RESUMEN
Roughly a third of the world's population is estimated to have latent Mycobacterium tuberculosis infection, being at risk of developing active tuberculosis (TB) during their lifetime. Given the inefficacy of prophylactic measures and the increase of drug-resistant M. tuberculosis strains, there is a clear and urgent need for the development of new and more efficient chemotherapeutic agents, with selective toxicity, to be implemented on patient treatment. The component enzymes of the shikimate pathway, which is essential in mycobacteria and absent in humans, stand as attractive and potential targets for the development of new drugs to treat TB. This review gives an update on published work on the enzymes of the shikimate pathway and some insight on what can be potentially explored towards selective drug development.
Asunto(s)
Antituberculosos/síntesis química , Proteínas Bacterianas/antagonistas & inhibidores , Inhibidores Enzimáticos/síntesis química , Regulación Bacteriana de la Expresión Génica , Mycobacterium tuberculosis/efectos de los fármacos , Ácido Shikímico/antagonistas & inhibidores , Antituberculosos/farmacología , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Diseño de Fármacos , Inhibidores Enzimáticos/farmacología , Humanos , Tuberculosis Latente/tratamiento farmacológico , Tuberculosis Latente/microbiología , Redes y Vías Metabólicas/efectos de los fármacos , Redes y Vías Metabólicas/genética , Mycobacterium tuberculosis/enzimología , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/crecimiento & desarrollo , Ácido Shikímico/química , Ácido Shikímico/metabolismo , Relación Estructura-Actividad , Tuberculosis Pulmonar/tratamiento farmacológico , Tuberculosis Pulmonar/microbiologíaRESUMEN
The herbicide glyphosate inhibits the shikimate pathway of the synthesis of amino acids such as phenylalanine, tyrosine, and tryptophan. However, much uncertainty remains concerning precisely how glyphosate kills plants or affects cellular redox homeostasis and related processes in glyphosate-sensitive and glyphosate-resistant crop plants. To address this issue, we performed an integrated study of photosynthesis, leaf proteomes, amino acid profiles, and redox profiles in the glyphosate-sensitive soybean (Glycine max) genotype PAN809 and glyphosate-resistant Roundup Ready Soybean (RRS). RRS leaves accumulated much more glyphosate than the sensitive line but showed relatively few changes in amino acid metabolism. Photosynthesis was unaffected by glyphosate in RRS leaves, but decreased abundance of photosynthesis/photorespiratory pathway proteins was observed together with oxidation of major redox pools. While treatment of a sensitive genotype with glyphosate rapidly inhibited photosynthesis and triggered the appearance of a nitrogen-rich amino acid profile, there was no evidence of oxidation of the redox pools. There was, however, an increase in starvation-associated and defense proteins. We conclude that glyphosate-dependent inhibition of soybean leaf metabolism leads to the induction of defense proteins without sustained oxidation. Conversely, the accumulation of high levels of glyphosate in RRS enhances cellular oxidation, possibly through mechanisms involving stimulation of the photorespiratory pathway.
Asunto(s)
Aminoácidos/metabolismo , Glicina/análogos & derivados , Herbicidas/farmacología , Homeostasis , Fotosíntesis , Proteínas de Plantas/metabolismo , Ácido Shikímico/antagonistas & inhibidores , Glicina/farmacología , Oxidación-Reducción , Proteómica , Ácido Shikímico/metabolismo , GlifosatoRESUMEN
Aspergiolide A is a novel anti-tumor anthraquinone derivant produced by marine-derived fungus Aspergillus glaucus. To identify its biosynthetic pathway and further improve the production, the effects of biosynthetic pathway specific inhibitors and precursors were investigated. Cerulenin and iodoacetamide, the specific inhibitors of polyketide pathway, could completely inhibit the aspergiolide A accumulation. Putative precursors of polyketide pathway could increase aspergiolide A production greatly, such as 6 mM acetate increased production by 135%. Simvastatin and citrate, the inhibitors of mevalonate pathway, stimulated the production by 63% and 179%, respectively. Considering that acetyl-CoA is the common starter unit in both polyketide and mevalonate pathway, a novel strategy was designed to stimulate the aspergiolide A accumulation. Combinations of 12 mM acetate with 0.3 mM simvastatin could increase the production by 151%, while the supplementation with 12 mM acetate and 12 mM citrate brought a 262% increase of aspergiolide A production. The strategy might be very useful to enhance the production of other secondary metabolites derived from polyketide pathway.
