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Lignan
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The lignans are a large group of low molecular weight polyphenols found in plants, particularly seeds, whole grains, and vegetables.[1] The name derives from the Latin word for "wood".[2] Lignans are precursors to phytoestrogens.[1][3] They may play a role as antifeedants in the defense of seeds and plants against herbivores.[4]
Biosynthesis and metabolism
[edit]Structures of some lignans
-
Matairesinol, illustrating the dibenzylbutyrolactone motif -
Secoisolariciresinol, illustrating the 9,9'-dihydroxydibenzylbutane motif -
Justicidin A, illustrating the arylnaphthalene motif -
Pinoresinol, illustrating the furanofuran motif -
Steganacin, illustrating the dibenzocyclooctadienelactone motif -
Podophyllotoxin, illustrating the aryltetralin motif
Lignans and lignin differ in their molecular weight, the former being small and soluble in water, the latter being high polymers that are undigestable. Both are polyphenolic substances derived by oxidative coupling of monolignols. Thus, most lignans feature a C18 cores, resulting from the dimerization of C9 precursors. The coupling of the lignols occurs at C8. Eight classes of lignans are: "furofuran, furan, dibenzylbutane, dibenzylbutyrolactone, aryltetralin, arylnaphthalene, dibenzocyclooctadiene, and dibenzylbutyrolactol."[5]
Many lignans are metabolized by mammalian gut microflora, producing so-called enterolignans.[6][7]
Food sources
[edit]Flax seeds and sesame seeds contain high levels of lignans.[1][8] The principal lignan precursor found in flaxseeds is secoisolariciresinol diglucoside.[1][8] Other foods containing lignans include cereals (rye, wheat, oat and barley), soybeans, tofu, cruciferous vegetables (such as broccoli and cabbage), and some fruits (particularly apricots and strawberries).[1] Lignans are not present in seed oil, and their contents in whole or ground seeds may vary according to geographic location, climate, and maturity of the seed crop, and the duration of seed storage.[1]
Secoisolariciresinol and matairesinol were the first plant lignans identified in foods.[1] Typically, lariciresinol and pinoresinol contribute about 75% to the total lignan intake, whereas secoisolariciresinol and matairesinol contribute only about 25%.[1]
Foods containing lignans:[1][9]
| Source | Lignan amount |
|---|---|
| Flaxseeds | 85.5 mg per oz (28.35 g) |
| Sesame seeds | 11.2 mg per oz |
| Brassica vegetables | 0.3-0.8 mg per half cup (125 ml) |
| Strawberries | 0.2 mg per half cup |
Prevalence and health effects
[edit]Lignans are the principal source of dietary phytoestrogens in typical Western diets, even though most research on phytoestrogen-rich diets has focused on soy isoflavones. Lignan's enterolignan products enterodiol and enterolactone have weak estrogenic activity, but they may also exert biological effects through non-estrogenic means.[1]
A 2021 review found that lignans have a positive effect on lipid profiles of patients with dyslipidemia related diseases.[10] As of 2022 there is limited evidence that dietary intake of lignans is associated with a reduced cancer and cardiovascular disease risk.[1]
See also
[edit]References
[edit]- ^ a b c d e f g h i j k "Lignans". Micronutrient Information Center, Linus Pauling Institute, Oregon State University. 2010. Retrieved 31 July 2017.
- ^ From lign- (Latin, "wood") + -an (chemical suffix).
- ^ Korkina, L; Kostyuk, V; De Luca, C; Pastore, S (2011). "Plant phenylpropanoids as emerging anti-inflammatory agents". Mini Reviews in Medicinal Chemistry. 11 (10): 823–35. doi:10.2174/138955711796575489. PMID 21762105.
- ^ Saleem, Muhammad; Kim, Hyoung Ja; Ali, Muhammad Shaiq; Lee, Yong Sup (2005). "An update on bioactive plant lignans". Natural Product Reports. 22 (6): 696–716. doi:10.1039/B514045P. PMID 16311631.
- ^ Umezawa, Toshiaki (2003). "Diversity in lignan biosynthesis". Phytochemistry Reviews. 2 (3): 371–90. doi:10.1023/B:PHYT.0000045487.02836.32. S2CID 6276953.
- ^ Adlercreutz, Herman (2007). "Lignans and Human Health". Critical Reviews in Clinical Laboratory Sciences. 44 (5–6): 483–525. doi:10.1080/10408360701612942. PMID 17943494. S2CID 31753060.
- ^ Heinonen, S; Nurmi, T; Liukkonen, K; Poutanen, K; Wähälä, K; Deyama, T; Nishibe, S; Adlercreutz, H (2001). "In vitro metabolism of plant lignans: New precursors of mammalian lignans enterolactone and enterodiol". Journal of Agricultural and Food Chemistry. 49 (7): 3178–86. doi:10.1021/jf010038a. PMID 11453749.
