Chemistry:Aucubin

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Aucubin is an iridoid glycoside.[1] Iridoids are commonly found in plants and function as defensive compounds.[1] Iridoids decrease the growth rates of many generalist herbivores.[2]

Natural occurrences

Aucubin, as other iridoids, is found in asterids such as Aucuba japonica (Garryaceae), Eucommia ulmoides (Eucommiaceae), Plantago asiatica, Plantago major, Plantago lanceolata (Plantaginaceae), Galium aparine (Rubiaceae), Euphrasia brevipila[3] and others. These plants are used in traditional Chinese and folk medicine.[4]

Agnuside is composed of aucubin and p-hydroxybenzoic acid.[5]

Health effects

Aucubin was found to protect against liver damage induced by carbon tetrachloride or alpha-amanitin in mice and rats when 80 mg/kg was dosed intraperitoneally.[6]

Chemistry

Aucubin is a monoterpenoid based compound.[7] Aucubin, like all iridoids, has a cyclopentan-[C]-pyran skeleton.[7] Iridoids can consist of ten, nine, or rarely eight carbons in which C11 is more frequently missing than C10.[7] Aucubin has 10 carbons with the C11 carbon missing. The stereochemical configurations at C5 and C9 lead to cis fused rings, which are common to all iridoids containing carbocyclic- or seco-skeleton in non-rearranged form.[7] Oxidative cleavage at C7-C8 bond affords secoiridoids.[8] The last steps in the biosynthesis of iridoids usually consist of O-glycosylation and O-alkylation. Aucubin, a glycoside iridoid, has an O-linked glucose moiety.

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Biosynthesis

Geranyl pyrophosphate (GPP) is the precursor for iridoids.[9] Geranyl phosphate is generated through the mevalonate pathway or the methylerythritol phosphate pathway.[9] The initial steps of the pathway involve the fusion of three molecules of acetyl-CoA to produce the C6 compound 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA).[9] HMG-CoA is then reduced in two steps by the enzyme HMG-CoA reductase.[9] The resulting mevalonate is then sequentially phosphorylated by two separate kinases, mevalonate kinase and phosphomevalonate kinase, to form 5-pyrophosphomevalonate.[9] Phosphosphomevalonate decarboxylase through a concerted decarboxylation reaction affords isopentenyl pyrophosphate (IPP).[9] IPP is the basic C5 building block that is added to prenyl phosphate cosubstrates to form longer chains.[9] IPP is isomerized to the allylic ester dimethylallyl pyrophosphate (DMAPP) by IPP isomerase.[9] Through a multi-step process, including the dephosphorylation DMAPP, IPP and DMAPP are combined to form the C10 compound geranyl pyrophosphate (GPP).[9] Geranyl pyrophosphate is a major branch point for terpenoid synthesis.[9]

Current[when?] biosynthesis studies suggest that the most probable synthetic sequence from 10-hydroxygerinol to 8-epi-iriotrial is the following: dephosphorylation of GPP, leads to a geranyl cation that is then hydroxylated to form 10-hydroxygeraniol; 10-hydroxylgeraniol is isomerized to 10-hydroxynerol; 10-hydroxynerol is oxidized using NAD to form a trialdehyde; finally the trialdehyde undergoes a double Michael addition to yield 8-epi-iridotrial.[10] 8-Epi-iridotrial is another branch point intermediate.[7]

The cyclization reaction to form the iridoid pyran ring may result from one of two routes:

  1. route 1 – a hydride nucleophillic attack on C1 will lead to 1-O-carbonyl atom attack on C3, yielding the lactone ring;
  2. route 2 – loss of proton from carbon 4 leads to the formation of a double bond C3-C4; consequently the 3-O-carbonyl atom will attach to C1.[7]

Based on deuterium tracking studies, the biosynthetic pathway for aubucin from the cyclized lactone intermediate is organism specific.[7] In Gardenia jasminoides, the cyclized lactone intermediate is glycosylated to form boschnaloside that is then hydroxylated on C10; boschnaloside is oxidized to geniposidic acid; geniposidic acid is then decarboxylated to form bartisioside; bartisioside is then hydroxylated to form aucubin.[7] The Scrophularia umbrosa biosynthetic pathway is different from Gardenia jasminoides. In Scrophularia umbrosa, the lactone intermediate is glycosylated and oxidized at the C11 carbonyl to form 8-epi-dexoy-loganic acid, which is then converted to deoxygeniposidic acid; deoxygeniposidic acid is hydroxylated at C10 to geniposidic acid; decarboxylation and hydroxylation of C6 leads to aucubin.[11]

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References

  1. ↑ 1.0 1.1 Nieminen M; Suomi J; Van Nouhuys S (2003). "Effect of iridoid glycoside content on oviposition host plant choice and parasitim in a specialist herbivore". J. Chem. Ecol. 29 (4): 823–843. doi:10.1023/A:1022923514534. PMID 12775146. 
  2. ↑ "Effect of qualitative and quantitative variation in allelochemicals on a generalist insect: Iridoid glycosides and southern armyworm". J. Chem. Ecol. 14 (1): 335–351. 1998. doi:10.1007/BF01022550. PMID 24277013. 
  3. ↑ Petrichenko, V. M., Sukhinina, T. V., Babiyan, L. K., & Shramm, N. I. (2006). Chemical composition and antioxidant properties of biologically active compounds from Euphrasia brevipila. Pharmaceutical Chemistry Journal, 40(6), 312–316. https://doi.org/10.1007/s11094-006-0117-4
  4. ↑ "Pharmacokinetic Study of an Iridoid Glucoside: Aucubin". Pharmaceutical Research 08 (8): 1059–1063. 1991. doi:10.1023/A:1015821527621. PMID 1924160. 
  5. ↑ Eva Hoberg; Beat Meier; Otto Sticher (September–October 2000). "An analytical high performance liquid chromatographic method for the determination of agnuside and p-hydroxybenzoic acid contents in Agni-casti fructose". Phytochemical Analysis 11 (5): 327–329. doi:10.1002/1099-1565(200009/10)11:5<327::AID-PCA523>3.0.CO;2-0. 
  6. ↑ "Protective effect of Aucuba japonica against carbontetrackmkxmms damage in rat". Drug Chem. Toxicol. 6 (5): 429–441. 1983. doi:10.3109/01480548309014165. PMID 6628265. 
  7. ↑ 7.0 7.1 7.2 7.3 7.4 7.5 7.6 7.7 "Biosynthesis Significance of iridoids in chemosystematics". J. Braz. Chem. Soc. 12 (2): 144–153. 2001. doi:10.1590/S0103-50532001000200004. 
  8. ↑ "Iridoids: a review". J. Nat. Prod. 43 (6): 649–707. 1980. doi:10.1021/np50012a001. PMID 20707392. 
  9. ↑ 9.00 9.01 9.02 9.03 9.04 9.05 9.06 9.07 9.08 9.09 McGarbey, D; Croteau R (1995). "Terpenoid Metabolism". The Plant Cell 7 (3): 1015–26. doi:10.1105/tpc.7.7.1015. PMID 7640522. 
  10. ↑ "Synthesis of cyclopenta[c]pyran skeleton of iridoid lactones". Tetrahedron 53 (43): 14507–14545. 1997. doi:10.1016/S0040-4020(97)00748-5. 
  11. ↑ "Late stages in the biosynthesis of aucubin in Scrophularia". Phytochemistry 35 (5): 1089–1093. 1993. doi:10.1016/0031-9422(93)85028-P. Bibcode: 1993PChem..33.1089D. 



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