Hormone regulatory pathway of SALICYLIC ACID (SA)
SALICYLIC ACID (SA)
Salicylic acid (SA) is a secondary metabolite produced by a wide range of prokaryotic and eukaryotic organisms including plants. Chemically, it belongs to a group of phenolic compounds defined as substances that possess an aromatic ring bearing hydroxyl group or its functional derivative. Long before SA’s regulatory role in multiple physiological processes of plants attracted people’s attention, the pharmacological properties of salicylates (general name of SA and its derivatives) had been prized. Salicylates have been known to possess medicinal properties since the 5th century B.C., when Hippocrates prescribed salicylate-rich willow leaf and bark for pain relief during childbirth (Rainsford 1984; Weissman 1991). However, the utilization of salicylate-containing plants for curing aches and fevers can be traced back to inhabitants of both the Old and New Worlds. In 1828, German scientist Johann A. Buchner purified a small quantity of the yellowish substance named salicin (a salicyl alcohol glucoside) from willow bark. Later, Raffaele Piria converted salicin into a sugar and an acid he named salicylic acid (SA). More natural sources of SA and other salicylates were identified, but the demand for SA as a pain reliever rapidly outstripped production capacity. In 1859, Hermann Kolbe and coworkers chemically synthesized SA. Subsequently, the synthetic process was improved, which led to the large-scale production of cheaply priced SA for greater medicinal use. In 1899, Bayer pharmaceutical company registered the trade name “Aspirin” for ASA. Today, Aspirin has become one of the most successful and widely used drugs worldwide.
Salicylic acid (SA) is involved in the regulation of pathogenesis related protein expression, leading to plant defense against biotrophic pathogens (Dempsey et al., 2011). It also plays an important role in the regulation of plant growth, development, ripening, flowering, and responses to abiotic stresses (Rivas-San Vicente and Plasencia, 2011; Hara et al., 2012). In general, low concentrations of SA may enhance the antioxidant capacity in plants, but high concentrations of SA may cause cell death or susceptibility to abiotic stresses (Hara et al., 2012). Currently, little information is available about the molecular mechanisms of SA in response to abiotic stresses.
BIOSYNTHESIS OF SALICYLIC ACID
It is largely believed that SA (ortho-hydrobenzoic acid) is a natural derivative of cinnamic acid, an intermediate in shikmic acid pathway, operative for the synthesis of phenolic compounds. However, two possibile routes have been proposed in this direction
(i) Decarboxylation of the side chain of cinnamic acid to generate benzoic acid, that undergoes hydroxylation, at C-2 position. Recently, this scheme, for the synthesis of SA has been reported in tobacco plants (Yalpani et al., 1993) and also in rice seedlings (Silverman et al., 1995). The enzyme that catalyzes E-oxidation of cinnamic acid to benzoic acid has been identified in Quercus pedunculata (Alibert and Ranjeva, 1971; Alibert et al., 1972). However, the other enzyme that is responsible for the conversion of benzoic acid to salicylic acid has not been characterized, so far.
(ii) Hydroxylation of cinnamic acid to o-coumaric acid followed by its decarboxylation to salicylic acid. The conversion of cinnamic acid to ocoumaric acid is believed to be catalyzed by trans-cinnamate-4-hydroxylase (Alibert and Ranjeva, 1971; Alibert et al., 1972) that was first detected in pea seedlings (Russel and Conn, 1967). Later on it was also identified in Quercus pedunculata (Alibert and Ranjeva, 1971; Alibert et al., 1972), tubers of Jeruselem artichoke (Garbiac et al., 1991) and Melilotus alba (Gestetner and Conn, 1974). However, the enzyme that activates the conversion of o-coumaric acid to SA has not yet been identified.
Moreover, incorporation of radioactive 14C-benzoic acid or 14C-cinnamic acid resulted in the formation of labeled SA in Gaultheria procumbens (Ellis and Amrchein, 1971). This observation strongly favours the belief that SA is synthesized from cinnamic acid, mediated by benzoic acid as an intermediate but El-Basyuni et al. (1964) believe that both the above systems are operative, in higher plants, in the synthesis of SA.
