MetaCyc Pathway: superpathway of rosmarinic acid biosynthesis
Inferred from experimentTraceable author statement to experimental support

Pathway diagram: superpathway of rosmarinic acid biosynthesis

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

Superclasses: BiosynthesisSecondary Metabolites BiosynthesisPhenylpropanoid Derivatives BiosynthesisCinnamates Biosynthesis

Some taxa known to possess this pathway include : Anchusa officinalis, Lithospermum erythrorhizon, Portulaca grandiflora, Solenostemon scutellarioides

Expected Taxonomic Range: Tracheophyta

General Background

This superpathway illustrates the metabolic steps of the rosmarinic acid biosynthesis. Rosmarinic acid (RA) is an ester of caffeic acid and 3,4-dihydrophenyllactic acid and is widely spread in species of the Lamiaceae and Boraginaceae [Petersen03a] but also occurs in lower plants such as ferns and hornworts [Takeda90] [Petersen03]. Beside rosmarinic acid its 3'-O-β-glucoside ( rosmarinic acid 3'-O-β-glucoside) has been identified in the hornwort Anthoceros agrestis [Vogelsang05] accumulating up to 1% of the cell dry weight. Other rosmarinic acid derivatives of biological importance are lithospermic acid, a conjugate of rosmarinic acid and caffeic acid, and lithospermic acid B a dimer of rosmarinic acid [Petersen03a].

The biosynthesis of rosmarinic acid has been extensively studied for two reasons. Rosmarinic acid has been shown to be a useful compound with regard to medicine virtue and as food additive. In addition, RA is considered as a preformed, constitutively accumulated compound involved in the defense against microbes [Szabo99]. The other reason was the challenge to unravel the interesting biosynthesis consisting of two parallel biosynthetic pathways that have to be regulated in a coordinated manner [Matsuno02].

About This Pathway

RA biosynthesis has been first investigated in Mentha arvense and Mentha x piperita [Ellis70] confirming the involvement of two parallel pathways for the making of rosmarinic acid. The metabolic origin for the formation of the two crucial compounds coumaroyl-CoA and 4-hydroxyphenyllactate was identified as L-phenylalanine and L-tyrosine, respectively. The most experimental support for the RA biosynthesis has been obtained from species of the Lamiaceae family ( Solenostemon scutellarioides, Anchusa officinalis) elucidating the detailed enzymatic steps resulting in the formation of RA ( rosmarinic acid biosynthesis I) [Petersen93] [Petersen03a].

Coumaroyl-CoA is one of the essential components being used for the assembly of rosmarinic acid. It is derived from L-phenylalanine in three well characterized enzymatic steps in plants catalyzed by L-phenylalanine-ammonia-lyase (PAL), cinnamic acid 4-hydroxylase (C4H) and 4-coumaric acid-CoA ligase (4CL) (compare phenylpropanoid biosynthesis, initial reactions).

The other metabolic branch contributing to the biosynthesis of RA originates from L-tyrosine resulting in the formation of 4-hydroxyphenyllactate (4HPL). The two moieties of the parallel pathways are connected by rosmarinic acid synthase (RAS) catalyzing a transesterification reaction [Petersen88] [Petersen91]. The RAS accepted caffeoyl-CoA and 3,4-dihydroxyphenyllactic acid (DHPL) resulting in the formation of rosmarinic acid. It should be noted that only the R(+)-stereoisomer of 3,4-dihydroxyphenyllactic acid is accepted by the RAS. On the other side 4-coumaroyl-CoA and either DHPL or its monohydroxylated isomer, 4-hydroxyphenyllactic acid (pHPL) was converted to their corresponding coumaroyl-hydroxyphenyllactates.

The enzymatic capability of RAS and the precedent enzyme hydroxypuruvate reductase [Hausler91] [Kim04] to accept different substrates (mono- or dihydroxylated forms of phenyllactates/phenylacetates) prompted the proposition for a potential second biosynthetic route for RA ( rosmarinic acid biosynthesis II). The enzyme catalyzing the entry step into this potential pathway is tyrosine hydroxylase (EC and has been purified from Portulaca grandiflora [Yamamoto01]. The formation of L-3,4-dihydroxyphenylalanine (DOPA) can also be accomplished by the action of polyphenol oxidases (EC (e.g. [Dry94]).

