TY - JOUR
T1 - 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
AU - Rosales-Acosta, Blanca
AU - Mendieta, Aarón
AU - Zúñiga, Clara
AU - Tamariz, Joaquín
AU - Hernández Rodríguez, César
AU - Ibarra-García, José Antonio
AU - Villa-Tanaca, Lourdes
N1 - Publisher Copyright:
© 2019 Asociación Española de Micología
PY - 2019/1/1
Y1 - 2019/1/1
N2 - 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.
AB - 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.
KW - Basidiomycete
KW - EC 1.1.1.34
KW - Ergosterol
KW - Fibrates
KW - Hmgr
KW - Inhibitor
KW - Statins
KW - Sterols
KW - Ustilago maydis
UR - http://www.scopus.com/inward/record.url?scp=85061162928&partnerID=8YFLogxK
U2 - 10.1016/j.riam.2018.05.004
DO - 10.1016/j.riam.2018.05.004
M3 - Artículo
C2 - 30745018
AN - SCOPUS:85061162928
SN - 1130-1406
VL - 36
SP - 1
EP - 8
JO - Revista Iberoamericana de Micologia
JF - Revista Iberoamericana de Micologia
IS - 1
ER -