Simvastatin and other inhibitors of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase of Ustilago maydis (Um-Hmgr) affect the viability of the fungus, its synthesis of sterols and mating / La simvastatina y otros inhibidores de la enzima 3-hidroxi-3-metilglutaril-coenzima A-reductasa de Ustilago maydis (Um-Hmgr) afectan a la viabilidad del hongo, la síntesis de esteroles y el mating

Background: The enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase (Hmgr) catalyzes the synthesis of mevalonate, a key compound for the synthesis of cholesterol in humans and ergosterol in fungi. Since the Hmgr enzymes of Saccharomyces cerevisiae, Schizosaccharomyces pombe and Candida glabrata are similar to the Hmgr enzymes of mammals, fungal Hmgr enzymes have been proposed as a model for studying antifungal agents. Aims: To examine the correlation between inhibiting Um-Hmgr enzyme and the viability, sterols synthesis and mating in Ustilago maydis. Methods: Using in silico analysis, the ORF codifying for Um-Hmgr was identified and the protein characteristics were deduced. The effect of the competitive inhibitors of Um-Hmgr on the viability of this basidiomycota, the synthesis of its sterols, and its mating were evaluated. Results: The Umhmgr gene (XP_011389590.1) identified putatively codifies a protein of 1443 aa (ca. MW = 145.5 kDa) that has a possible binding domain in the endoplasmic reticulum (ER) and high identity with the Hmgr catalytic domain of humans and other yeasts. The inhibition of Um-Hmgr caused a decrease of viability and synthesis of sterols, and also the inhibition of mating. The activity of Um-Hmgr is mainly located in the membrane fraction of the fungus. Conclusions: Given our results we believe U. maydis is a valid model for studying synthetic inhibitors with lipid-lowering or antifungal activity. Additionally, we propose the Hmgr enzyme as an alternative molecular target to develop compounds for treating both phytopathogenic and pathogenic human fungi

Antecedentes: La enzima 3-hidroxi-3-metilglutaril-coenzima A-reductasa (Hmgr) cataliza la síntesis de mevalonato, compuesto clave precursor en la biosíntesis del colesterol en el ser humano y en la del ergosterol en los hongos. Las enzimas Hmgr de Saccharomyces cerevisiae, Schizosaccharomyces pombe y Candida glabrata presentan similitud con la Hmgr de los mamíferos, motivo por el cual se han propuesto como modelo para el estudio de antifúngicos. Objetivos: Estudiar la correlación que existe entre la inhibición de la enzima Um-Hmgr y la viabilidad, la síntesis de esteroles y el mating en Ustilago maydis. Métodos: Por medio de un análisis in silico se identificó el ORF de la Um-Hmgr, y se dedujeron las características de la proteína. Se evaluó el efecto de los inhibidores competitivos de la enzima Um-Hmgr en la viabilidad, la síntesis de esteroles y el mating. Resultados: El gen Umhmgr (XP_011389590.1) codifica una proteína putativa de 1.443 aa (MW = 145,5 kDa), con un posible dominio de unión al retículo endoplásmico (RE) y una identidad alta con el dominio catalítico de la Hmgr humana y de otras levaduras. La inhibición de la Um-Hmgr ocasionó una disminución en la viabilidad y síntesis de esteroles del hongo, así como la inhibición del mating. La actividad de la Um-Hmgr está localizada principalmente en la fracción membranal del hongo. Conclusiones: La enzima Um-Hmgr está anclada probablemente al RE y presenta una elevada homología con el dominio catalítico de otras Hmgr de eucariotas. La Um-Hmgr participa en la síntesis de esteroles de este basidiomiceto, y su inhibición provoca la pérdida de la viabilidad, la reducción de los niveles de esteroles y del mating del hongo

Simvastatin and other inhibitors of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase of Ustilago maydis (Um-Hmgr) affect the viability of the fungus, its synthesis of sterols and mating.

BACKGROUND: The enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase (Hmgr) catalyzes the synthesis of mevalonate, a key compound for the synthesis of cholesterol in humans and ergosterol in fungi. Since the Hmgr enzymes of Saccharomyces cerevisiae, Schizosaccharomyces pombe and Candida glabrata are similar to the Hmgr enzymes of mammals, fungal Hmgr enzymes have been proposed as a model for studying antifungal agents. AIMS: To examine the correlation between inhibiting Um-Hmgr enzyme and the viability, sterols synthesis and mating in Ustilago maydis. METHODS: Using in silico analysis, the ORF codifying for Um-Hmgr was identified and the protein characteristics were deduced. The effect of the competitive inhibitors of Um-Hmgr on the viability of this basidiomycota, the synthesis of its sterols, and its mating were evaluated. RESULTS: The Umhmgr gene (XP_011389590.1) identified putatively codifies a protein of 1443 aa (ca. MW=145.5kDa) that has a possible binding domain in the endoplasmic reticulum (ER) and high identity with the Hmgr catalytic domain of humans and other yeasts. The inhibition of Um-Hmgr caused a decrease of viability and synthesis of sterols, and also the inhibition of mating. The activity of Um-Hmgr is mainly located in the membrane fraction of the fungus. CONCLUSIONS: Given our results we believe U. maydis is a valid model for studying synthetic inhibitors with lipid-lowering or antifungal activity. Additionally, we propose the Hmgr enzyme as an alternative molecular target to develop compounds for treating both phytopathogenic and pathogenic human fungi.