If an enzyme name is shown in bold, there is experimental evidence for this enzymatic activity.
|Superclasses:||Biosynthesis → Secondary Metabolites Biosynthesis → Phenylpropanoid Derivatives Biosynthesis → Lignans Biosynthesis|
Expected Taxonomic Range: Viridiplantae
Lignans are a group of dimeric and/or oligomeric plant natural compounds of phenylpropanoid origin. They represent a structurally highly diverse compound class that is characterized by a 8,8'-linkage found in the C6-C3 dimers of coniferyl alcohol or other cinnamoyl alcohols although other interunit linkages (e.g. 8-5', 8-O-4) may also occur [Lewis99a] [Fuss03].
Lignans and lignins are biosynthesized in two major branches which descend from the phenylpropanoid pathway. During the conquest of land this pathway has been substantially advanced with consequences for derivative biosyntheses such as for lignins/lignans, hydrolyzable and condensed tannins and flavonoids [Stafford00]. Lignans are widespread among the plant kingdom but have not been found in aquatic plants such as algae indicating their crucial contribution to adaptation and fitness of terrestrial plants [Ayres90] [Burlat01]. The structural biopolymers lignins and lignans accomplish different tasks in plants, lignins are involved in structural support and lignans have been attributed to protection and defense as their primary physiological functions. Taken together lignins and lignans count for about 30% of carbon in vascular plants [Lewis99a].
Beside their recognized functions as defense compounds in plants some lignans have attracted the attention of scientists because of their application in medicine and human health [MacRae84]. Lignans possess most effective health protective and curative properties and have been employed as antioxidants [Bloedon04], anti-carcinogenic agents [Ford99] [Saleem05] and phytoestrogens [Dixon04].
Lignans can be subdivided into several structural subfamilies. The matairesinol pathway is an excellent example for a pathway that not only contains several types of lignans but also gives rise to other lignan subfamilies. (+)-pinoresinol (a furofuran) is sequentially converted to (+)-lariciresinol (a benzylaryltetrahydrofuran), (-)-secoisolariciresinol (a dibenzylbutane) and (-)-matairesinol (a dibenzylbutyrolactone) which is an intermediate in the biosynthetic route towards podophyllotoxin (an aryltetrahydronaphthalene) (compare podophyllotoxin and 6-methoxypodophyllotoxin biosynthesis).
About This Pathway
Most lignans are optically active which results from the stereo-specific linkage that builds the various dimers. The unique protein that mediates the regio- and stereospecificity of bimolecular phenoxy radical coupling to generate oligomeric lignans and polymeric lignins has been identified and characterized [Davin97]. It could be demonstrated that this protein forms a multigene family in plants [Kim02a] which are not limited to the formation of lignans but has been found to be involved in other biosyntheses of various phenolics employing corresponding radicals. The protein named 'dirigent protein' (DP) does not express any catalytic activity and serves only to bind and orientate the coniferyl alcohol-derived free radicals [Davin00] [Davin05]. The first step of the biosynthesis therefore includes two proteins, one enzyme which may be a unspecific oxidase and/or laccase and the dirigent protein mediating the radical-radical coupling with two coniferyl alcohol radical substrates [Halls02] [Halls04].
Two distinct enzyme classes of (+)-pinoresinol/(+)-lariciresinol reductase (PLR) have been identified that catalyze the second step in the matairesinol biosynthesis. Those enzymes are bifunctional and catalyze the enantioselective reduction of (+)-pinoresinol and (+)-lariciresinol towards (-)-secoisolaricinol as discovered in Forsythia [DinkovaKostova96] - left branch of the pathway- or engenders the formation of the opposite enantiomer (+)-secoisolariciresinol from (-)-pinoresinol and (-)-lariciresinol intermediates as demonstrated in western red cedar [Fujita99] - right branch of the pathway. Those enantiospecific enzymes have also been found in different species of the same genus [vonHeimendahl05].
Another bifunctional enzyme, i.e. (-)-secoisolariciresinol dehydrogenase (SDH) affords the formation of (-)-matairesinol [Umezawa91] via the stable intermediate (-)-lactol [Xia01a]. The reaction mechanism was investigated in detail by means of the crystallized protein and it was shown that a catalytic triad with a strictly conserved tyrosine residue [Youn05] was essential for catalytic activity [Moinuddin06].
Davin00: Davin LB, Lewis NG (2000). "Dirigent proteins and dirigent sites explain the mystery of specificity of radical precursor coupling in lignan and lignin biosynthesis." Plant Physiol 123(2);453-62. PMID: 10859176
Davin97: Davin LB, Wang HB, Crowell AL, Bedgar DL, Martin DM, Sarkanen S, Lewis NG (1997). "Stereoselective bimolecular phenoxy radical coupling by an auxiliary (dirigent) protein without an active center." Science 275(5298);362-6. PMID: 8994027
DinkovaKostova96: Dinkova-Kostova AT, Gang DR, Davin LB, Bedgar DL, Chu A, Lewis NG (1996). "(+)-Pinoresinol/(+)-lariciresinol reductase from Forsythia intermedia. Protein purification, cDNA cloning, heterologous expression and comparison to isoflavone reductase." J Biol Chem 271(46);29473-82. PMID: 8910615
Fujita99: Fujita M, Gang DR, Davin LB, Lewis NG (1999). "Recombinant pinoresinol-lariciresinol reductases from western red cedar (Thuja plicata) catalyze opposite enantiospecific conversions." J Biol Chem 274(2);618-27. PMID: 9872995
Halls04: Halls SC, Davin LB, Kramer DM, Lewis NG (2004). "Kinetic study of coniferyl alcohol radical binding to the (+)-pinoresinol forming dirigent protein." Biochemistry 43(9);2587-95. PMID: 14992596
Kim02a: Kim MK, Jeon JH, Davin LB, Lewis NG (2002). "Monolignol radical-radical coupling networks in western red cedar and Arabidopsis and their evolutionary implications." Phytochemistry 61(3);311-22. PMID: 12359517
Lewis99a: Lewis NG, Davin LB, Sarkanen S (1999). "The nature and function of lignins." In: Comprehensive natural products chemistry Vol. 3: Barton Sir DHR, Nakanishi K. (eds.-in-chief), Carbohydrates and their derivatives including tannins, cellulose and related lignins. Amsterdam, New York: Elsevier 1999, 617-745.
