Metabolic Modeling Tutorial
discounted EARLY registration ends Dec 31, 2014
Metabolic Modeling Tutorial
discounted EARLY registration ends Dec 31, 2014
Metabolic Modeling Tutorial
discounted EARLY registration ends Dec 31, 2014
Metabolic Modeling Tutorial
discounted EARLY registration ends Dec 31, 2014
Metabolic Modeling Tutorial
discounted EARLY registration ends Dec 31, 2014
twitter

MetaCyc Pathway: podophyllotoxin and 6-methoxypodophyllotoxin biosynthesis

Enzyme View:

This view shows enzymes only for those organisms listed below, in the list of taxa known to possess the pathway. 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

Some taxa known to possess this pathway include ? : Linum flavum , Linum nodiflorum

Expected Taxonomic Range: Spermatophyta

Summary:
General Background

Podophyllotoxin is an aryltetralin lignan that has been attracted a lot of attention because of its use in anticancer treatments. Podophyllotoxin is highly toxic and for that reason of limited medicinal use, however it is the starting substance that allows the production of semi-synthetic derivatives such as etoposide and teniposide applied in cancer therapy (reviewed in [Gordaliza04]). The mode of action of these drugs is based on interactions with the DNA/topoisomerase II complexes causing DNA double-strand breaks that are followed by cell arrest in the G2-phase [Imbert98].

Although podophyllotoxin and congeners are found in various families of higher plants such as Berberidaceae, Polygalaceae, Apiaceae, Linaceae, Labiaceae and Fabaceae the compound does not accumulate to an exploitable level. The only plants that provide useful amounts of podophyllotoxin are Podophyllum emodi (Indian Podophyllum) and Podophyllum peltatum (American Podophyllum) with 4.3 and 0.25% of dry weight, respectively [Gordaliza04].

The chemical synthesis of podophyllotoxin is possible however not economic yet. That is why podophyllotoxin is still preferably isolated from wild growing Podophyllum species. However, the heavy use of these plants in the past has put them on the list of endangered species [Airi97] and alternative ways of establishing cell and organ cultures are now intensively investigated to prevent the depletion of natural resources [Petersen01a] [Kuhlmann02] [Fuss03].

Other approaches to boost the production of podophyllotoxin by adding synthetic or natural elicitors to the cultures such as coronalon and indanoyl-isoleucine [Berim05] and methyl jasmonate (MeJA) [vanFurden05] have been of moderate success but have proven useful to elucidate the underlying pathways.

About This Pathway

The biosynthesis of podophyllotoxin is not completely known. Although the late steps in the biosynthesis have been corroborated with enzymatic data the early steps are not well understood. The research of Sakakibara and coworkers [Sakakibara03] points to the lignan yatein as intermediate in the biosynthetic route towards podophyllotoxin and 6-methoxypodophyllotoxin. A synthetic sequence has been proposed that starts with matairesinol and forms yatein in four steps, however, the enzymes catalyzing those reactions remain to be characterized [Sakakibara03]. Nevertheless, the data are supported by the identification of the presumed intermediates in planta (e.g. [Suzuki02e]).

(-)-Matairesinol has been established as direct precursor for podophyllotoxin and yatein was shown to be effectively converted to podophyllotoxin [Broomhead91]. (-)-Matairesinol if formed through a series of reactions that start with the stereospecific coupling of coniferyl alcohol (see matairesinol biosynthesis) however ferulic acid and methylenedioxy-substituted cinnamic acid could also be incorporated into lignans [Seidel02].

The first established enzyme involved in the late steps of the formation of podophyllotoxin and dervatives thereof is deoxypodophyllotoxin 6-hydroxylase (DOP6H). The enzyme, a cytochrome P450-dependent monooxygenase, specifically 6-hydroxylated deoxypodophyllotoxin to β-peltatin indicating that the formation of 6-methoxypodophyllotoxin does not proceed via podophyllotoxin [Molog01]. It appears that podophyllotoxin requires a 7-hydroxylase and is also formed from deoxypodophyllotoxin [Van95a] which ascertaines its function as branching compound for the biosynthesis of those two major lignans. However, the expected cytochrome P450 protein remains to be isolated and characterized.

The second enzyme identified in the biosynthetic route is β-peltatin 6-O-methyltransferase (β-pelatatin 6OMT) that has been partially purified from cell-suspension cultures of Linum nodiflorum [Kranz03]. The resulting β-peltatin-A methylether is hydroxylated at position 6 to form the corresponding 6-methylpodophyllotoxin. The catalyzing enzyme still remains to be identified.

An alternative pathway has been proposed that involves the formation of 7'-hydroxymatairesinol, which is efficiently metabolized into 5-methoxypodophyllotoxin [Xia00] but the actual enzymes involved in this pathway still need to be identified.

