The 3-hydroxy-3-methylglutaryl coenzyme-A reductases from fungi: A proposal as a therapeutic target and as a study model

Andrade-Pavón, Dulce; Sánchez-Sandoval, Eugenia; Rosales-Acosta, Blanca; Ibarra, J. Antonio; Tamariz, Joaquı́n; Hernández‐Rodríguez, César; Villa‐Tanaca, Lourdes

doi:10.1016/j.riam.2013.10.004

Cited by 19 publications

(15 citation statements)

References 24 publications

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“…Inhibition of the enzyme or disruption of the encoding gene decreased the virulence of various plant and human pathogenic fungi, such as Aspergillus fumigatus, Candida albicans or Fusarium graminearum (Seong et al, 2006;Tashiro et al, 2012;Leal et al, 2013), indicating that HMG-CoA reductase may also affect the pathogenicity. Moreover, ergosterol and its biosynthesis are currently among the most important targets of antifungal therapy, therefore, ergosterol biosynthesis and its regulation are intensively studied areas (Macreadie et al, 2006;Burg and Espenshade, 2011;Andrade-Pavón et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

CRISPR-Cas9-mediated disruption of the HMG-CoA reductase genes of Mucor circinelloides and subcellular localization of the encoded enzymes

Nagy

Vaz

Szebenyi

et al. 2019

Fungal Genetics and Biology

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Terpenoid compounds, such as sterols, carotenoids or the prenyl groups of various proteins are synthesized via the mevalonate pathway. A rate-limiting step of this pathway is the conversion of 3-methylglutaryl-CoA (HMG-CoA) to mevalonic acid catalyzed by the HMG-CoA reductase. Activity of this enzyme may affect several biological processes, from the synthesis of terpenoid metabolites to the adaptation to various environmental conditions. In this study, the three HMG-CoA reductase genes (i.e. hmgR1, hmgR2 and hmgR3) of the βcarotene producing filamentous fungus, Mucor circinelloides were disrupted individually and simultaneously by a recently developed in vitro plasmid-free CRISPR-Cas9 method. Examination of the mutants revealed that the function of hmgR2 and hmgR3 are partially overlapping and involved in the general terpenoid biosynthesis. Moreover, hmgR2 seemed to have a special role in the ergosterol biosynthesis. Disruption of all three genes affected the germination ability of the spores and the sensitivity to hydrogen peroxide. Disruption of the hmgR1 gene had no effect on the ergosterol production and the sensitivity to statins but caused a reduced growth at lower temperatures. By confocal fluorescence microscopy using strains expressing GFP-tagged HmgR proteins, all three HMG-CoA reductases were localized in the endoplasmic reticulum.

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Section: Introductionmentioning

confidence: 99%

CRISPR-Cas9-mediated disruption of the HMG-CoA reductase genes of Mucor circinelloides and subcellular localization of the encoded enzymes

Nagy

Vaz

Szebenyi

et al. 2019

Fungal Genetics and Biology

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“…HMGRs are bound to the endoplasmic reticulum membranes through their N-terminal domains that contain eight transmembrane (TM) helices. On the other end, the C-terminal domain of the protein projects into the cytosol and contains the entire reductase catalytic activity [ 38 , 39 , 40 ]. Both proteins share a sterol-sensing domain (SSD), normally displayed in membrane proteins, responsible for sterol regulation.…”

Section: Resultsmentioning

confidence: 99%

Are Point Mutations in HMG-CoA Reductases (Hmg1 and Hmg2) a Step towards Azole Resistance in Aspergillus fumigatus?

et al. 2021

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Invasive aspergillosis, mainly caused by Aspergillus fumigatus, can lead to severe clinical outcomes in immunocompromised individuals. Antifungal treatment, based on the use of azoles, is crucial to increase survival rates. However, the recent emergence of azole-resistant A. fumigatus isolates is affecting the efficacy of the clinical therapy and lowering the success rate of azole strategies against aspergillosis. Azole resistance mechanisms described to date are mainly associated with mutations in the azole target gene cyp51A that entail structural changes in Cyp51A or overexpression of the gene. However, strains lacking cyp51A modifications but resistant to clinical azoles have recently been detected. Some genes have been proposed as new players in azole resistance. In this study, the gene hmg1, recently related to azole resistance, and its paralogue hmg2 were studied in a collection of fifteen azole-resistant strains without cyp51A modifications. Both genes encode HMG-CoA reductases and are involved in the ergosterol biosynthesis. Several mutations located in the sterol sensing domain (SSD) of Hmg1 (D242Y, G307D/S, P309L, K319Q, Y368H, F390L and I412T) and Hmg2 (I235S, V303A, I312S, I360F and V397C) were detected. The role of these mutations in conferring azole resistance is discussed in this work.

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“…Mammals and fungi share many enzymes from the initial steps of sterol biosynthesis pathway such as 3‐hydroxy‐3‐methylglutaryl coenzyme A (HMG‐CoA) reductase (EC 2.3.3.34), but enzymes involved in the final steps are different rendering different final products such as cholesterol and ergosterol, in mammals and in fungi respectively (Andrade‐Pavón et al . ). The complete pathway was studied and reported in the pathogenic filamentous fungus, Aspergillus fumigatus (Fig.…”

Section: Biosynthesis Of Cell Membrane Componentsmentioning

confidence: 97%

“…In the case of ergosterol as well as cholesterol synthesis, the enzyme 3‐hydroxy‐3‐methylglutaryl coenzyme‐A reductase (HMGR) (EC 1.1.1.34) plays a crucial role in the conversion of HMG‐Co‐A into mevalonate (Andrade‐Pavón et al . ). Statins like lovastatin and simvastatin are known inhibitors of HMGR.…”

Section: Enzyme Inhibitors As Potential Antifungal Agentsmentioning

confidence: 97%

Fungal cell membrane-promising drug target for antifungal therapy

et al. 2016

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SummaryIncrease in invasive fungal infections over the past few years especially in immunocompromised patients prompted the search for new antifungal agents with improved efficacy. Current antifungal armoury includes very few effective drugs like Amphotericin B; new generation azoles, including voriconazole and posaconazole; echinocandins like caspofungin and micafungin to name a few. Azole class of antifungals which target the fungal cell membrane are the first choice of treatment for many years because of their effectiveness. As the fungal cell membrane is predominantly made up of sterols, glycerophospholipids and sphingolipids, the role of lipids in pathogenesis and target identification for improved therapeutics were largely pursued by researchers during the last few years. Present review focuses on cell membrane as an antifungal target with emphasis on membrane biogenesis, structure and function of cell membrane, cell membrane inhibitors, screening assays, recent advances and future prospects.

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The 3-hydroxy-3-methylglutaryl coenzyme-A reductases from fungi: A proposal as a therapeutic target and as a study model

Cited by 19 publications

References 24 publications

CRISPR-Cas9-mediated disruption of the HMG-CoA reductase genes of Mucor circinelloides and subcellular localization of the encoded enzymes

CRISPR-Cas9-mediated disruption of the HMG-CoA reductase genes of Mucor circinelloides and subcellular localization of the encoded enzymes

Are Point Mutations in HMG-CoA Reductases (Hmg1 and Hmg2) a Step towards Azole Resistance in Aspergillus fumigatus?

Fungal cell membrane-promising drug target for antifungal therapy

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