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.

中文翻译：

---

辛伐他汀和其他酶（3-羟基-3-甲基戊二酰辅酶A的抑制因子）可能是真菌的生存力，甾醇的合成和交配的原因。

背景

3-羟-3-甲基戊二酰辅酶A还原酶（Hmgr）催化甲羟戊酸酯的合成，甲羟戊酸酯是人类合成胆固醇和真菌中麦角甾醇的关键化合物。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，因此提出了真菌Hmgr酶作为研究抗真菌剂的模型。

目的

为了研究抑制Um-Hmgr酶与Ustilago maydis中的活力，固醇合成和交配之间的关系。

方法

使用计算机分析，鉴定了编码Um-Hmgr的ORF，并推导了蛋白质特征。评估了Um-Hmgr竞争性抑制剂对该担子菌活力，其甾醇的合成及其交配的影响。

结果

鉴定出的Umhmgr基因（XP_011389590.1）推定编码1443 aa（约MW = 145.5 kDa）的蛋白质，该蛋白质在内质网（ER）中具有可能的结合域，并且与人和其他酵母的Hmgr催化域具有高度同一性。抑制Um-Hmgr会导致活力和甾醇合成降低，并抑制交配。Um-Hmgr的活性主要位于真菌的膜部分。

结论

根据我们的研究结果，我们认为马氏假单胞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，我们提出了Hmgr酶作为替代分子靶标，以开发用于治疗植物病原性和致病性人类真菌的化合物。