Asunto(s)
Antraquinonas/síntesis química , Aspergillus/metabolismo , Biología Marina , Acetatos/farmacología , Antraquinonas/antagonistas & inhibidores , Ácido Mevalónico/antagonistas & inhibidores , Ácido Shikímico/antagonistas & inhibidores , Simvastatina/farmacologíaRESUMEN
The aetiological agent of tuberculosis (TB), Mycobacterium tuberculosis, is responsible for millions of deaths annually. The increasing prevalence of the disease, the emergence of multidrug-resistant strains, and the devastating effect of human immunodeficiency virus co-infection have led to an urgent need for the development of new and more efficient antimycobacterial drugs. Since the shikimate pathway is present and essential in algae, higher plants, bacteria, and fungi, but absent from mammals, the gene products of the common pathway might represent attractive targets for the development of new antimycobacterial agents. In this review we describe studies on shikimate pathway enzymes, including enzyme kinetics and structural data. We have focused on mycobacterial shikimate pathway enzymes as potential targets for the development of new anti-TB agents.
Asunto(s)
Sistemas de Liberación de Medicamentos/métodos , Diseño de Fármacos , Mycobacterium tuberculosis/enzimología , Ácido Shikímico/metabolismo , Transducción de Señal/efectos de los fármacos , Animales , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/síntesis química , Humanos , Mycobacterium tuberculosis/efectos de los fármacos , Ácido Shikímico/antagonistas & inhibidores , Ácido Shikímico/síntesis química , Transducción de Señal/fisiologíaRESUMEN
The shikimate pathway is essential for production of a plethora of aromatic compounds in plants, bacteria, and fungi. Seven enzymes of the shikimate pathway catalyze sequential conversion of erythrose 4-phosphate and phosphoenol pyruvate to chorismate. Chorismate is then used as a substrate for other pathways that culminate in production of folates, ubiquinone, napthoquinones, and the aromatic amino acids tryptophan, phenylalanine, and tyrosine. The shikimate pathway is absent from animals and present in the apicomplexan parasites Toxoplasma gondii, Plasmodium falciparum, and Cryptosporidium parvum. Inhibition of the pathway by glyphosate is effective in controlling growth of these parasites. These findings emphasize the potential benefits of developing additional effective inhibitors of the shikimate pathway. Such inhibitors may function as broad-spectrum antimicrobial agents that are effective against bacterial and fungal pathogens and apicomplexan parasites.
Asunto(s)
Apicomplexa/metabolismo , Glicina/análogos & derivados , Ácido Shikímico/metabolismo , Secuencia de Aminoácidos , Animales , Apicomplexa/crecimiento & desarrollo , Regulación de la Expresión Génica , Glicina/farmacología , Datos de Secuencia Molecular , Liasas de Fósforo-Oxígeno/química , Liasas de Fósforo-Oxígeno/genética , Liasas de Fósforo-Oxígeno/metabolismo , Ácido Shikímico/antagonistas & inhibidores , GlifosatoRESUMEN
(6S)-6-Fluoroshikimic acid inhibited the growth of Escherichia coli B on minimal medium (MIC, 0.25 micrograms ml-1), and it protected mice challenged intraperitoneally with the same organism (50% protective dose, 0.06 mg kg of body weight-1). We propose that inhibitors of bacterial aromatic biosynthesis have the potential for use in human medicine.