METABOLISM OF SALICYLIC ACID
Salicylic acid is known to form conjugates with a number of molecules (Ibrahim and Tower, 1959; Griffiths, 1959; Lee et al., 1995) by glycosylation and less frequently by estrification (Popova et al., 1997). The glucose esters of SA have been reported in suspension cultures of soybean, mung bean (Apte and Laloraya, 1982) and that of sunflwoer hypocotyls (Klambt, 1962) and also in other higher plants (Griffith, 1959; Ibrahim and Tower, 1959). Similarly, the conjugate (glucoside), b-glucoside-SA, has been identified in suspension culture of Mallotus japonicus (Tanaka et al., 1990) and in the roots of Avena sativa seedlings (Balke and Schulz, 1987; Yalpani et al., 1992a). Nonetheless, they also identified an enzyme, SAglycosyltransferase (Gtase), that catalyzes the metabolism of SA to Eglucoside-SA. The presence of a conjugate with amino acids (salicyl aspartic acid) is also reported in wild grapes (Silverman et al., 1995) and French bean (Bourne et al., 1991).
Although, SA-2-O-E-D-glucoside is a predominant conjugate in plants, but other metabolites could be formed by estrification or additional hydroxylation of the aromatic ring. Out of them, 2,3-dihydroxybenzoic acid (O-pyrocatechuic acid) and 2,5-dihydrobenzoic acid (Gentisic acid) were identified in the leaves of Astilbe sinensis and Lycopersicon esculentum, fed with 14C-cinnamic acid and 14C-benzoic acid (Billek and Schmook, 1967; Chadha and Brown, 1974).
Proposed pathway for salicylic acid biosynthesis in plants
An overview of the salicylic acid (SA) signaling pathways.
Pathogen secretion of the phytotoxin coronatine indirectly promotes MYC2 activation of NAC genes, which inhibit SA accumulation through the down-regulation of isochorismate synthase 1 (ICS1) expression. Indirect activation of BENZOIC ACID/SALICYLIC ACID CARBOXYL METHYLTRANSFERASE 1 (BSMT1) expression by NAC genes may also result in BSMT1-mediated conversion of SA into methyl salicylate (MeSA). Pathogens may also indirectly promote abscisic acid (ABA) accumulation to inhibit SA production through ICS1. Pathogen detection elicits SA biosynthesis via PHYTOALEXIN DEFICIENT 4 (PAD4) and ENHANCED DISEASE SUSCEPTIBILITY 1 (EDS1) interactions with ICS1 and EDS5, whereas pathogens may activate other antagonistic phytohormone pathways via effectors. The accumulation of SA results in changes in the cellular redox potential and facilitates thioredoxin (TRX)-mediated NON-EXPRESSOR OF PATHOGENESIS-RELATED GENES 1 (NPR1) deoligomerization; conversely, NPR1 re-oligomerization requires S-nitrosothiol (SNO), a nitric oxide donor.A recent study has indicated that NPR3 and NPR4 act as SA receptors and regulate NPR1 functions. NPR1 and TGAs directly regulate PATHOGENESIS-RELATED 1 (PR1) expression, which results in PR1 protein production and secretion into the apoplast, where it exerts its antimicrobial activity on the proliferating pathogens. NPR1 also positively regulates TBF1 expression and, in turn, TBF1 promotes SA-dependent BiP2 expression. The resulting BiP2 protein binds to Unfolded Protein Response (UPR) regulatory proteins, such as IRE1, to prevent activation of the UPR in the absence of biotic stress. IRE1, an endoplasmic reticulum (ER)-bound, transmembrane protein with kinase/endonuclease activity, orchestrates the coordinated expression of UPR genes following SA or pathogen treatment. Examples of inhibitory effects between jasmonic acid (JA) and SA pathways include the indirect negative regulation of the JA pathway by SA, such as indirect inhibition of CORONATINE-INSENSITIVE 1 (COI1) by cytosolic NPR1, and JA interaction with COI1, which indirectly inhibits the SA pathway. In addition, JA signalling proteins MITOGEN-ACTIVATED PROTEIN KINASE 4 (MPK4) and SUPPRESSOR OF SA INSENSITIVITY 2 (SSI2) indirectly regulate SA-mediated defense. Yellow boxes indicate proteins. Red boxes indicate phytohormones. Solid lines indicate direct causation/interaction. Dotted lines indicate indirect causation/interaction. S–S, disulfide bridges; Ps, Pseudomonas syringae.