It is not known precisely at what stage or order in the rosmarinic acid biosynthesis the two hydroxygroups in the 3- and 3'-position of the phenolic rings of 4-coumaroyl-4'-hydroxyphenyllactate are introduced. These two last steps are catalyzed by two separate cytochrome P450 dependent monooxygenases introducing hydroxyl groups to the 3- and 3'-position of 4-coumaroyl-4'-hydroxyphenyllactate [Petersen97] [Matsuno02]. Whereas the 3-hydroxylation of this hydroxycinnamic acid ester has been established the 3'-hydroxylation has yet to be fully characterized.

Subpathways: rosmarinic acid biosynthesis II, rosmarinic acid biosynthesis I

Created 07-Sep-2006 by Foerster H, TAIR


Dry94: Dry IB, Robinson SP (1994). "Molecular cloning and characterisation of grape berry polyphenol oxidase." Plant Mol Biol 26(1);495-502. PMID: 7948897

Ellis70: Ellis BE, Towers GH (1970). "Biogenesis of rosmarinic acid in Mentha." Biochem J 118(2);291-7. PMID: 5484678

Hausler91: Hausler E, Petersen M, Alfermann AW (1991). "Hydroxyphenylpyruvate reductase from cell suspension cultures of Coleus blumei Benth." Z. Naturforsch. 46c, 371-376.

Kim04: Kim KH, Janiak V, Petersen M (2004). "Purification, cloning and functional expression of hydroxyphenylpyruvate reductase involved in rosmarinic acid biosynthesis in cell cultures of Coleus blumei." Plant Mol Biol 54(3);311-23. PMID: 15284489

Matsuno02: Matsuno M, Nagatsu A, Ogihara Y, Ellis BE, Mizukami H (2002). "CYP98A6 from Lithospermum erythrorhizon encodes 4-coumaroyl-4'-hydroxyphenyllactic acid 3-hydroxylase involved in rosmarinic acid biosynthesis." FEBS Lett 514(2-3);219-24. PMID: 11943155

Petersen03: Petersen M (2003). "Cinnamic acid 4-hydroxylase from cell cultures of the hornwort Anthoceros agrestis.." Planta 217(1);96-101. PMID: 12721853

Petersen03a: Petersen M, Simmonds MS (2003). "Rosmarinic acid." Phytochemistry 62(2);121-5. PMID: 12482446

Petersen88: Petersen M, Alfermann AW (1988). "Two new enzymes of rosmarinic acid biosynthesis from cell cultures of Coleus blumei: Hydroxyphenylpyruvate reductase and rosmarinic acid synthase." Z. Naturforsch., 43c, 501-504.

Petersen91: Petersen M (1991). "Characterization of rosmarinic acid synthase from cell cultures of Coleus blumei." Phytochemistry, 30(9), 2877-2881.

Petersen93: Petersen M, Hausler E, Karwatzki B, Meinhard J (1993). "Proposed biosynthetic pathway for rosmarinic acid in cell cultures of Coleus blumei Benth." Planta, 189, 10-14.

Petersen97: Petersen M (1997). "Cytochrome p450-dependent hydroxylation in the biosynthesis of rosmarinic acid in Coleus." Phytochemistry, 45(6), 1165-1172.

Szabo99: Szabo E, Thelen A, Petersen M (1999). "Fungal elicitor preparations and methyl jasmonate enhance rosmarinic acid accumulation in in vitro-cultures of Coleus blumei." Plant Cell Rep. 18, 485-489.

Takeda90: Takeda R, Hasegawa J, Shinozaki M (1990). "The first isolation of lignans, megacerotonic acid and anthocerotonic acid, from non-vascular plants, anthocerotae (hornworts)." Tetrahedron letters, 31(29), 4159-4162.

Vogelsang05: Vogelsang K, Schneider B, Petersen M (2005). "Production of rosmarinic acid and a new rosmarinic acid 3'-O-β-D: -glucoside in suspension cultures of the hornwort Anthoceros agrestis Paton." Planta NIL;1-5. PMID: 16133208

Yamamoto01: Yamamoto K, Kobayashi M, Yoshitama K, Teramoto S, Kosamine A (2001). "Isolation and purification of tyrosine hydroxylase from Portulaca grandiflora." Plant Cell Physiol., 42(9), 969-975.

