User:Chodulik/Aucubin

Aucubin is an iridoid glycoside {{cite journal |author=Nieminen M, Suomi J, Van Nouhuys S |title=Effect of iridoid glycoside content on oviposition host plant choice and parasitim in a specialist herbivore |journal=J Chem. Ecol |volume=29 |issue=4 |pages=823-843 |year=2003 |pmid=12775146 |doi=10.1023/A:1022923514534 |url=}}. Iridoids are commonly found in plants and function as defensive compounds . Irioids decrease the growth rates of many generalist herbivores {{cite journal |author= Puttick G, Bowers M |title=Effect of qualitative and quantitative variation in allelochemicals on a generalist insect: Iridoid glycosides and southern armyworm |journal=J. Chem. Ecol |volume=14|issue= |pages=335-351|year=1998 |pmid= |doi=10.1007/BF01022550 |url=}}. Aucubin is found in the leaves of Aucuba japonica (Cornaceae), Eucommia ulmoides (Eucommiaceae), and Plantago asiatic (Plantaginaceae), etc, plants used in traditional Chinese and folk medicine {{cite journal |author= Suh N, Shim C, Lee M, Kim S, Chung, I |title= Pharmacokinetic Study of an Iridoid Glucoside: Aucubin |journal= Pharmaceutical Research |volume= 8|issue= 8|pages= 1059-1063|year= 1991 |pmid= 1924160|doi= 10.1023/A:1015821527621 |url=}}. Aucubin was found to protect against liver damage induced by carbon tetrachloride or alpha-amanitin in mice and rats when 80mg/kg was dosed intraperitoneally {{cite journal |author= Yang K, Kwon S, Choe H, Yun H, and Chang I |title= Protective effect of Aucuba japonica against carbontetrachloride induced liver damage in rat |journal= Drug Chem. Toxicol. |volume= 6|issue= |pages= 429-441|year= 1983|pmid= 6628265|doi= 10.3109/01480548309014165 |url=}}.

Aucubin is a monoterpenoid based compound {{cite journal |author= Sampio-Santos M, Kaplan M |title= Biosynthesis Significance of iridoids in chemosystematics |journal= J. Braz. Chem. Soc.|volume= 12|issue= 2 |pages= 144-153|year= 2001|pmid= |doi= 10.1590/S0103-50532001000200004 |url=}}. Aucubin, like all iridoids, has a cyclopentan-[C]-pyran skeleton . Iridoids can consist of ten, nine, or rarely eight carbons in which C11 is more frequently missing than C10 . 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 carbocylclic- or seco-skeleton in non-rearranged form . Oxidative cleavage at C7-C8 bond affords secoiridoids {{cite journal |author= El-Naggar L, Beal J |title= Iridoids: a review |journal= J. Nat. Prod. |volume= 46|issue= |pages= 649-707|year= 1980|pmid= |doi= 10.1021/np50012a001 |url=}}. 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.

File:Iridoid ring numbering.PNG

Geranyl pyrophosphate is the precursor for iridoids {{cite journal |author= McGarbey, D, Croteau R |title= Terpenoid Metabolism |journal= The Plant Cell |volume= 7|issue= |pages= 1015-26|year= 1995|pmid= PMC160903|doi= 10.1105/tpc.7.7.1015 |url=}}. Geranyl phosphate is generated through the mevalonate pathway . 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) . HMG-CoA is then reduced in two steps by the enzyme HMG-CoA reductase . The resulting mevalonate is then sequentially phosphorylated by two seperate kinases, mevalonate kinase and phosphomevalonate kinase, to form 5-pyrophosphomevalonate . Phosphosphomevalonate decarboxylase through a concerted decarboxylation reaction affords isopentenyl pyrophosphate (IPP) . IPP is the basic C5 building block that is added to prenyl phosphate cosubstrates to form longeer chains . IPP is isomerized to the allylic ester dimethylallyl pyrophosphate (DMAPP) by IPP isomerase . Through a multistep process, including the dephosphorylation DMAPP, IPP and DMAPP are combinded to from the C10 compound geranyl pyrophosphate (GPP) . Geranyl pyrophosphate is a major branch point for terpenoid synthesis .

Current biosynthetic studies suggest that the most probably 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 {{cite journal |author= Nangia A, Prasuna G, Rao P |title= Synthesis of cyclopenta[c]pyran skeleton of iridoid lactones |journal= Tetrahedron |volume= 53|issue= 43|pages= 14507-14545|year= 1997|pmid= |doi= 10.1016/S0040-4020(97)00748-5 |url=}}. 8-Epi-iridotrial is another branch point intermediate .

The cyclizaton reaction to form the iridoid pyrane ring may result from one of two routes: route 1 - a hydride

nucleophillic attack on C1 will lead to 1-O-carbonyl atom attack on C3, yielding the lactone ring; route 2 - loss

of proton from carbon 4 leads to the formation of a double bond C3-C4; consequently the 3-0-carbonyl atom will

attach to C1 .

Based on deuterium tracking studies, the biosynthetic pathway for aubucin from the cyclized lactone

intermediate is organism specific . 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 . 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 aubucin {{cite journal |author= Damtoft S, Jensen S, Jessen C, Knudsen T |title= Late stages in the biosynthesis of aucubin in Scrophularia |journal= Phytochemistry |volume= 35|issue= 5|pages= 1089-1093|year= 1993|pmid= |doi= 10.1016/0031-9422(93)85028-P |url=}}.

File:Acubinbiosynthesisscheme.PNG