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Pathway Description
Diterpenoid Biosynthesis
Arabidopsis thaliana
Category:
Metabolite Pathway
Sub-Category:
Metabolic
Created: 2020-06-26
Last Updated: 2023-10-28
Diterpenes consist of four isoprene (organic hydrocarbon compound) units and are naturally synthesized in plants as metabolites. PathBank shows the gibberellin precursor biosynthesis pathway in cress, and some of those reactions appear in this pathway. A major intermediate of this pathway in thale cress is geranylgeranyl diphosphate (GGDP), which enters the cytosol via the terpenoid backbone biosynthesis subpathway to start diterpenoid biosynthesis, specifically of plant hormones, such as a number of gibberellins and their catabolites. Many of these enzymes use flavoproteins (for reduction/oxidation) and/or iron ions as their cofactors. The enzyme geranyllinalool synthase (EC 4.2.3.144) is a component of the herbivore-induced indirect defense system and catalyzes a reaction with GGDP whose product, (E,E)-geranyllinalool, is a precursor to the volatile compound 4,8,12-trimethyl-1,3,7,11-tridecatetraene (TMTT), which is released by many plants in response to damage. GGDP can, using the enzyme ent-copalyl diphosphate synthase, create ent-copalyl diphosphate, which uses ent-kaur-16-ene synthase to create ent-kaurene. Aconitine and veatchine (both diterpenoid alkaloids derived from amination, although acontinine is more well-known as it is the plant toxin "monkshood" or that is known to induce arrhythmias by activating voltage-gated sodium channels) can form from ent-kaurene, although the specific reaction scheme for these formations is still unclear. Via ent-kaurene monooxygenase (often referred to misleadingly as ent-kaurene oxidase), an enzyme localized to the chloroplast outer membrane, three successive oxidations are catalyzed, converting ent-kaurene into first ent-16-kauren-19-ol, then ent-kaurenal, and then finally into ent-kaurenoate. At this point in the pathway, the reactions begin to take place in the endoplasmic reticulum membrane. Here, ent-kaurenoate oxidase (an enzyme localized to the endoplasmic reticulum outer membrane) catalyzes the conversion of ent-kaurenoate into gibberellin A12 via three successive oxidations: from ent-kaurenoate to ent-7-alpha-hydroxykaurenoate to ent-7alpha-Hydroxykaur-16-en-19-oic acid, which then in the final oxidation forms the product 6beta,7beta-Dihydroxykaurenoic acid; however, this acid, ent-7alpha-Hydroxykaur-16-en-19-oic acid, can also then use ent-kaurenoate oxidase again to form gibberellin A12 aldehyde. Gibberellin A12 aldehyde can form gibberellin A12 and gibberellin A53 aldehyde. Gibberellin A53 aldehyde forms gibberellin A53 in the cytosol. Here, gibberellin-44 dioxygenase (EC 1.14.11.12) is an oxidoreductase that catalyzes the conversion of gibberellin A12 and gibberellin A53 to gibberellin A9 and gibberellin A20 respectively, via a three-step oxidation at C-20 of the gibberellin A skeleton. Also in the cytosol exists a theoretical gibberellin-44 dioxygenase (a not yet elucidated enzyme), which catalyzes the reaction in the gibberellin biosynthesis pathway whereby gibberellin A12 becomes gibberellin A15 open lactone (also subsequently, gibberellin A24) and gibberellin A44 open lactone becomes gibberellin A19. Gibberellins A9 and A20 form A51 and A29 respectively, and gibberellin 2beta-dioxygenase (EC 1.14.11.13) catalyzes the formation of their catabolites. Gibberellin A20, via the cytosolic gibberellin 3-oxidase (an enzyme that requires ascorbic acid as a cofactor and is encoded by 4 differentially expressed genes (GA3ox1, GA3ox2, GA3ox3, GA3ox4) in thale cress), forms gibberellin A1, which in a reaction catalyzed by gibberellin 2beta-dioxygenase, forms gibberellin A8 and its catabolite. There are many offshoots in this pathway that are not described in detail or fully elucidated in Arabidopsis thaliana, but all assume a similar chain of reactions and ultimately result in the production of different gibberellin catabolites.
References
Diterpenoid Biosynthesis References
Helliwell CA, Sullivan JA, Mould RM, Gray JC, Peacock WJ, Dennis ES: A plastid envelope location of Arabidopsis ent-kaurene oxidase links the plastid and endoplasmic reticulum steps of the gibberellin biosynthesis pathway. Plant J. 2001 Oct;28(2):201-8. doi: 10.1046/j.1365-313x.2001.01150.x.
