstrom resolution, respectively. The
enzyme is a homotetramer, consisting of an alpha/beta single domain monomer containing seven parallel beta-strands flanked by eight alpha-helices on both sides. Its overall monomeric structure is similar to that of
NAD(H)-dependent
short-chain dehydrogenases/
reductases, with a conserved Asp47 forming a hydrogen bond with both
hydroxyl groups of the
adenine ribose of
NAD(H), and thus specificity toward
NAD(H) instead of
NADP(H). The highly conserved catalytic triad (Ser153, Tyr167, and Lys171) is adjacent to both
NAD(+) and substrate molecules, where Tyr167 functions as a general base. Following analysis of high resolution structures of the apo-form and two complex forms, the molecular basis for both the enantio-specificity and the reaction mechanism of
secoisolariciresinol dehydrogenase is discussed and compared with that of
pinoresinol-
lariciresinol reductase.