- ^ a b Landete, José (2012). "Plant and mammalian lignans: A review of source, intake, metabolism, intestinal bacteria and health". Food Research International. 46 (1): 410–24. doi:10.1016/j.foodres.2011.12.023.
- ^ Milder IE, Arts IC, van de Putte B, Venema DP, Hollman PC (2005). "Lignan contents of Dutch plant foods: a database including lariciresinol, pinoresinol, secoisolariciresinol and matairesinol". British Journal of Nutrition. 93 (3): 393–402. doi:10.1079/BJN20051371. PMID 15877880.
- ^ Yang, C., Xia, H., Wan, M. (2021). "Comparisons of the effects of different flaxseed products consumption on lipid profiles, inflammatory cytokines and anthropometric indices in patients with dyslipidemia related diseases: systematic review and a dose–response meta-analysis of randomized controlled trials". Nutrition & Metabolism. 18 (1): 91. doi:10.1186/s12986-021-00619-3. PMC 8504108. PMID 34635132.
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External links
[edit]Lignan
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Definition and Chemistry
Overview
Lignans are a class of low molecular weight polyphenols characterized by a diphenylbutane skeleton, formed through the dimerization of two C9 monolignol units to yield a C18 core structure.[1] These compounds are secondary metabolites derived from phenylpropanoid pathways in plants and serve as precursors to lignins, the complex polymers that provide structural support in vascular tissues.[1] The term "lignan" originates from the Latin word lignum, meaning "wood," reflecting their close biochemical relationship to lignin.[4] Lignans were first defined in 1936 by R.D. Haworth as β-β'-linked phenylpropanoid dimers, with early isolations including matairesinol from Podophyllum resin in the 1930s.[5] Over time, lignans have been classified into eight major subgroups based on their skeletal variations and oxygenation patterns, encompassing diverse forms such as furofurans and dibenzylbutanes.[6] Lignans exhibit several general properties that contribute to their ecological and potential biological roles. They possess antioxidant capabilities, scavenging free radicals through their polyphenolic nature.[1] These compounds are particularly prevalent in seeds, underscoring their importance in plant defense.[3]Structure and Classification
Lignans are characterized by a core structure consisting of two phenylpropane (C6-C3) units linked together through a β-β' bond in the propane chains, forming a diphenylbutane skeleton, which may include cyclized forms such as the 2,6-diaryl-3,7-dioxabicyclo[3.3.0]octane in furofuran lignans, though variations occur based on cyclization and substitution patterns. This dimeric framework often includes multiple chiral centers, leading to stereoisomers such as enantiomers and diastereomers that influence their biological properties. The formation of this core involves oxidative dimerization of monolignols, such as coniferyl alcohol, primarily at the 8-8' positions, a process mediated by enzymes like laccases or peroxidases and directed by proteins to achieve stereoselectivity.[7] Lignans are classified into eight major structural classes based on their carbon skeleton, cyclization patterns, and oxygenation:- Furofuran lignans: Feature two fused furan rings in a tetrahydrofurofuran system; representative example is pinoresinol, a common precursor in many plants.
- Dibenzylbutane lignans: Characterized by an open-chain butane linkage between two benzyl groups, often with hydroxyl substitutions; secoisolariciresinol is a key dietary example found in flaxseed.
- Aryltetralin lignans: Contain a tetralin ring fused to an aryl group, typically with a lactone or ether bridge; podophyllotoxin exemplifies this class, noted for its antitumor activity.
- Arylnaphthalene lignans: Possess a naphthalene core with an attached aryl substituent, often featuring quinone methide functionality; justicidin B is a typical member.
- Dibenzylbutyrolactone lignans: Include a butyrolactone ring connecting two benzyl moieties; matairesinol and arctigenin are prominent examples with lactone-mediated stability.
- Furan lignans: Structured around a single furan ring linking the phenylpropane units; tanegool represents this simpler cyclized form.
- Dibenzoquinoline lignans: Feature a quinoline ring system fused to benzene rings, arising from further oxidation and cyclization; these are less common but occur in certain genera like Zanthoxylum.
- Arylbenzofuran lignans: Comprise a benzofuran core attached to an aryl group, with ether linkages; burseranin is an example highlighting the furan-aromatic fusion.