Moinuddin06: Moinuddin SG, Youn B, Bedgar DL, Costa MA, Helms GL, Kang C, Davin LB, Lewis NG (2006). "Secoisolariciresinol dehydrogenase: mode of catalysis and stereospecificity of hydride transfer in Podophyllum peltatum." Org Biomol Chem 4(5);808-16. PMID: 16493463
Stafford00: Stafford E (2000). "The evolution of phenolics in plants." In: Recent advances in phytochemistry, Evolution of metabolic pathways (Romeo JT, Ibrahim R, Varin L, DeLuca V (eds.), Elsevier Science Ltd., 34, 25-55.
Umezawa91: Umezawa T, Davin LB, Lewis NG (1991). "Formation of lignans (-)-secoisolariciresinol and (-)-matairesinol with Forsythia intermedia cell-free extracts." J Biol Chem 266(16);10210-7. PMID: 2037574
vonHeimendahl05: von Heimendahl CB, Schafer KM, Eklund P, Sjoholm R, Schmidt TJ, Fuss E (2005). "Pinoresinol-lariciresinol reductases with different stereospecificity from Linum album and Linum usitatissimum." Phytochemistry 66(11);1254-63. PMID: 15949826
Xia01a: Xia ZQ, Costa MA, Pelissier HC, Davin LB, Lewis NG (2001). "Secoisolariciresinol dehydrogenase purification, cloning, and functional expression. Implications for human health protection." J Biol Chem 276(16);12614-23. PMID: 11278426
Youn05: Youn B, Moinuddin SG, Davin LB, Lewis NG, Kang C (2005). "Crystal structures of apo-form and binary/ternary complexes of Podophyllum secoisolariciresinol dehydrogenase, an enzyme involved in formation of health-protecting and plant defense lignans." J Biol Chem 280(13);12917-26. PMID: 15653677
Chu93: Chu A, Dinkova A, Davin LB, Bedgar DL, Lewis NG (1993). "Stereospecificity of (+)-pinoresinol and (+)-lariciresinol reductases from Forsythia intermedia." J Biol Chem 268(36);27026-33. PMID: 8262939
Gang99: Gang DR, Kasahara H, Xia ZQ, Vander Mijnsbrugge K, Bauw G, Boerjan W, Van Montagu M, Davin LB, Lewis NG (1999). "Evolution of plant defense mechanisms. Relationships of phenylcoumaran benzylic ether reductases to pinoresinol-lariciresinol and isoflavone reductases." J Biol Chem 274(11);7516-27. PMID: 10066819
Gang99a: Gang DR, Costa MA, Fujita M, Dinkova-Kostova AT, Wang HB, Burlat V, Martin W, Sarkanen S, Davin LB, Lewis NG (1999). "Regiochemical control of monolignol radical coupling: a new paradigm for lignin and lignan biosynthesis." Chem Biol 6(3);143-51. PMID: 10074466
Hemmati07: Hemmati S, Schmidt TJ, Fuss E (2007). "(+)-Pinoresinol/(-)-lariciresinol reductase from Linum perenne Himmelszelt involved in the biosynthesis of justicidin B." FEBS Lett 581(4);603-10. PMID: 17257599
Lewis99: Lewis NG, Davin LB (1999). "Lignans: Biosynthesis and function." In: Comprehensive natural products chemistry Vol. 1: Barton Sir DHR, Nakanishi K. (eds.-in-chief), Carbohydrates Polyketides and other Secondary Metabolites including Fatty Acids and their Derivatives. Amsterdam, New York: Elsevier 1999, 639-712.
Min03: Min T, Kasahara H, Bedgar DL, Youn B, Lawrence PK, Gang DR, Halls SC, Park H, Hilsenbeck JL, Davin LB, Lewis NG, Kang C (2003). "Crystal structures of pinoresinol-lariciresinol and phenylcoumaran benzylic ether reductases and their relationship to isoflavone reductases." J Biol Chem 278(50);50714-23. PMID: 13129921
Nakatsubo08: Nakatsubo T, Mizutani M, Suzuki S, Hattori T, Umezawa T (2008). "Characterization of Arabidopsis thaliana pinoresinol reductase, a new type of enzyme involved in lignan biosynthesis." J Biol Chem 283(23);15550-7. PMID: 18347017
Umezawa90: Umezawa T, Davin LB, Lewis NG (1990). "Formation of the lignan, (-) secoisolariciresinol, by cell free extracts of Forsythia intermedia." Biochem Biophys Res Commun 171(3);1008-14. PMID: 2222424
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