Salicylate synthetase

Before doing this, however, it is useful to briefly consider the biosynthesis of anacardic acids. It is believed that anacardic acids are synthesized from long chain fatty acids via a modification of the methyl salicylate synthetase scheme (11. 12). In effect a fatty acid, such as palmitate (Cie) is elongated by six carbons by the addition of three acetate units in a series of condensation and dehydration steps, followed by ring closure and aromatization to form a C22 saturated anacardic acid (5. 10. U ). Similarly, margaric acid (C17) is synthesized to a C23 saturated anacardic acid. A comparative study on the biosynthesis of anacardic acids in resistant and susceptible plants, using fatty acid precursors will be the subject of a separate publication. 

Salicylic Acid.—It has recently been demonstrated (see last year s Report ) that whereas 6-methylsalicylic acid in both micro-organisms and higher plants is acetate-derived, salicylic add itself is formed in both groups of organisms by the shikimic add pathway. Further confirmation of this has come from Marshall and Ratledge, who have studied the enzymology of biosynthesis of salicylic acid in Mycobacterium smegmatis. These authors isolated the enzyme salicylate synthetase, which catalyses the last step (see Scheme 1) in synthesis of salicylic acid (1) from isochorismic add (2), formed in turn from chorismic (3) and shikimic adds (4). The enzyme has no cofactor requirements and converts (2) directly into (1). No evidence could be obtained for the presence in bacterial cultures of the possible intermediate 2,3-dihydroxy-2,3-dihydrobenzoic add. 

Salicylate synthetase was also detected in two other Mycobacterium spedes, M. tuberculosis and M. fortuitum, which contain salicylic acid in their myco-bactins. However, it was definitely absent from M. phlei, which lacks salicylic acid but has 6-methylsaIicylic acid. Furthermore, in M. phlei, salicylic acid failed to operate as a feedback control, as it did in the other three organisms. 

It is likely that the madurastatins are biosynthesized on a nonribosomal peptide synthetase, from salicylic acid as the starter acid. L-Serine is probably the precursor to the aziridine moiety, with epimerization occurring on the enzyme-bound amino acid as found for other nonribosomal peptides, with aziridine formation occurring at a late stage. Compounds 120 and 123 could therefore be biosynthetic precursors to 119 and 122, respectively. 

Pharmacology Salicylates have analgesic, antipyretic, anti-inflammatory, and antirheumatic effects. Salicylates lower elevated body temperature through vasodilation of peripheral vessels, thus enhancing dissipation of excess heat. The anti-inflammatory and analgesic activity may be mediated through inhibition of the prostaglandin synthetase enzyme complex. 

Figure 7.60 The interaction of salicylate ion and mitochondrial energy production. Salicylate can diffuse into the mitochondrial matrix, where it ionizes and loses a proton. This changes the predominantly negative charge and reduces the flow of protons through ATP synthetase. So ATP levels fall (j).

Another important example of the importance of chirality, related to rheumatology, is that shown by some members of the NSAID family of aryl acids. Certain molecules which inhibit prostaglandin synthetase in vitro show in vivo antiinflammatory actions. Such compounds include several families of acidic NSAIDs, particularly the aryl acids salicylates, indomethacin analogs, phenylacetic acids, fenamic acids and enolic compounds. With respect to the indomethacin analogs, an important characteristic has emerged, namely, the requirement for a sinister absolute configuration (the S form, which happens to be -t-) at the chiral centre. For these drugs the (5)-(-l-) enantiomers show dominant, if not exclusive, activity. ... 

Fig. 22.7 Consensus effects of Spd and Spm on salicyclic acid metabolism and signaling cascade. Description is same as in legends to Fig. 22.1. GH3.5 GH3-like phytohormone amino acid synthetase, MeSA methyl salicylate, NPRl non-expressor of pathogenesis-related gene 1, NPR3 NPRl-like protein 3, NPR4 NPRl-like protein 4, SA sahcylic acid, SA-Asp Salicyloyl-L-aspartic acid, SAMT SAM-dependent carboxyl methyltransferase, TGA TGA transcription factor...

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