Biosynthesis and Occurrence
Biosynthesis in Plants
Lignans in plants are secondary metabolites derived from the phenylpropanoid pathway, which originates from the amino acid phenylalanine produced via the shikimate pathway.[8] The initial steps involve the deamination of phenylalanine by phenylalanine ammonia-lyase (PAL) to yield cinnamic acid, followed by hydroxylation at the 4-position by cinnamate 4-hydroxylase (C4H) to form p-coumaric acid.[9] Subsequent activation of p-coumaric acid to 4-coumaroyl-CoA by 4-coumarate:CoA ligase (4CL), along with hydroxylation, methylation, and reduction reactions mediated by enzymes such as p-coumaroyl shikimate 3'-hydroxylase (C3'H), 5-O-(4-coumaroyl)shikimate 3'-hydroxylase, cinnamoyl-CoA reductase (CCR), and cinnamyl alcohol dehydrogenase (CAD), lead to the formation of monolignols like p-coumaryl alcohol, coniferyl alcohol, and sinapyl alcohol. The defining step in lignan biosynthesis is the oxidative dimerization of two monolignol units, typically coniferyl alcohols, at the β-β' (8-8') position to form the core lignan skeleton. This regio- and stereospecific coupling is catalyzed by peroxidases or laccases, which generate phenoxy radicals, in conjunction with dirigent proteins that direct the stereochemistry to produce optically active products such as (+)-pinoresinol.[10] The reaction can be represented as:
Downstream modifications include stereospecific reduction of pinoresinol to lariciresinol and then to secoisolariciresinol by pinoresinol-lariciresinol reductase (PLR), an NADPH-dependent enzyme, followed by further dehydration or oxidation steps to yield diverse lignans like matairesinol.[9]
Lignan biosynthesis is tightly regulated and often upregulated in response to environmental stresses, including UV irradiation and herbivory, which trigger accumulation particularly in seeds, bark, and heartwood as part of plant defense mechanisms.[8] Transcription factors such as MYB and AP2/ERF, along with microRNAs targeting pathway genes like PAL and DIR, modulate enzyme expression under these conditions, enhancing lignan production to bolster stress tolerance.[11]
Recent advances as of 2025 include the development of synthetic yeast consortia for de novo biosynthesis of lignans, mimicking plant metabolic regulation to produce compounds like secoisolariciresinol from ferulic acid, enabling sustainable production.[12] Additionally, studies have elucidated the role of polyamine signaling in upregulating lignan production in species like Linum album through pathways involving transcription factors and enzyme activation.[13] Integrative metabolomic and transcriptomic analyses have further identified key genes and pathways associated with lignan accumulation during seed development.[14]
Natural Distribution
Lignans are widely distributed across the plant kingdom, occurring in over 70 families and present in various plant parts such as seeds, grains, vegetables, fruits, woods, and resins.[15] They are particularly abundant in seeds of species from the Linaceae and Pedaliaceae families, including flax (Linum usitatissimum) and sesame (Sesamum indicum), as well as in grains like rye (Secale cereale) and wheat (Triticum aestivum), cruciferous vegetables such as broccoli (Brassica oleracea), and fruits like strawberries (Fragaria × ananassa).[16] Trace amounts are also found in woody tissues and resins, for example in knots of Norway spruce (Picea abies).[16] Concentrations of lignans vary significantly by plant species and tissue, with flaxseeds exhibiting the highest levels, reaching up to 301 mg/100 g primarily as secoisolariciresinol diglucoside.[3] In contrast, cereals like rye and wheat contain lower amounts, typically ranging from 0.2 to 0.8 mg/100 g, while broccoli and strawberries have around 0.6 mg/100 g and 0.2 mg/100 g, respectively.[3] Sesame seeds also serve as a rich source, with total lignan content up to 373 mg/100 g (primarily sesamin and sesamolin).[17] Ecologically, lignans play key defensive roles in plants, deterring pathogens and herbivores through their antioxidant, antibacterial, antiviral, and antifungal properties, which help mitigate oxidative stress and microbial invasion.[18] Unlike insoluble lignins, which form rigid cell wall structures, lignans contribute to flexible precursors in cell walls while remaining soluble and bioactive, aiding plant resilience without compromising structural integrity.[18] Environmental factors influence lignan accumulation, with higher levels often observed in plants under stress conditions such as UV exposure or pathogen attack, enhancing adaptive responses across diverse ecosystems.[16] Beyond edible plants, non-food examples include podophyllotoxin, an aryltetralin lignan found in Podophyllum species (Berberidaceae family), which has been utilized historically for its medicinal properties in traditional practices.[19]Metabolism
Metabolism in Plants
