Structural and mechanistic comparison of the Cyclopropane Mycolic Acid Synthases (CMAS) protein family of Mycobacterium tuberculosis
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...
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2018
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paper:paper_0006291X_v498_n2_p288_Defelipe2023-06-08T14:30:22Z Structural and mechanistic comparison of the Cyclopropane Mycolic Acid Synthases (CMAS) protein family of Mycobacterium tuberculosis 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 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. 2018 https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_0006291X_v498_n2_p288_Defelipe http://hdl.handle.net/20.500.12110/paper_0006291X_v498_n2_p288_Defelipe |
| institution |
Universidad de Buenos Aires |
| institution_str |
I-28 |
| repository_str |
R-134 |
| collection |
Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
| topic |
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 |
| spellingShingle |
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 Structural and mechanistic comparison of the Cyclopropane Mycolic Acid Synthases (CMAS) protein family of Mycobacterium tuberculosis |
| topic_facet |
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 |
| description |
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. |
| title |
Structural and mechanistic comparison of the Cyclopropane Mycolic Acid Synthases (CMAS) protein family of Mycobacterium tuberculosis |
| title_short |
Structural and mechanistic comparison of the Cyclopropane Mycolic Acid Synthases (CMAS) protein family of Mycobacterium tuberculosis |
| title_full |
Structural and mechanistic comparison of the Cyclopropane Mycolic Acid Synthases (CMAS) protein family of Mycobacterium tuberculosis |
| title_fullStr |
Structural and mechanistic comparison of the Cyclopropane Mycolic Acid Synthases (CMAS) protein family of Mycobacterium tuberculosis |
| title_full_unstemmed |
Structural and mechanistic comparison of the Cyclopropane Mycolic Acid Synthases (CMAS) protein family of Mycobacterium tuberculosis |
| title_sort |
structural and mechanistic comparison of the cyclopropane mycolic acid synthases (cmas) protein family of mycobacterium tuberculosis |
| publishDate |
2018 |
| url |
https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_0006291X_v498_n2_p288_Defelipe http://hdl.handle.net/20.500.12110/paper_0006291X_v498_n2_p288_Defelipe |
| _version_ |
1768542965857255424 |