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] [Kim04c] 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 18.104.22.168) 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 22.214.171.124) (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.
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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.
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