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MetaCyc Pathway: menthol biosynthesis
Inferred from experiment

Pathway diagram: menthol biosynthesis

If an enzyme name is shown in bold, there is experimental evidence for this enzymatic activity.

Superclasses: BiosynthesisSecondary Metabolites BiosynthesisTerpenoids BiosynthesisMonoterpenoids Biosynthesis

Some taxa known to possess this pathway include : Mentha spicata, Mentha x piperita

Expected Taxonomic Range: Lamiaceae

Monoterpenoids, the main volatile components in essential oils, have been used historically in the food, perfume and pharmaceutical industries because of their culinary, fragrance and antimicrobial properties. Commercially, menthol is one of the most valuable monoterpenes. The essential oils of the genus Mentha (mint) occurs in the peltate glandular trichomes. The monoterpene constituents of the essential oils of mint are distinguished by the position of oxygenation on the p-menthane ring [Lawrence81]. Of the agronomically important mints, peppermint (M. piperita L.) produces almost exclusively monoterpenes bearing an oxygen function at position C-3 such as menthol (responsible for the cooling sensation of peppermint), whereas spearmint types such as native spearmint ( Mentha spicata) and Scotch spearmint (M. gentilis var cardiaca) produce almost exclusively monoterpenes bearing an oxygen function at position C-6, typified by carvone (responsible for the typical spearmint note).

The biosynthesis of p-menthane monoterpenes in Mentha species proceeds from geranyl pyrophosphate via the cyclic olefin limonene. Biosynthetic investigations have demonstrated that regiospecificity is established very early on the monoterpene biosynthesis pathways in which (-)-4S-limonene, the common precursor of both oxygenated series, undergoes cytochrome P450-mediated hydroxylation at C-3 to yield (-)-trans-isopiperitenol or at C-6 to afford (-)-trans-carveol. The remaining enzymatic machinery responsible for the subsequent redox transformations of isopiperitenol to menthol is present in both peppermint and spearmint species; however, carveol is a poor substrate for these reactions, with the consequence that only the dehydrogenation product, carvone, accumulates in spearmint types [Croteau91]. Typically, superior oils of peppermint contain high quantities of menthol, moderate amounts of menthone and low levels of pulegone and menthofurane (both of which are undesirable for their hepatotoxicity in humans).

In the final reductive step of the menthol biosynthesis pathway, (-)-menthone and (+)-isomenthone are reduced to (-)-menthol and (+)-neoisomenthol, respectively, by MMR and to (+)-neomenthol and (+)-isomenthol by MNR; the latter three monoterpenol isomers are minor constituents of peppermint oil.


Croteau91: Croteau R., Karp F., Wagschal K.C., Satterwhite D.M., Hyatt D.C., Skotland C.B. "Biochemical characterization of a spearmint mutant that resembles peppermint in monoterpene content." Plant Physiol. (1991) 96:744-752.

Lawrence81: Lawrence B.M. (1981). "Monoterpene interrelationships in the Mentha genus: a biosynthetic discussion." Essential Oils. Allured Publishing, Wheaton, IL, pp 1-81.

Turner04a: Turner GW, Croteau R (2004). "Organization of monoterpene biosynthesis in Mentha. Immunocytochemical localizations of geranyl diphosphate synthase, limonene-6-hydroxylase, isopiperitenol dehydrogenase, and pulegone reductase." Plant Physiol 136(4);4215-27. PMID: 15542490

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

Alonso92: Alonso WR, Rajaonarivony JI, Gershenzon J, Croteau R (1992). "Purification of 4S-limonene synthase, a monoterpene cyclase from the glandular trichomes of peppermint (Mentha x piperita) and spearmint (Mentha spicata)." J Biol Chem 267(11);7582-7. PMID: 1559995

Bertea01: Bertea CM, Schalk M, Karp F, Maffei M, Croteau R (2001). "Demonstration that menthofuran synthase of mint (Mentha) is a cytochrome P450 monooxygenase: cloning, functional expression, and characterization of the responsible gene." Arch Biochem Biophys 390(2);279-86. PMID: 11396930

Bertea03: Bertea C, Schalk M, Mau CJ, Karp F, Wildung MR, Croteau R (2003). "Molecular evaluation of a spearmint mutant altered in the expression of limonene hydroxylases that direct essential oil monoterpene biosynthesis." Phytochemistry 64(7);1203-11. PMID: 14599518

Bohlmann00: Bohlmann J, Martin D, Oldham NJ, Gershenzon J (2000). "Terpenoid secondary metabolism in Arabidopsis thaliana: cDNA cloning, characterization, and functional expression of a myrcene/(E)-beta-ocimene synthase." Arch Biochem Biophys 375(2);261-9. PMID: 10700382