Models for salicylic acid (SA) perception in planta
(a–d)The data of Fu et al. (2012) indicate that NON-EXPRESSOR OF PATHOGENESIS-RELATED 3 (NPR3) and NPR4 function as SA receptors. (a)Binding of NPR1 by NPR4 in the absence of SA leads to NPR1 degradation via the 26S proteasome. The Cullin3 (CUL3) adaptor protein is omitted for simplicity. (b)Basal SA levels allow for binding of SA to NPR4, thereby limiting the ability of NPR4 to act as a CUL3 substrate adaptor and binding NPR1 for degradation. Low levels of NPR1 accumulate and subsequently activate basal resistance responses, whilst some NPR4-dependent NPR1 degradation continues. (c)Moderate SA levels experienced in effector-triggered immunity (ETI) in neighboring cells (systemic tissue) allow for SA binding to NPR4, limit NPR4–NPR1 interaction and, in turn, permit NPR1-dependent expression of systemic acquired resistance (SAR) genes. A pool of NPR1 undergoes degradation via NPR3 interaction. (d) Cells subjected to direct avirulent pathogen attack experience high SA accumulation, leading to subsequent NPR3-dependent NPR1 degradation and ETI/programmed cell death (PCD) inhibition. (e) Wu et al. (2012) postulate that NPR1 functions as the SA receptor. The NPR1 oligomer contains transitional metal ions (M), such as copper, to facilitate the binding of SA. Reducing conditions in the cell begin the de-oligomerization of NPR1, but SA is required for complete oligomer disassembly. The nuclear NPR1 oligomer interacts with the PATHOGENESIS-RELATED 1 (PR1) promoter via an unknown transcription factor (TF X) and binds with a TGA2 dimer on SA induction.
Uses of Salicylic Acid
Ø Medicinal use
1. Salicylic acid as a medication is used most commonly to help remove the outer layer of the skin. As such, it is used to treat warts, psoriasis, acne, ringworm, dandruff, and ichthyosis.
2. Similar to other hydroxy acids, salicylic acid is a key ingredient in many skincare products for the treatment of seborrhoeic dermatitis, acne, psoriasis, calluses, corns, keratosis pilaris, acanthosis nigricans, ichthyosis and warts.
Uses in manufacturing
1. Salicylic acid is used in the production of other pharmaceuticals, including 4-aminosalicylic acid, sandulpiride, and landetimide (via Salethamide).
2. Salicylic acid was one of the original starting materials for making acetylsalicylic acid (aspirin) in 1897.
3. Bismuth subsalicylate, a salt of bismuth and salicylic acid, is the active ingredient in stomach relief aids such as Pepto-Bismol, is the main ingredient of Kaopectate and "displays anti-inflammatory action (due to salicylic acid) and also acts as an antacid and mild antibiotic".
4. Other derivatives include methyl salicylate used as a liniment to soothe joint and muscle pain and choline salicylate used topically to relieve the pain of mouth ulcers.
Other uses
1. Salicylic acid is used as a food preservative, a bactericidal and an antiseptic.
2. Sodium salicylate is a useful phosphor in the vacuum ultraviolet spectral range, with nearly flat quantum efficiency for wavelengths between 10 and 100 nm. It fluoresces in the blue at 420 nm. It is easily prepared on a clean surface by spraying a saturated solution of the salt in methanol followed by evaporation.
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