MetaCyc Pathway: farnesylcysteine salvage pathway
Inferred from experiment

Enzyme View:

Pathway diagram: farnesylcysteine salvage pathway

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.

Synonyms: farnesylcysteine detoxification pathway, (E,E)-farnesyl diphosphate biosynthesis II, all trans-farnesyl diphosphate biosynthesis II, farnesylcysteine from farnesylated protein salvage pathway

Superclasses: BiosynthesisCofactors, Prosthetic Groups, Electron Carriers BiosynthesisPolyprenyl BiosynthesisAll-Trans-Farnesyl-PP-Biosynthesis

Some taxa known to possess this pathway include : Arabidopsis thaliana col, Ipomoea batatas, Nicotiana tabacum

Expected Taxonomic Range: Viridiplantae

Protein prenylation is an important regulatory modification that can often affect the ability of proteins to interact with membranes or other proteins. Through a series of successive reactions, prenylated proteins typically end up with a C-terminal cysteine residue bearing a farnesylcysteine or geranylgeranylcysteine methyl ester. Therefore, during the process of prenylated protein degradation, S-(2E,6E)-farnesyl-L-cysteine or all-trans-geranylgeranylcysteine are typically released [Crowell07, Huizinga10]. The pathway depicted here shows a way that these isoprenylcysteine compounds can be recycled for further use in the cell while preventing the accumulation of potentially dangerous substances. For instance, free S-(2E,6E)-farnesyl-L-cysteine can cause problems for cells by acting as a competitive inhibitor of regulatory isoprenylcysteine methyltransferases (ICMTs) that modify prenylated proteins [Huizinga10]. And, (2E,6E)-farnesol can be toxic at high levels [Hemmerlin00]. Meanwhile, (2E,6E)-farnesyl diphosphate is an important compound used for protein prenylation, sterol biosynthesis, and sesquiterpene biosynthesis [Thai99].

Although this pathway has been hypothesized to occur in Arabidopsis thaliana col and other important enzymatic activities associated with the pathway have been detected in Nicotiana tabacum and Ipomoea batatas, there is no direct evidence for all of the enzymes present in the pathway in any one species. It is also unclear what other species this pathway is likely to exist in. Given the widespread occurence of prenylated proteins and biosynthetic pathways that utilize (2E,6E)-farnesyl diphosphate in the plant kingdom, numerous plant species may use this pathway. However, there are alternative mechanisms for metabolizing S-(2E,6E)-farnesyl-L-cysteine and farnesylcysteine methyl esters that depend on the activity of flavin-dependent monooxygenases or cysteine Β-lyases shown to exist in pigs and rats [Park, Sausen90] which may also exist in some plants. Yeast also certainly generate farnesylated proteins [Fujiyama91], but the fate of S-(2E,6E)-farnesyl-L-cysteine and farnesylcysteine methyl esters in fungi is unknown. Currently, there is no evidence for the existence of this pathway in prokaryotes.

Interestingly, blocks in early steps in this pathway can affect biological processes that depend on protein prenylation. For instance, abscisic acid (ABA)-mediated signaling in Arabidopsis thaliana col involves the targeted methylation of the farnesylcysteine residue on prenylated proteins via isoprenylcysteine methyltransferases (ICMTs). Normal ABA signaling is disrupted when mutants with lowered farnesylcysteine lyase activity have elevated levels of free S-(2E,6E)-farnesyl-L-cysteine that acts as a competitive inhibitor of ICMTs [Crowell07, Huizinga10].

Citations: [Crick97, Bentinger98, Zhang96a]

Variants: trans, trans-farnesyl diphosphate biosynthesis

Created 16-Aug-2010 by Dreher KA, TAIR


Bentinger98: Bentinger M, Grunler J, Peterson E, Swiezewska E, Dallner G (1998). "Phosphorylation of farnesol in rat liver microsomes: properties of farnesol kinase and farnesyl phosphate kinase." Arch Biochem Biophys 353(2);191-8. PMID: 9606952

Crick97: Crick DC, Andres DA, Waechter CJ (1997). "Novel salvage pathway utilizing farnesol and geranylgeraniol for protein isoprenylation." Biochem Biophys Res Commun 237(3);483-7. PMID: 9299388

Crowell07: Crowell DN, Huizinga DH, Deem AK, Trobaugh C, Denton R, Sen SE (2007). "Arabidopsis thaliana plants possess a specific farnesylcysteine lyase that is involved in detoxification and recycling of farnesylcysteine." Plant J 50(5);839-47. PMID: 17425716

Fujiyama91: Fujiyama A, Tsunasawa S, Tamanoi F, Sakiyama F (1991). "S-farnesylation and methyl esterification of C-terminal domain of yeast RAS2 protein prior to fatty acid acylation." J Biol Chem 266(27);17926-31. PMID: 1917931

Hemmerlin00: Hemmerlin A, Bach TJ (2000). "Farnesol-induced cell death and stimulation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase activity in tobacco cv bright yellow-2 cells." Plant Physiol 123(4);1257-68. PMID: 10938345