Bohlmann97: Bohlmann J, Steele CL, Croteau R (1997). "Monoterpene synthases from grand fir (Abies grandis). cDNA isolation, characterization, and functional expression of myrcene synthase, (-)-(4S)-limonene synthase, and (-)-(1S,5S)-pinene synthase." J Biol Chem 272(35);21784-92. PMID: 9268308

Bohlmann99: Bohlmann J, Phillips M, Ramachandiran V, Katoh S, Croteau R (1999). "cDNA cloning, characterization, and functional expression of four new monoterpene synthase members of the Tpsd gene family from grand fir (Abies grandis)." Arch Biochem Biophys 368(2);232-43. PMID: 10441373

Chen04a: Chen F, Ro DK, Petri J, Gershenzon J, Bohlmann J, Pichersky E, Tholl D (2004). "Characterization of a root-specific Arabidopsis terpene synthase responsible for the formation of the volatile monoterpene 1,8-cineole." Plant Physiol 135(4);1956-66. PMID: 15299125

Choi08a: Choi HW, Lee BG, Kim NH, Park Y, Lim CW, Song HK, Hwang BK (2008). "A role for a menthone reductase in resistance against microbial pathogens in plants." Plant Physiol 148(1);383-401. PMID: 18599651

Colby93: Colby SM, Alonso WR, Katahira EJ, McGarvey DJ, Croteau R (1993). "4S-limonene synthase from the oil glands of spearmint (Mentha spicata). cDNA isolation, characterization, and bacterial expression of the catalytically active monoterpene cyclase." J Biol Chem 268(31);23016-24. PMID: 8226816

Davis05a: Davis EM, Ringer KL, McConkey ME, Croteau R (2005). "Monoterpene Metabolism. Cloning, Expression, and Characterization of Menthone Reductases from Peppermint." Plant Physiol NIL. PMID: 15728344

Duetz03: Duetz WA, Bouwmeester H, van Beilen JB, Witholt B (2003). "Biotransformation of limonene by bacteria, fungi, yeasts, and plants." Appl Microbiol Biotechnol 61(4);269-77. PMID: 12743755

Faldt03: Faldt J, Martin D, Miller B, Rawat S, Bohlmann J (2003). "Traumatic resin defense in Norway spruce (Picea abies): methyl jasmonate-induced terpene synthase gene expression, and cDNA cloning and functional characterization of (+)-3-carene synthase." Plant Mol Biol 51(1);119-33. PMID: 12602896

Gershenzon90: Gershenzon J., Croteau R. "Biochemistry of the mevalonic acid pathway to terpenoids." (1990) Plenum Press, NY.

Iijima04: Iijima Y, Davidovich-Rikanati R, Fridman E, Gang DR, Bar E, Lewinsohn E, Pichersky E (2004). "The biochemical and molecular basis for the divergent patterns in the biosynthesis of terpenes and phenylpropenes in the peltate glands of three cultivars of basil." Plant Physiol 136(3);3724-36. PMID: 15516500

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

Lupien99: Lupien S, Karp F, Wildung M, Croteau R (1999). "Regiospecific cytochrome P450 limonene hydroxylases from mint (Mentha) species: cDNA isolation, characterization, and functional expression of (-)-4S-limonene-3-hydroxylase and (-)-4S-limonene-6-hydroxylase." Arch Biochem Biophys 368(1);181-92. PMID: 10415126

Mahmoud03: Mahmoud SS, Croteau RB (2003). "Menthofuran regulates essential oil biosynthesis in peppermint by controlling a downstream monoterpene reductase." Proc Natl Acad Sci U S A 100(24);14481-6. PMID: 14623962

Martin04b: Martin DM, Faldt J, Bohlmann J (2004). "Functional characterization of nine Norway Spruce TPS genes and evolution of gymnosperm terpene synthases of the TPS-d subfamily." Plant Physiol 135(4);1908-27. PMID: 15310829

Mau10: Mau CJ, Karp F, Ito M, Honda G, Croteau RB (2010). "A candidate cDNA clone for (-)-limonene-7-hydroxylase from Perilla frutescens." Phytochemistry 71(4);373-379. PMID: 20079506

Ringer03: Ringer KL, McConkey ME, Davis EM, Rushing GW, Croteau R (2003). "Monoterpene double-bond reductases of the (-)-menthol biosynthetic pathway: isolation and characterization of cDNAs encoding (-)-isopiperitenone reductase and (+)-pulegone reductase of peppermint." Arch Biochem Biophys 418(1);80-92. PMID: 13679086

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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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