Pubmed: 11722763
Falara V, Alba JM, Kant MR, Schuurink RC, Pichersky E: Geranyllinalool synthases in solanaceae and other angiosperms constitute an ancient branch of diterpene synthases involved in the synthesis of defensive compounds. Plant Physiol. 2014 Sep;166(1):428-41. doi: 10.1104/pp.114.243246. Epub 2014 Jul 22.
Pubmed: 25052853
Keeling CI, Dullat HK, Yuen M, Ralph SG, Jancsik S, Bohlmann J: Identification and functional characterization of monofunctional ent-copalyl diphosphate and ent-kaurene synthases in white spruce reveal different patterns for diterpene synthase evolution for primary and secondary metabolism in gymnosperms. Plant Physiol. 2010 Mar;152(3):1197-208. doi: 10.1104/pp.109.151456. Epub 2009 Dec 31.
Pubmed: 20044448
Kawaide H, Imai R, Sassa T, Kamiya Y: Ent-kaurene synthase from the fungus Phaeosphaeria sp. L487. cDNA isolation, characterization, and bacterial expression of a bifunctional diterpene cyclase in fungal gibberellin biosynthesis. J Biol Chem. 1997 Aug 29;272(35):21706-12. doi: 10.1074/jbc.272.35.21706.
Pubmed: 9268298
Sun TP, Kamiya Y: The Arabidopsis GA1 locus encodes the cyclase ent-kaurene synthetase A of gibberellin biosynthesis. Plant Cell. 1994 Oct;6(10):1509-18. doi: 10.1105/tpc.6.10.1509.
Pubmed: 7994182
Fall RR, West CA: Purification and properties of kaurene synthetase from Fusarium moniliforme. J Biol Chem. 1971 Nov 25;246(22):6913-28.
Pubmed: 4331199
Lin LG, Ung CO, Feng ZL, Huang L, Hu H: Naturally Occurring Diterpenoid Dimers: Source, Biosynthesis, Chemistry and Bioactivities. Planta Med. 2016 Oct;82(15):1309-1328. doi: 10.1055/s-0042-114573. Epub 2016 Aug 19.
Pubmed: 27542177
Koksal M, Potter K, Peters RJ, Christianson DW: 1.55A-resolution structure of ent-copalyl diphosphate synthase and exploration of general acid function by site-directed mutagenesis. Biochim Biophys Acta. 2014 Jan;1840(1):184-90. doi: 10.1016/j.bbagen.2013.09.004. Epub 2013 Sep 12.
Pubmed: 24036329
Toyomasu T, Kawaide H, Ishizaki A, Shinoda S, Otsuka M, Mitsuhashi W, Sassa T: Cloning of a full-length cDNA encoding ent-kaurene synthase from Gibberella fujikuroi: functional analysis of a bifunctional diterpene cyclase. Biosci Biotechnol Biochem. 2000 Mar;64(3):660-4. doi: 10.1271/bbb.64.660.
Pubmed: 10803977
Yamaguchi S, Smith MW, Brown RG, Kamiya Y, Sun T: Phytochrome regulation and differential expression of gibberellin 3beta-hydroxylase genes in germinating Arabidopsis seeds. Plant Cell. 1998 Dec;10(12):2115-26. doi: 10.1105/tpc.10.12.2115.
Pubmed: 9836749
Williams J, Phillips AL, Gaskin P, Hedden P: Function and substrate specificity of the gibberellin 3beta-hydroxylase encoded by the Arabidopsis GA4 gene. Plant Physiol. 1998 Jun;117(2):559-63. doi: 10.1104/pp.117.2.559.
Pubmed: 9625708
Mitchum MG, Yamaguchi S, Hanada A, Kuwahara A, Yoshioka Y, Kato T, Tabata S, Kamiya Y, Sun TP: Distinct and overlapping roles of two gibberellin 3-oxidases in Arabidopsis development. Plant J. 2006 Mar;45(5):804-18. doi: 10.1111/j.1365-313X.2005.02642.x.
Pubmed: 16460513
Matsushita A, Furumoto T, Ishida S, Takahashi Y: AGF1, an AT-hook protein, is necessary for the negative feedback of AtGA3ox1 encoding GA 3-oxidase. Plant Physiol. 2007 Mar;143(3):1152-62. doi: 10.1104/pp.106.093542. Epub 2007 Feb 2.
Pubmed: 17277098
Chiang HH, Hwang I, Goodman HM: Isolation of the Arabidopsis GA4 locus. Plant Cell. 1995 Feb;7(2):195-201. doi: 10.1105/tpc.7.2.195.
Pubmed: 7756830
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