Rosales-Acosta Blanca, Mendieta Aarón, Zúñiga Clara, Tamariz Joaquín, Hernández Rodríguez César, Ibarra-García José Antonio, Villa-Tanaca Lourdes
Departamento de Microbiología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Prol. Carpio y Plan de Ayala S/N, 11340 Ciudad de México, Mexico.
Departamento de Química Orgánica, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Prol. Carpio y Plan de Ayala S/N, 11340 Ciudad de México, Mexico.
Rev Iberoam Micol. 2019 Jan-Mar;36(1):1-8. doi: 10.1016/j.riam.2018.05.004. Epub 2019 Feb 8.
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.
To examine the correlation between inhibiting Um-Hmgr enzyme and the viability, sterols synthesis and mating in Ustilago maydis.
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.
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.
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.
3-羟基-3-甲基戊二酰辅酶A还原酶（Hmgr）催化甲羟戊酸的合成，甲羟戊酸是人类合成胆固醇以及真菌合成麦角固醇的关键化合物。由于酿酒酵母、粟酒裂殖酵母和光滑念珠菌的Hmgr酶与哺乳动物的Hmgr酶相似，真菌Hmgr酶已被提议作为研究抗真菌剂的模型。
研究抑制玉米黑粉菌的Um-Hmgr酶与该菌的活力、固醇合成及交配之间的相关性。
通过电子分析鉴定编码Um-Hmgr的开放阅读框（ORF），并推导其蛋白质特性。评估Um-Hmgr竞争性抑制剂对这种担子菌活力、固醇合成及其交配的影响。
鉴定出的Umhmgr基因（XP_011389590.1）推测编码一个1443个氨基酸的蛋白质（约MW=145.5kDa），该蛋白质在内质网（ER）中可能具有结合结构域，并且与人类和其他酵母的Hmgr催化结构域具有高度同源性。抑制Um-Hmgr会导致活力和固醇合成下降，同时也会抑制交配。Um-Hmgr的活性主要位于真菌的膜部分。
基于我们的研究结果，我们认为玉米黑粉菌是研究具有降脂或抗真菌活性的合成抑制剂的有效模型。此外，我们提议将Hmgr酶作为开发用于治疗植物致病真菌和人类致病真菌的化合物的替代分子靶点。
