If an enzyme name is shown in bold, there is experimental evidence for this enzymatic activity.
|Superclasses:||Biosynthesis → Secondary Metabolites Biosynthesis → Phenylpropanoid Derivatives Biosynthesis → Cinnamates Biosynthesis|
Expected Taxonomic Range: Tracheophyta
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] [Kim04a] 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 22.214.171.124) 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 126.96.36.199) (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.
Kim04a: 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
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.
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
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
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
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
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
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
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
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
Showing only 20 references. To show more, press the button "Show all references".
©2014 SRI International, 333 Ravenswood Avenue, Menlo Park, CA 94025-3493