Credits:
Created 16-Feb-2007 by Foerster H , TAIR


References

Airi97: Airi S, Rawal RS, Dhar U, Purohit AN (1997). "Population studies on Podophyllum hexandrum Royle - a dwindling medicinal plant of the Himalaya ." Plant Genet. Resour. Newsl. 110, 20-34.

Berim05: Berim A, Spring O, Conrad J, Maitrejean M, Boland W, Petersen M (2005). "Enhancement of lignan biosynthesis in suspension cultures of Linum nodiflorum by coronalon, indanoyl-isoleucine and methyl jasmonate." Planta 222(5);769-76. PMID: 16136333

Broomhead91: Broomhead J, Rahman MM, Dewick PM, Jackson DE, Lucas JA (1991). "Matairesinol as precursor of Podophyllum lignans." Phytochemistry, 30(5), 1489-1492.

Fuss03: Fuss E (2003). "Lignans in plant cell and organ cultures: An overview." Phytochemistry Reviews, 2, 307-320.

Gordaliza04: Gordaliza M, Garcia PA, del Corral JM, Castro MA, Gomez-Zurita MA (2004). "Podophyllotoxin: distribution, sources, applications and new cytotoxic derivatives." Toxicon 44(4);441-59. PMID: 15302526

Imbert98: Imbert TF (1998). "Discovery of podophyllotoxins." Biochimie 80(3);207-22. PMID: 9615861

Kranz03: Kranz K, Petersen M (2003). "β-peltatin 6-O-methyltransferase from suspension cultures of Linum nodiflorum." Phytochemistry 64(2);453-8. PMID: 12943762

Kuhlmann02: Kuhlmann S, Kranz K, Lucking B, Alfermann AW, Petersen M (2002). "Aspects of cytotoxic lignan biosynthesis in suspension cultures of Linum nodiflorum." Phytochemistry Reviews, 1, 37-43.

Molog01: Molog GA, Empt U, Kuhlmann S, van Uden W, Pras N, Alfermann AW, Petersen M (2001). "Deoxypodophyllotoxin 6-hydroxylase, a cytochrome P450 monooxygenase from cell cultures of Linum flavum involved in the biosynthesis of cytotoxic lignans." Planta 214(2);288-94. PMID: 11800394

Petersen01a: Petersen M, Alfermann AW (2001). "The production of cytotoxic lignans by plant cell cultures." Appl Microbiol Biotechnol 55(2);135-42. PMID: 11330705

Sakakibara03: Sakakibara N, Suzuki S, Umezawa T, Shimada M (2003). "Biosynthesis of yatein in Anthriscus sylvestris." Org Biomol Chem 1(14);2474-85. PMID: 12956064

Seidel02: Seidel V, Windhovel J, Eaton G, Alfermann AW, Arroo RR, Medarde M, Petersen M, Woolley JG (2002). "Biosynthesis of podophyllotoxin in Linum album cell cultures." Planta 215(6);1031-9. PMID: 12355164

Suzuki02e: Suzuki S, Sakakibara N, Umezawa T, Shimada M (2002). "Survey and enzymatic formation of lignans of Anthriscus sylvestris." J Wood Sci, 48, 536-541.

Van95a: Van Uden W, Bouma AS, Bracht Waker JE, Middel O, Wichers HJ, De Waard P, Woerdenbag HJ, Kellogg RM, Pras N (1995). "The production of podophyllotoxin and its 5-methoxy derivative through bioconversion of cyclodextrin-complexed desoxypodophyllotoxin by plant cell cultures." Plant Cell, Tissue and Organ Culture, 42, 73-79.

vanFurden05: van Furden B, Humburg A, Fuss E (2005). "Influence of methyl jasmonate on podophyllotoxin and 6-methoxypodophyllotoxin accumulation in Linum album cell suspension cultures." Plant Cell Rep 24(5);312-7. PMID: 15818489

Xia00: Xia ZQ, Costa MA, Proctor J, Davin LB, Lewis NG (2000). "Dirigent-mediated podophyllotoxin biosynthesis in Linum flavum and Podophyllum peltatum." Phytochemistry 55(6);537-49. PMID: 11130663

Other References Related to Enzymes, Genes, Subpathways, and Substrates of this Pathway

Latendresse13: Latendresse M. (2013). "Computing Gibbs Free Energy of Compounds and Reactions in MetaCyc."


Report Errors or Provide Feedback
Please cite the following article in publications resulting from the use of MetaCyc: Caspi et al, Nucleic Acids Research 42:D459-D471 2014
Page generated by SRI International Pathway Tools version 18.5 on Sun Nov 23, 2014, BIOCYC14B.