Lignans, following their biosynthesis from phenylpropanoid precursors, undergo post-synthetic modifications that enhance their stability and facilitate intracellular management. A primary modification is glycosylation, catalyzed by uridine diphosphate-dependent glycosyltransferases (UGTs), which attach glucose or other sugar moieties to the phenolic hydroxyl groups of lignan aglycones. This process increases water solubility, enabling the transport and long-term storage of lignans as inactive conjugates within plant vacuoles. For instance, in Isatis indigotica, tandem UGT71B5 enzymes (IiUGT71B5a and IiUGT71B5b) selectively glycosylate (+)-pinoresinol to form monoglucosides and diglucosides, with IiUGT71B5a exhibiting broader substrate promiscuity for both mono- and di-substitution.[20] Similarly, in flax (Linum usitatissimum), UGT74S1 converts secoisolariciresinol to its diglucoside form (SDG), which accumulates in the seed hull at concentrations up to 30 mg/g dry weight; the hull itself constitutes about 22.6% of the total seed weight and exemplifies how glycosylation supports accumulation in reproductive tissues.[2] Glycosylation also plays a dynamic role in stress responses, where reversible deglycosylation releases bioactive aglycone forms to combat oxidative damage. In Arabidopsis thaliana, UGT71C1 glycosylates lignans such as lariciresinol and pinoresinol; mutants deficient in this enzyme accumulate higher aglycone levels, enhancing tolerance to methyl viologen-induced oxidative stress through improved reactive oxygen species (ROS) scavenging.[21] The aglycone forms of these lignans inhibit lipid peroxidation more effectively than their glycosides, suggesting that β-glucosidases hydrolyze conjugates during abiotic stresses to mobilize antioxidants. This equilibrium between glycosylation and deglycosylation allows plants to balance storage with rapid activation of defense compounds.[22] Transport of lignans involves ATP-binding cassette (ABC) transporters, which actively sequester glycosylated forms into vacuoles or direct them to sink tissues like seeds, thereby preventing autotoxicity from their reactive phenolic structures. While specific lignan transporters remain undercharacterized, plant ABC proteins—particularly subfamilies ABCG and ABCC—facilitate the vacuolar import of phenylpropanoid derivatives and other secondary metabolites, maintaining cytosolic homeostasis.[23] In flax seeds, dirigent proteins assist in stereospecific lignan assembly before ABC-mediated transport to the seed coat, where compartmentalization isolates potentially cytotoxic intermediates from metabolic machinery.[2] Vacuolar storage of these glycosides, as seen in Arabidopsis leaf vacuoles containing related small glycosylated lignin oligomers, underscores the role of sequestration in averting premature oxidation or unwanted coupling reactions.[24] Soluble lignans function as intermediates in lignin differentiation, where glycosylated forms stored in vacuoles can be deglycosylated and oxidized under developmental or stress-induced conditions to contribute to the polymerization of insoluble lignins in cell walls. In Arabidopsis, vacuolar glycosylated lignin oligomers—structurally akin to lignan dimers—serve as reservoirs that, upon mobilization, participate in radical coupling to extend the lignin matrix, illustrating how plants regulate the transition from soluble precursors to structural polymers.[24]Metabolism in Humans
Dietary lignans, such as secoisolariciresinol diglucoside (SDG), are ingested through plant-based foods and primarily reach the colon intact, as they resist hydrolysis by enzymes in the upper gastrointestinal tract, including the stomach and small intestine.[25] This resistance allows the lignans to serve as substrates for colonic microbial transformation.[26] In the colon, gut microbiota metabolize plant lignans through a series of enzymatic reactions, including deglycosylation, demethylation, dehydroxylation, and dehydrogenation/oxidation, to produce bioactive enterolignans: enterodiol and enterolactone.[25] Key bacteria involved include Eggerthella lenta, which contributes to dehydroxylation steps via enzymes like catechol lignan dehydroxylase, alongside other species such as Blautia producta for demethylation and Ruminococcus for oxidation.[27] A critical early transformation involves the conversion of secoisolariciresinol to enterodiol, mediated by bacterial reductases and dehydrogenases:
This step is part of a cooperative microbial consortium pathway that further oxidizes enterodiol to enterolactone.[26][27]
Following microbial conversion, enterolignans are absorbed across the colonic epithelium into the bloodstream, where they undergo phase II conjugation in the liver, primarily forming glucuronides and sulfates for enhanced solubility and transport.[25] These conjugated forms enter systemic circulation via enterohepatic recirculation and are ultimately excreted predominantly in urine (as monoglucuronides) and to a lesser extent in feces, with free forms appearing in fecal matter.[26] The plasma elimination half-life of enterolignans varies, typically ranging from 4 to 24 hours, with enterodiol exhibiting a shorter half-life (around 4-9 hours) compared to enterolactone (12-15 hours).[28][29]
The efficiency of enterolignan production is influenced by factors such as gut microbiota composition, dietary fiber intake—which supports microbial activity—and individual physiological differences, leading to distinct phenotypes: "producers" who efficiently generate high levels of enterolignans (up to 10-fold more in urine and plasma) versus "non-producers" with minimal conversion due to lacking key bacterial strains.[25][26] Variations in microbiota diversity, often shaped by diet and genetics, account for inter-individual differences in bioavailability.[27]