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Tuberculosis (TB) is a chronic disease caused by the bacillus Mycobacterium tuberculosis(Mtb) and remains a leading cause of mortality worldwide. The bacteria has an external wall which protects it from being killed, and the enzymes involved in the biosynthesis of the cell wall components have been proposed as promising targets for future drug development efforts. Cyclopropane Mycolic Acid Synthases (CMAS) constitute a group of ten homologous enzymes which belong to the mycolic acid biosynthesis pathway. These enzymes have S-adenosyl-L-methionine (SAM) dependent methyltransferase activity with a peculiarity, each one of them has strong substrate selectivity and reaction specificity, being able to produce among other things cyclopropanes or methyl-alcohol groups from the lipid olefin group. How each CMAS processes its substrate and how the specificity and selectivity are encoded in the protein sequence and structure, is still unclear. In this work, by using a combination of modeling tools, including comparative modeling, docking, all-atom MD and QM/MM methodologies we studied in detail the reaction mechanism of cmaA2, mmaA4, and mmaA1 CMAS and described the molecular determinants that lead to different products. We have modeled the protein-substrate complex structure and determined the free energy pathway for the reaction. The combination of modeling tools at different levels of complexity allows having a complete picture of the CMAS structure-activity relationship. © 2017 Elsevier Inc.


Documento: Artículo
Título:Structural and mechanistic comparison of the Cyclopropane Mycolic Acid Synthases (CMAS) protein family of Mycobacterium tuberculosis
Autor:Defelipe, L.A.; Osman, F.; Marti, M.A.; Turjanski, A.G.
Filiación:Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Intendente Güiraldes, Ciudad Autónoma de Buenos Aires, 2620, Argentina
IQUIBICEN-UBA/CONICET, Intendente Güiraldes, Ciudad Autónoma de Buenos Aires, 2620, Argentina
Palabras clave:Bioinformatics; CMAS; Methyltransferase; Mycolic acids; QM/MM; Tuberculosis; bacterial enzyme; cyclopropane mycolic acid synthase; protein cmaA2; protein mmaA1; protein mmaA4; unclassified drug; bacterial protein; bicarbonate; cyclopropane; cyclopropane derivative; methyltransferase; mixed function oxidase; mma4 protein, Mycobacterium tuberculossis; amino acid sequence; Article; comparative study; energy; enzyme activity; enzyme mechanism; enzyme structure; enzyme substrate complex; molecular docking; molecular model; Mycobacterium tuberculosis; nonhuman; priority journal; structure activity relation; chemistry; enzyme active site; enzymology; metabolism; molecular dynamics; Mycobacterium tuberculosis; structure activity relation; Bacterial Proteins; Bicarbonates; Catalytic Domain; Cyclopropanes; Methyltransferases; Mixed Function Oxygenases; Models, Molecular; Molecular Docking Simulation; Molecular Dynamics Simulation; Mycobacterium tuberculosis; Structure-Activity Relationship
Página de inicio:288
Página de fin:295
Título revista:Biochemical and Biophysical Research Communications
Título revista abreviado:Biochem. Biophys. Res. Commun.
CAS:bicarbonate, 144-55-8, 71-52-3; cyclopropane, 75-19-4; methyltransferase, 9033-25-4; mixed function oxidase, 9040-60-2; Bacterial Proteins; Bicarbonates; cyclopropane; Cyclopropanes; Methyltransferases; Mixed Function Oxygenases; mma4 protein, Mycobacterium tuberculossis


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---------- APA ----------
Defelipe, L.A., Osman, F., Marti, M.A. & Turjanski, A.G. (2018) . Structural and mechanistic comparison of the Cyclopropane Mycolic Acid Synthases (CMAS) protein family of Mycobacterium tuberculosis. Biochemical and Biophysical Research Communications, 498(2), 288-295.
---------- CHICAGO ----------
Defelipe, L.A., Osman, F., Marti, M.A., Turjanski, A.G. "Structural and mechanistic comparison of the Cyclopropane Mycolic Acid Synthases (CMAS) protein family of Mycobacterium tuberculosis" . Biochemical and Biophysical Research Communications 498, no. 2 (2018) : 288-295.
---------- MLA ----------
Defelipe, L.A., Osman, F., Marti, M.A., Turjanski, A.G. "Structural and mechanistic comparison of the Cyclopropane Mycolic Acid Synthases (CMAS) protein family of Mycobacterium tuberculosis" . Biochemical and Biophysical Research Communications, vol. 498, no. 2, 2018, pp. 288-295.
---------- VANCOUVER ----------
Defelipe, L.A., Osman, F., Marti, M.A., Turjanski, A.G. Structural and mechanistic comparison of the Cyclopropane Mycolic Acid Synthases (CMAS) protein family of Mycobacterium tuberculosis. Biochem. Biophys. Res. Commun. 2018;498(2):288-295.