Carrera Ingeniería Bioquímica

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Subject: search.filters.subject.AHAS

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    Identificación de nuevos inhibidores de la enzima acetohidroxiácido sintasa (AHAS) de Candida albicans mediante cribado virtual de fragmentos
    (Universidad Técnica de Ambato. Facultad de Ciencia e Ingeniería en Alimentos y Biotecnología. Carrera de Ingeniería Bioquímica, 2021-09) Robalino Velasco, Amada Margarita; García Solís, Mario Daniel
    The enzyme acetohydroxyacid synthase (EC 2.2.1.6., AHAS), is considered a new therapeutic target for the control of invasive fungal infections (IFIs) due to its crucial activity in the biosynthesis of essential amino acids (BCAAs) in the fungal agents that cause these diseases. The herbicides of the sulfonylurea and triazolopyrimidine families are some of the most promising compounds for the development of an IFIs treatment by the inhibition of AHAS. These project focuses on the identification of possible new inhibitors of the AHAS enzyme in the yeast, Candida albicans, using virtual fragment screening. The parental structures used for virtual screening are the central fragments of the herbicides Chlorimuron ethyl (CE) and Metosulam (MT), which were selected by a structural analysis of its binding mode to AHAS. This analysis yielded the fragments FRAG1 and FRAG2, based on CE, and FRAGMT, based on MT. Fragment screening was performed on the ACFIS2.0 server, a tool that provided approximately 250. The analysis of calculated Gibbs free energy, the ligand -CaAHAS binding mode and ADME properties allowed the best molecules to be identified. Using this method, it was determined that ligands KIN102, KIN97 KIN20, (generated from FRAG1); PAD271, KIN192, PAD181 (generated from FRAG2), PAD281, PAD165 and PAD180 (generated from FRAGMT) present a higher affinity than CE and MT when binding C. albicans AHAS. Also, these ligands exhibited binding modes analogous to their parental herbicides; therefore, the ligands could act as possible inhibitors of AHAS and potentially become drugs for the treatment of IFIs.
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    Modelamiento computacional de la enzima acetohidroxiácido sintasa (AHAS) de Mycobacterium tuberculosis
    (Universidad Técnica de Ambato. Facultad de Ciencia e Ingeniería en Alimentos y Biotecnología. Carrera de Ingeniería Bioquímica, 2021-09) Jurado Barona, Evelyn Katherine; García Solís, Mario Daniel
    Tuberculosis is a disease caused by the pathogen Mycobacterium tuberculosis. It annually produces millions of deaths worldwide. The severity of this condition is caused by the progressive appearance of multidrug resistant strains (MDR-TB) and extensively drug resistant tuberculosis (XDR-TB). For this reason, it is common to use long treatments that produce unwanted effects in patients. Given the lack of effective and well tolerated drugs to treat tuberculosis, it is necessary to investigate new targets which will slow down the spread of the pathogen. The enzyme acetohydroxyacid synthase (AHAS) is amongst the most promising targets. AHAS is the first enzyme in the branched chain amino acid biosynthetic pathway (BCAAs). It has been already shown that AHAS is crucial for the survival of Arabidopsis thaliana, Candida albicans, Saccharomyces cerevisiae, and other organisms. Here, a model of Mycobacterium tuberculosis AHAS complex was obtained using the Swiss-Model. The model was derived from its closest structure, S. cerevisiae AHAS. The MtAHAS complex exhibited the same structural features described previously for AtAHAS and ScAHAS, including its resemblance to the Maltese cross. The interactions with cofactors and the most important motifs involved in the inhibition with methyl metsulfuron were elucidated using the software WinCoot and LigPlot. The hexadecameric complex of MtAHAS generated provides a platform for the rational design of enzyme inhibitors for the effective treatment of different strains of Mycobacterium tuberculosis.
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    Mecanismo, estructura e inhibición de la enzima Acetohidroxiácido Sintasa
    (Universidad Técnica de Ambato. Facultad de Ciencia e Ingeniería en Alimentos y Biotecnología. Carrera de Ingeniería Bioquímica, 2021-03) Albán Ruiz, Arianna Gabriela; García Solís, Mario Daniel
    The Acetohydroxy acid ctase (AHAS, E.C. 2.2.1.6) or acetolactate withouttase (ALS), is an enzyme dependent on thiamine diphosphate (ThDP) which is present in plants and microorganism. It participates in branched-chain amino acid biosynthesis BCAAs. In the presence of ThDP, FAD and a divalent metallic, it comprises the condensation of two pyruvate molecules into 2-acetolatate or a pyruvate molecule or one of 2-cetobutirate into 2-acete-2-hydroxybutyrate to form the valine, leucine and isoleucine. Structurally, four catalytic subunits (CSUs) interact with four (plant) or eight (yeast) regulatory subunits RSUs forming the enzyme complex AHAS. CSU owns the active site, while RSU increases the CSU activity and provides enzymatic sensitivity to feedback inhibition. Its inhibition has a biocidal effect, which occurs through different reactions and molecular interactions, where the best known is produced by molecules with herbicidal activity, making the enzyme an important target for the development of more than 58 herbicides. In recent years, research has focused on using AHAS inhibitor herbicides as antimicrobials, taking advantage of the absence of the enzyme in humans. Also, mutations and new inhibitors are being studied with promising results. Therefore, this study proposes to consolidate the available literature about the structure, function, and inhibition of AHAS to contribute to future projects by defining research needs in this area and the prospects for the use of the enzyme or its inhibitors in medical, biotechnological, bioinformatics, other applications.