title: The 3-hydroxy-3-methylglutaryl coenzyme-A reductases from fungi: a proposal as a therapeutic target and as a study model.
abstract: The enzyme 3-hydroxy-3-methylglutaryl coenzyme-A reductase (HMGR) catalyzes the conversion of HMG-Co-A into mevalonate. This step is the limiting point for the synthesis of cholesterol in mammals and ergosterol in fungi. We describe in this article the genome organization of HMGR coding genes and those deduced from different fungi, recount the evidence showing statins as HMGR inhibitors for ergosterol synthesis and its effect in yeast viability, and propose fungal HMGR (HMGRf) as a model to study the use of pharmaceutical compounds to inhibit cholesterol and ergosterol synthesis. Bibliographical search and bioinformatic analyses were performed and discussed. HMGRfs belong to the class I with a high homology in the catalytic region. The sterol biosynthetic pathway in humans and fungi share many enzymes in the initial steps (such as the HMGR enzyme), but in the last steps enzymes are different rendering the two final products: cholesterol in mammals and ergosterol in fungi. With regards to inhibitors such as statins and other compounds, these affect also fungal viability. Since HMGR from Schizosaccharomyces pombe and Ustilago maydis are very similar to the human HMGR in the catalytic regions, we propose that fungal enzymes can be used to test inhibitors for a potential use in humans. We consider that HMGRf is a good therapeutic target to design and test new antifungal compounds. This manuscript is part of the series of works presented at the "V International Workshop: Molecular genetic approaches to the study of human pathogenic fungi" (Oaxaca, Mexico, 2012).
authors.affiliation: Departamento de Microbiología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, México, D.F., México.
authors.forename: Dulce
authors.initials: D
authors.lastname: Andrade-Pavón
authors.affiliation: Departamento de Microbiología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, México, D.F., México.
authors.forename: Eugenia
authors.initials: E
authors.lastname: Sánchez-Sandoval
authors.affiliation: Departamento de Microbiología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, México, D.F., México.
authors.forename: Blanca
authors.initials: B
authors.lastname: Rosales-Acosta
authors.affiliation: Departamento de Microbiología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, México, D.F., México.
authors.forename: José Antonio
authors.initials: JA
authors.lastname: Ibarra
authors.affiliation: Departamento de Microbiología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, México, D.F., México.
authors.forename: Joaquín
authors.initials: J
authors.lastname: Tamariz
authors.affiliation: Departamento de Microbiología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, México, D.F., México.
authors.forename: César
authors.initials: C
authors.lastname: Hernández-Rodríguez
authors.affiliation: Departamento de Microbiología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, México, D.F., México. Electronic address: lourdesvilla@hotmail.com.
authors.forename: Lourdes
authors.initials: L
authors.lastname: Villa-Tanaca
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002175:Candida / Q000201:enzymology; D002784:Cholesterol / Q000096:biosynthesis; D018360:Crystallography, X-Ray; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D004875:Ergosterol / Q000096:biosynthesis; D005656:Fungal Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D005658:Fungi / Q000187:drug effects / Q000201:enzymology*; D005800:Genes, Fungal; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000737:chemistry / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D058990:Molecular Targeted Therapy; D009181:Mycoses / Q000188:drug therapy / Q000382:microbiology; D009249:NADP / Q000378:metabolism; D012377:Rodentia / Q000378:metabolism; D012568:Schizosaccharomyces / Q000201:enzymology; D013045:Species Specificity; D014588:Ustilago / Q000201:enzymology
chemical_list: D000935:Antifungal Agents; D005656:Fungal Proteins; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D009249:NADP; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases; D004875:Ergosterol
keywords: (EC 1.1.1.34); 3-Hidroxi-3-metilglutaril coenzima A reductasa; 3-Hydroxy-3-methylglutaryl coenzyme A reductase; Ergosterol synthesis; Síntesis de colesterol