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

Andersson82: Andersson SM, Pispa JP (1982). "Purification and properties of human liver tyrosine aminotransferase." Clin Chim Acta 125(2);117-23. PMID: 6128088

Arita02: Arita DY, Di Marco GS, Schor N, Casarini DE (2002). "Purification and characterization of the active form of tyrosine hydroxylase from mesangial cells in culture." J Cell Biochem 87(1);58-64. PMID: 12210722

Blakley77: Blakley ER (1977). "The catabolism of L-tyrosine by an Arthrobacter sp." Can J Microbiol 23(9);1128-39. PMID: 20216

Blau: Blau N, Bonafe L, Thony B "Tetrahydrobiopterin deficiencies without hyperphenylalaninemia: diagnosis and genetics of dopa-responsive dystonia and sepiapterin reductase deficiency." Mol Genet Metab 74(1-2);172-85. PMID: 11592814

Cho98: Cho SH, Na JU, Youn H, Hwang CS, Lee CH, Kang SO (1998). "Tepidopterin, 1-O-(L-threo-biopterin-2'-yl)-beta-N-acetylglucosamine from Chlorobium tepidum." Biochim Biophys Acta 1379(1);53-60. PMID: 9468332

Cho99: Cho SH, Na JU, Youn H, Hwang CS, Lee CH, Kang SO (1999). "Sepiapterin reductase producing L-threo-dihydrobiopterin from Chlorobium tepidum." Biochem J 340 ( Pt 2);497-503. PMID: 10333495

Chung00: Chung HJ, Kim YA, Kim YJ, Choi YK, Hwang YK, Park YS (2000). "Purification and characterization of UDP-glucose:tetrahydrobiopterin glucosyltransferase from Synechococcus sp. PCC 7942." Biochim Biophys Acta 1524(2-3);183-8. PMID: 11113566

Collier72: Collier RH, Kohlhaw G (1972). "Nonidentity of the aspartate and the aromatic aminotransferase components of transaminase A in Escherichia coli." J Bacteriol 1972;112(1);365-71. PMID: 4404056

DeEknamkul87: De-Eknamkul W, Ellis BE (1987). "Purification and characterization of tyrosine aminotransferase activities from Anchusa officinalis cell cultures." Arch Biochem Biophys 257(2);430-8. PMID: 2889425

DeEknamkul87a: De-Eknamkul W, Ellis BE (1987). "Tyrosine aminotransferase: the entrypoint enzyme of the tyrosine-derived pathway in rosmarinic acid biosynthesis." Phytochemistry, 26(7), 1941-1946.

Dietrich91: Dietrich JB, Lorber B, Kern D (1991). "Expression of mammalian tyrosine aminotransferase in Saccharomyces cerevisiae and Escherichia coli. Purification to homogeneity and characterization of the enzyme overproduced in the bacteria." Eur J Biochem 201(2);399-407. PMID: 1682148

El83: El Mestikawy S, Glowinski J, Hamon M (1983). "Tyrosine hydroxylase activation in depolarized dopaminergic terminals--involvement of Ca2+-dependent phosphorylation." Nature 302(5911);830-2. PMID: 6133218

Gelfand77: Gelfand DH, Steinberg RA (1977). "Escherichia coli mutants deficient in the aspartate and aromatic amino acid aminotransferases." J Bacteriol 1977;130(1);429-40. PMID: 15983

Gu98: Gu W, Song J, Bonner CA, Xie G, Jensen RA (1998). "PhhC is an essential aminotransferase for aromatic amino acid catabolism in Pseudomonas aeruginosa." Microbiology 144 ( Pt 11);3127-34. PMID: 9846749

Haavik91: Haavik J, Le Bourdelles B, Martinez A, Flatmark T, Mallet J (1991). "Recombinant human tyrosine hydroxylase isozymes. Reconstitution with iron and inhibitory effect of other metal ions." Eur J Biochem 199(2);371-8. PMID: 1676967

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

Maier95: Maier J, Ninnemann H (1995). "Biosynthesis of pteridines in Neurospora crassa, Phycomyces blakesleeanus and Euglena gracilis: detection and characterization of biosynthetic enzymes." Photochem Photobiol 61(1);43-53. PMID: 7899493

Mataga91: Mataga N, Imamura K, Watanabe Y (1991). "6R-tetrahydrobiopterin perfusion enhances dopamine, serotonin, and glutamate outputs in dialysate from rat striatum and frontal cortex." Brain Res 551(1-2);64-71. PMID: 1680529

Mavrides75: Mavrides C, Orr W (1975). "Multispecific aspartate and aromatic amino acid aminotransferases in Escherichia coli." J Biol Chem 250(11);4128-33. PMID: 236311

Oka82: Oka K, Ashiba G, Sugimoto T, Matsuura S, Nagatsu T (1982). "Kinetic properties of tyrosine hydroxylase purified from bovine adrenal medulla and bovine caudate nucleus." Biochim Biophys Acta 706(2);188-96. PMID: 6127111

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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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