Metabolites fungal

The fungal metabolites patulin (10) and multicolic acid (79) are derived in nature via oxidative cleavages of polyketide derived aromatic intermediates a similar pathway has been established for the tetronic acid penicillic acid (185). By contrast, the biosynthesis of carolic acid (76a) which is found with dehydrocarolic acid (75) in P. charlesii, has been shown to occur from Krebs cycle intermediates. 

The biosynthesis of patulin (10) has been studied extensively, since the molecule represents a relatively simple model system in which to examine the detailed enzymology of polyketide biosynthesis. Patulin is biosynthesized by the fungus Penicillium patulum via an oxidative pathway from 6-methylsalicylic acid (188) which is synthesized from acetyl-CoA and malonyl-CoA. The major pathway from (188) and the biosynthetic relationships of the phenolic secondary metabolites of P. patulum are 

The biosynthesis of the fungal tetronic acids penicillic acid (185) and carolic acid (76 a), which are closely related structurally to patulin and multicolic acid, have also been studied extensively. Early work with C-labelled precursors has clearly demonstrated the polyketide origin of penicillic acid, and also the intermediacy of orsellinic acid 

A small number of simple substituted quinazolines can be formed in the course of tryptophan degradation by microorganisms (131, 132). In Pseudomonas species, three pathways of tryptophan degradation are known the aromatic pathway in Ps. fluorescens, the quinoline pathway in Ps. acidovorans, and the quinazoline pathway in Ps. aeruginosa. Investigations with [P- C]-tryptophan have provided evidence for a new pathway from tryptophan through the intermediates, formylkynurenine and N-formylaminoacetophenone, forming 4-methylquinazoline with ammonia and free 2-aminoacetophenone. Reacylation of the product and cyclization with ammonia produces other derivatives of 4-methyl-quinazoline. 

Yamazaki et al. (221) have postulated that the tryptoquivalines may be biogenetically derived from four amino acids tryptophan, anthranilic acid, valine and alanine. Deoxynortryptoquivalone is thought to be the first compound formed in the biosynthesis of the tryptoquivaline series. Oxidation of the secondary amine in this compound to a hydroxylamine would result in nortryptoquivalone. Oxidative loss of the side-chain would lead to FTE or FTJ. Alternatively, reduction of the side-chain carbonyl group would afford nortryptoquivaline. The geminal dimethyl group at C-15 may result from incorporation of a Cj-unit into deoxynortryptoquivalone or from the direct participation of methylalanine rather than alanine in the initial step of the biosynthesis. 

The antibiotic tryptanthrin (103) has been biosynthetically prepared from one mole of tryptophan and one mole of anthranilic acid. Feeding tryptophan plus substituted anthranilic acids, or substituted tryptophans plus anthranilic acid has resulted in the generation of the expected tryptanthrin derivatives. No substrate specificity (except for bromotryp-tophan) was observed in the enzymes involved in tryptanthrin biosynthesis. The anthranilic acid moiety of these compounds is the result of tryptophan degradation (65, 183). 

Originally there was some debate of the structure of flavipucine (syn. glutamicine) an alkaloid from Aspergillus flavipes, however the constitution (106) has been deduced by X-ray crystallography (P.S. White, J.A. Findlay and W.H.J. 

A probable co-metabolite of the fiingus is isoflavipucine which has structure (107) (Findlay et al., Canad.J.Chem., 1977, 55, 600). Flavipucine has been synthesised (N.N. Girotra, Z.S. Zelawski and N.L. Wendler, Chem.Comm., 1975, 566 Girotra and Wendler, Heterocycles, 1978, 9, 417 but also see Findlay, ibid., 

Flavipucine is readily converted into its isomer by heat or by base treatment. 

Streptomyces species yield the bicyclic base abikoviromycin (108) (M. Onda et al., Chem.pharm.Bull., 1974, 22, 2916 1975, 

tendae is a source of a number of relative complex antibiotics containing a pyridine nucleus. Some examples 

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A few natural products with oxirane rings fused to five-membered rings are known. These include the antibiotic methylenomycin-A (82) (79H(13)353, 79JOC4210,80JA3904, 81CC714) and the truly remarkable fungal metabolite trichoviridine (83), which appears to be the first example of an isocyanide epoxide (76CPB832). 

