Anti biosynthetic pathways

Recently, a new polyketide biosynthetic pathway in bacteria that parallels the well studied plant PKSs has been discovered that can assemble small aromatic metabolites.8,9 These type III PKSs10 are members of the chalcone synthase (CHS) and stilbene synthase (STS) family of PKSs previously thought to be restricted to plants.11 The best studied type III PKS is CHS. Physiologically, CHS catalyzes the biosynthesis of 4,2, 4, 6 -tetrahydroxychalcone (chalcone). Moreover, in some organisms CHS works in concert with chalcone reductase (CHR) to produce 4,2 ,4 -trihydroxychalcone (deoxychalcone) (Fig. 12.1). Both natural products constitute plant secondary metabolites that are used as precursors for the biosynthesis of anthocyanin pigments, anti-microbial phytoalexins, and chemical inducers of Rhizobium nodulation genes.12... 

For example, the anti (25) and syn (4-hydroxyphenyl)acetaldoximes, 26, are established intermediates in the biosynthesis of the cyanogenic glucoside of sorghum, dhurrin, 27, and the biochemical pathway for its production in the plant was shown to originate in the A -hydroxylation of tyrosine, in the presence of NADPH/O2, as outlined in equation 15". It was further suggested that the Z (syn) isomer, 26, is utilized preferentially over E(anti )-25 in the subsequent biosynthesis of dhurrin, 27. The same authors provided evidence that the biosynthesis of the aldoxime, 25, proceeds via an aci-nitro containing intermediate, R R C=N(0)0H, that is positioned between Af-hydroxytyrosine and anti-25 in the biosynthetic pathway . 

It has been established that DXS catalyzes the first step in a novel biosynthetic pathway leading to isoprenoids in bacteria, algae, plant chloroplasts, and in the malaria parasite, Plasmodium falciparum. DXS is therefore a novel target for antibiotics, herbicides, or anti-malarials. Our work has contributed to an understanding of the novel biosynthetic pathway and could further open new perspectives on how to inhibit the pathway in pathogenic bacteria, protists, or weeds. 

Within the natural products field, the investigation of complete biosynthetic pathways at the enzyme level has been especially successful for plant alkaloids of the monoterpenoid indole alkaloid family generated from the monoterpene gluco-side secologanin and decarboxylation product of tryptophan, tryptamine [3-5]. The most comprehensive enzymatic data are now available for the alkaloids ajmalicine (raubasine) from Catharanthus roseus, and for ajmaline from Indian Rauvolfia serpentina [6] the latter alkaloid with a six-membered ring system bearing nine chiral carbon atoms. Entymatic data exsist also for vindoline, the vincaleucoblastin (VLB) precursor for which some studies on enzymatic coupling of vindoline and catharanthine exist in order to get the so-called dimeric Catharanthus indole-alkaloids VLB or vincristine [7-9] with pronounced anti-cancer activity [10, 11]. 

Two of the better known "anti-juvenile "Hormone" agents, preco-cenes (9) and fluoromevalonate (10) are inhibitors of JH biosynthesis. The mode of action of fluoromevalonate at the molecular level is unknown. Elucidation of the mode of action of precocenes indicates that these plant chromene derivatives reach the site of JH biosynthesis, the corpora allata (CA), where they undergo a lethal epoxidation leading to extensive macromolecular alkylation and ultimately cause cell death (11, 12). Bioactivation of precocenes to the highly reactive precocene epoxide (13) in the corpora allata is almost certainly catalyzed by methyl farnesoate (MF) epoxidase (14), a cytochrome P-450 sonooxygenase (15) tdtich is the last enzyme of the JH biosynthetic pathway (at least in locusts and cockroaches). 

In principle, other coenzyme biosynthetic pathways that occur in pathogenic bacteria but not in humans should qualify as anti-infective drug targets with a favorable toxicity profile. Novel anti-infective principles would be highly desirable in light of the rapid spread of resistant pathogens. 

Wallaart TE, Bouwmeester HJ, Hille J, Poppinga L, Maijers NC. Amorpha-4,11-diene synthase cloning and functional expression of a key enzyme in the biosynthetic pathway of the novel anti-malarial drug artemisinin. Planta 2001 212 460-465. 

A new dibenzodiazepine alkaloid, diazepinomicin 265, was isolated from the culture of a marine actinomycete of the genus Micromonospora Compound 265 showed modest anti-microbial activity against selected Gram-positive bacteria with MICs of about 32 pg mL". The method of expression the biosynthetic pathway genes in transformed host cells, and the novel polynucleotide sequences and their encoded proteins involved in the biosynthesis of 265 were discussed. Derivatives of 268 were prepared. ... 

Many reviews have dealt with the distribution, structure, properties and biosynthesis of iridoids and secoiridoids [131-137] without distinguish between the biosynthetic pathway route. In our case, some of the most studied activities, as anti-inflammatory, antitumoral-chemopreventive, and protective by iridoids biosynthesized by route IIa, have been discussed. 

To date no drugs preferentially target leishmanial components of the pyrimidine biosynthetic pathway. This is likely due to similarities in enzymatic activities shared between Leishmania and humans. For example, acivicin and PALA inhibit both human and leishmanial pyrimidine biosynthesis. Similarly, classical inhibitors such as methotrexate, which target leishmanial DHFR-TS, an essential component of thymidylate synthesis, are poor anti-leishmanial drugs because they also inhibit the human enzyme. ... 

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