Huizinga10: Huizinga DH, Denton R, Koehler KG, Tomasello A, Wood L, Sen SE, Crowell DN (2010). "Farnesylcysteine Lyase is Involved in Negative Regulation of Abscisic Acid Signaling in Arabidopsis." Mol Plant 3(1);143-55. PMID: 19969520

Park: Park SB, Howald WN, Cashman JR "S-oxidative cleavage of farnesylcysteine and farnesylcysteine methyl ester by the flavin-containing monooxygenase." Chem Res Toxicol 7(2);191-8. PMID: 8199308

Sausen90: Sausen PJ, Elfarra AA (1990). "Cysteine conjugate S-oxidase. Characterization of a novel enzymatic activity in rat hepatic and renal microsomes." J Biol Chem 265(11);6139-45. PMID: 2318851

Thai99: Thai L, Rush JS, Maul JE, Devarenne T, Rodgers DL, Chappell J, Waechter CJ (1999). "Farnesol is utilized for isoprenoid biosynthesis in plant cells via farnesyl pyrophosphate formed by successive monophosphorylation reactions." Proc Natl Acad Sci U S A 96(23);13080-5. PMID: 10557276

Zhang96a: Zhang FL, Casey PJ (1996). "Protein prenylation: molecular mechanisms and functional consequences." Annu Rev Biochem 65;241-69. PMID: 8811180

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

Bede01: Bede JC, Teal PE, Goodman WG, Tobe SS (2001). "Biosynthetic pathway of insect juvenile hormone III in cell suspension cultures of the sedge Cyperus iria." Plant Physiol 127(2);584-93. PMID: 11598232

Carter04: Carter C, Pan S, Zouhar J, Avila EL, Girke T, Raikhel NV (2004). "The vegetative vacuole proteome of Arabidopsis thaliana reveals predicted and unexpected proteins." Plant Cell 16(12);3285-303. PMID: 15539469

Heather11: Heather Fitzpatrick A, Bhandari J, Crowell DN (2011). "Farnesol kinase is involved in farnesol metabolism, ABA signaling, and flower development in Arabidopsis." Plant J. PMID: 21395888

Inoue04: Inoue Y, Shiraishi A, Hada T, Hirose K, Hamashima H, Shimada J (2004). "The antibacterial effects of terpene alcohols on Staphylococcus aureus and their mode of action." FEMS Microbiol Lett 237(2);325-31. PMID: 15321680

Inoue84: Inoue, H., Tsuji, H., Uritani, I. (1984). "Characterization and Activity Change of Farnesol Dehydrogenase in Black Rot Fungusinfected Sweet Potato." Agricultural and Biological Chemistry. 48 (3):733-738.

Inoue94: Inoue H, Korenaga T, Sagami H, Koyama T, Ogura K (1994). "Phosphorylation of farnesol by a cell-free system from Botryococcus braunii." Biochem Biophys Res Commun 200(2);1036-41. PMID: 8179579

Jaquinod07: Jaquinod M, Villiers F, Kieffer-Jaquinod S, Hugouvieux V, Bruley C, Garin J, Bourguignon J (2007). "A proteomics dissection of Arabidopsis thaliana vacuoles isolated from cell culture." Mol Cell Proteomics 6(3);394-412. PMID: 17151019

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

Mayoral09: Mayoral JG, Nouzova M, Navare A, Noriega FG (2009). "NADP+-dependent farnesol dehydrogenase, a corpora allata enzyme involved in juvenile hormone synthesis." Proc Natl Acad Sci U S A 106(50);21091-6. PMID: 19940247

Oguni71: Oguni, I., Uritani, I. (1971). "Participation of farnesol in the biosynthesis of ipomeamarone." Plant and Cell Physiology.12(4): 507-515.

Shchepin03: Shchepin R, Hornby JM, Burger E, Niessen T, Dussault P, Nickerson KW (2003). "Quorum sensing in Candida albicans: probing farnesol's mode of action with 40 natural and synthetic farnesol analogs." Chem Biol 10(8);743-50. PMID: 12954333

Xie00: Xie H, Shao Y, Becker JM, Naider F, Gibbs RA (2000). "Synthesis and biological evaluation of the geometric farnesylated analogues of the a-factor mating peptide of Saccharomyces cerevisiae." J Org Chem 65(25);8552-63. PMID: 11112575

Yu05: Yu, J. S., Kleckley, T. S., Wiemer, D. F. (2005). "Synthesis of Farnesol Isomers via a Modified Wittig Procedure." Org. Lett., 7 (22): 4803 -4806.

Zhang97: Zhang L, Tschantz WR, Casey PJ (1997). "Isolation and characterization of a prenylcysteine lyase from bovine brain." J Biol Chem 272(37);23354-9. PMID: 9287348

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Please cite the following article in publications resulting from the use of MetaCyc: Caspi et al, Nucleic Acids Research 42:D459-D471 2014
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