The fungal metabolite (+)-brefeldin A (325) displays potent antitumor, antifungal, antiviral, antimitotic, and immunosuppressive activities. Recently, Romo and Wang described a highly concise total synthesis of 325 by a combined /J-lactone-CM approach (Scheme 63), that again underlines the high tolerance of sensitive functionality exhibited by the second-generation Ru catalysts [ 145]. 

Kojic acid is a fungal metabolite (5-hydroxy-4 pyran 4-1-2 methyl) known to inhibit tyrosinase and used to treat melasma at concentration of 2-4% twice a day. The stability is one of its advantages if compared with hydroquinone. Unfortunately, it is considered to have a high sensitizing potential. 

It has been suggested that the transformations accomplished by the brown-rot fungus Gleophyllum striatum may involve hydroxyl radicals, and this is supported by the overall similarity in the structures of the fungal metabolites with those produced with Fenton s reagent (Wetzstein et al. 1997). 

Verhagen FJM, HJ Swarts, JBPA Wijnberg, JA Field (1998) Biotransformation of the major fungal metabolite 3,5-dichloro-p-anisyl alcohol under anaerobic conditions and its role in formation of bis(3,5-dichloro-4-hydroxyphenyl)methane. Appl Environ Microbiol 64 3225-3231. 

Naphth-l-ol is an established fungal metabolite of naphthalene and may play a role in the association of naphthalene with humic material (Burgos et al. 1996). 

Metabolites may also play a role in the association of the substrate with humic and fulvic acid components. Two illustrations are given (a) naphth-l-ol, an established fungal metabolite of naphthalene, may play a role in the association of naphthalene with humic material (Burgos et al. 1996) and (b) it has been shown that C-labeled metabolites of [9- C]-anthracene including 2-hydroxyanthracene-3-carboxylate and phthalate were not extractable from soil with acetone or dichloromethane, and required alkaline hydrolysis for their recovery (Richnow et al. 1998). 

Whereas plausible fungal metabolites from anthracene, acenaphthylene, fluorene, and benz[fl]anthracene—anthracene-9,10-quinone, acenaphthene-9,10-dione, fluorene-9-one, and benz[fl]anthracene-7,12-quinone—were found transiently in compost-amended soil, these were formed even in sterile controls by abiotic reactions (Wischmann and Steinhart 1997). 

The fungal metabolite, 5-A-acetylardeemin, possessing a hexacyclic structure with a l,4-dihydro-3,6-dioxo-pyra-zino[2,l-A]quinazoline skeleton, is the best multidrug resistance reversal agent known to date <1998MI45>. Hexahydro-3,6-dioxo-pyrazino[2,l-7]quinazolines have been claimed as endothelial nitric oxide synthetase regulators useful in the treatment of cardiovascular disorders <2004EP1471066>. 

Two of the most carcinogenic compounds known dibenzo[a,l]pyrene, a polycyclic aromatic hydrocarbon (PAH) and aflatoxin Bi, a fungal metabolite. 

The most famous fungal metabolites are, of course, the penicillins and cephalosporins. The association of sulfur and penicillin has a curious history. Penicillin was investigated chemically in 1932 by Harold Raistrick and his colleagues.14 The antibacterial activity could be extracted into ether from acid solution but on solvent evaporation the residue was without antibacterial activity. Clearly, penicillin was not a well-behaved natural product If only Raistrick had carried out a back-extraction from ether into dilute alkali, penicillin might have become available in the 1930s (and Raistrick would have become a Nobel Laureate). 

W.B. Turner and D.C. Aldridge, Fungal Metabolites II, Academic Press, London, 1983. 

Antibodies have and likely will find additional use in transplantation-related medicine. In general, cell-mediated immunological mechanisms are responsible for mediating rejection of transplanted organs. In many instances, transplant patients must be maintained on immunosuppressive drugs (e.g. some steroids and, often, the fungal metabolite cyclosporine). However, complications may arise if a rejection episode is encountered that proves unresponsive to standard immunosuppressive therapy. Orthoclone OKT-3 was the first monoclonal antibody-based product to find application in this regard. 

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