5- Methylsalicylic acid

In 1955, 6-methylsalicylic acid was the first fungal metabolite to be used to test the acetate hypothesis for the biosynthesis of aromatic compounds. The original proposal had been made by Collie in 1907 and then developed by Birch in 1953. This experiment, like many early biosynthetic studies, was carried out by 

Biosynthetic modifications of 6-methylsalicylic add (4.1) and orsellinic acid (4.6) occur in several fungi to generate further tetraketide metabolites. Decarboxylation of these compounds followed by hydroxylation and oxidation leads to a family of toluquinones. These are widespread as metabolites of Penicillhan and Aspergillus spedes. They are exemplified by fumigatin (4.7) and spinulosin (4.8), which were isolated from Aspergillus fumigatus. 

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SPENCER, J.B., JORDAN, P.M., Purification and properties of 6-methylsalicylic acid synthase from Penicilliumpatulum, Biochem. J., 1992,288,839-846. 

The scope of the reaction has not yet been developed. It is known that salicylic acid, 3-, 4-, and 5-methylsalicylic acids, and p-hydroxybenzoic acid undergo the reaction, but 3,5-dibromosalicylic acid, 3-nitrosalicylic acid,... 

Little information is available regarding tissue distribution or metabolic products of nonsteroidal anti-inflammatory drugs in cattle. The early synthetic compounds were simple derivatives either of salicylic acid such as acetylsalicylic acid and methylsalicylic acid, or of pyrazolone such as metamizole, oxyphenbuta-zone, phenylbutazone, propylphenazone, and suxibuzone. Modern nonsteroidal anti-inflammatory drugs are derivatives either of anthranilic acid such as dido-... 

Methylsalicylic acid, unlike acetylsalicylic acid, is nearly exclusively used as an external rubifacient drug for painful muscles or joints and distributed as ointments or liniments due to their irritating effects on the gastrointestinal mucosa. Absorption through intact skin is possible and has led to prosecution following detection in race-horse urine. 

FIGURE I Predicted and observed DOM binding constants using the Flory-Huggins equation and methylsalicylic acid as a DOM analog. 

S. antibioticus produces another unusual macrolide antibiotic [45] called chlorothricin (57) containing, in addition to the aglycone (modified methylsalicylic acid), saccharides, dideoxyhexoses in the first place. Their biosynthesis was investigated by the incorporation of stable isotopes [45-47]. The compounds were only active in a synthetic medium and inactive in a complex one [48]. Compounds designated MC031-034 (58-61) are similar to chlorothricin mentioned above and were isolated from the cultivation broth of Streptomyces sp. collected in Japan. Another compound, 2-hydroxychlorothricin (62), with antitumor activity, was isolated [66] from Streptomyces K818. 

Cell-free systems capable of in vitro synthesis of 6-methylsalicylic acid (6-MS A) and a related tetraketide, orsellinic acid, were developed long before the advent of recombinant DNA technologies in the field of natural product biosynthesis [113-115] (Fig. 5). Since then, the biosynthetic mechanisms and molecular recognition features of 6-methylsalicylic acid synthase (6-MSAS) have been extensively studied. 6-MSAS initiates synthesis with an acetyl group derived from acetyl Co A, extends the polyketide chain to a tetraketide via three decar-boxylative condensations of malonyl CoA-derived extender units, and uses NADPH to specifically reduce one of resulting carbonyls to a hydroxyl group. In its natural producer, Penicillium patulum, the product, 6-MSA is subsequently glycosylated to form the antibiotic patulin [116]. 

Fig. 5. Biosynthetic pathways for (I) 6-methylsalicylic acid and (II) the triacetic acid lactone. The structures of the intermediates have not been identified. The stereochemical course of the prochiral carbons (C-2 and C-4 in the triketide intermediate, C-3 and C-5 in 6-MSA) was investigated using R)- and (S)- [l- C,2- H]malonic acid extender substrate analogs in a coupled assay with 6-MSAS and succinyl-CoA transferase. The distinguishable hydrogens originating from the chiral malonyl CoA are labeled with H and H. Triacetic acid lactone synthesis is catalyzed by 6-MSAS in the absence NADPH...

Dimroth P, Greull G, Seyfferet R, Lynen F (1972) Hoppe Syler s Z Physiol Chem 353 126 Dimroth P,Ringelmann E, Lynen F (1976) Eur J Biochem 68 591 Bhogal P, Shoolingin-Jordan P. Incorporation of novel substrates into 6-methylsalicylic acid and triacetic acid lactone analogues by 6-methyl salicylic acid synthase. In Polyketides chemistry, biochemistry, molecular genetics. 1996. Royal Society of Chemistry, Bristol, UK, p 19... 

Beck J, Ripka S, Siegner A, Schiltz E, Schweizer. The multifunctional 6-methylsalicylic acid synthase gene of Penicillium patulum. Its gene structure relative to that of other polyketide synthases. Eur. J. Biochem. 1990 192 487-498. 

Child CJ, Spencer JB, Bhogal P, Shoolingin-Jordan PM. Structural similarities between 6-methylsalicylic acid synthase from Penicillium patulum and vertebrate type 1 fatty acid synthase evidence from thiol modification studies. Biochemistry 1996 35 12267-12274. 

Methylsalicylic acid has also been proposed for determination of fluoride [43]. 

The Th complexes with organic reagents have been applied in determinations of fluoride in waters [57] and in organic compounds [4,56]. The Alizarin S method has been automated [55]. The aluminium complex with Xylenol Orange has been used for determining fluorine in phosphates [59]. Fluorine was determined in dental preparations with the use of methylsalicylic acid [43]. 

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