Proteins from Mycobacterium tuberculosis: Difference between revisions

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Alexander Berchansky

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 Tuberculosis continues to be a global health threat. Pyrazinamide (PZA) is an important first-line drug in multidrug-resistant tuberculosis treatment. The emergence of strains resistant to pyrazinamide represents an important public health problem, as both first- and second-line treatment regimens include pyrazinamide. It becomes toxic to ''Mycobacterium tuberculosis'' when converted to pyrazinoic acid by the <scene name='Journal:JBSD:11/Cv/5'>bacterial pyrazinamidase (PncA) enzyme</scene>. PZA resistance is caused mainly by the loss of enzyme activity by mutation, the mechanism of resistance is not completely understood. In our studies, we analysed three mutations (D8G, S104R and C138Y) of PncA which are resistance for <scene name='Journal:JBSD:11/Cv/6'>PZA</scene>. Binding pocket analysis solvent accessibility analysis, molecular docking and interaction analysis were performed to understand the interaction behaviour of mutant enzymes with PZA. Molecular dynamics simulations were conducted to understand the three dimensional conformational behaviour of <scene name='Journal:JBSD:11/Cv/3'>native</scene> and mutants PncA. Our analysis clearly indicates that the mutation (<scene name='Journal:JBSD:11/Cv/8'>D8G</scene>, <scene name='Journal:JBSD:11/Cv/9'>S104R</scene> and <scene name='Journal:JBSD:11/Cv/10'>C138Y</scene>) in PncA is responsible for rigid binding cavity which in turns abolishes conversion of PZA to its active form and is the sole reason for PZA resistance. Excessive hydrogen bonding between PZA binding cavity residues and their neighboring residues are the reason of rigid binding cavity during simulation. We present an exhaustive analysis of the binding-site flexibility and its 3D conformations that may serve as new starting points for structure-based drug design and helps there researchers to design new inhibitor with consideration of rigid criterion of binding residues due to mutation of this essential target.
-=== Enoyl-Acyl-Carrier Protein Reductase ===
+=== Enoyl-Acyl-Carrier Protein Reductase <ref>PMID:19130456</ref>===
-Enoyl-Acyl-Carrier Protein Reductase is a target of anti-bacterial drugs such as triclosan (TCL). These drugs are used against tuberculosis infection. <scene name='43/434541/Cv/10'>Enoyl-Acyl-Carrier Protein Reductase is a tetramer</scene>. InhA ENR <scene name='43/434541/Cv/11'>active site contains NAD and TCL</scene>.<ref>PMID:19130456</ref>
+[[Enoyl-Acyl-Carrier Protein Reductase]] is a target of anti-bacterial drugs such as triclosan (TCL). These drugs are used against tuberculosis infection. <scene name='43/434541/Cv/10'>Enoyl-Acyl-Carrier Protein Reductase is a tetramer</scene> (PDB code [[3fne]]). InhA ENR <scene name='43/434541/Cv/11'>active site contains NAD and triclosan derivative</scene>.
+===  Crystal structure of the essential biotin-dependent carboxylase AccA3 from Mycobacterium tuberculosis<ref>pmid 28469974</ref> ===
+Biotin-dependent acetyl-CoA carboxylases catalyze the committed step in type II fatty acid biosynthesis, the main route for production of membrane phospholipids in bacteria, and are considered a key target for antibacterial drug discovery. Here we describe the first structure of AccA3, an essential component of the acetyl-CoA carboxylase system in ''Mycobacterium tuberculosis'' (MTb). The structure, sequence comparisons, and modeling of ligand-bound states reveal that the ATP cosubstrate-binding site shows distinct differences compared to other bacterial and eukaryotic biotin carboxylases, including all human homologs. This suggests the possibility to design MTb AccA3 subtype-specific inhibitors.
+''Mycobacterium tuberculosis'' <scene name='76/763765/Cv/2'>AccA3 adopts the ATPgrasp superfamily fold</scene>, and crystallized as a <scene name='76/763765/Cv/3'>dimer in the asymmetric unit</scene>. <scene name='76/763765/Cv/4'>The ordered structure of domain B is missing in chain B</scene>.
+Previous structures have shown defined ‘open’ and ‘closed’ states of the B-domain<ref>pmid 19213731</ref><ref>pmid 7915138</ref>. In addition, the biotin carboxylase domain of pyruvate carboxylase from ''Bacillus thermodenitrificans'' displays what appears to be an intermediate, but defined, conformation <ref>pmid 17642515</ref>. In the current structure, however, while <scene name='76/763765/Cv/6'>protomer A</scene> represents the previously observed ‘closed’ state, <scene name='76/763765/Cv/7'>protomer B</scene> represent a different structural state where no conformation is present in high enough occupancy to be possible to reliably model. MTb AccA3, subunit A (blue) and subunit B (yellow), unbound BDC from Escherichia coli (gray) (PDB [[1bnc]]). Based on the location of the segment of positive difference density relative to protomer B, it is, however, clear that the location of the B-domain in the partially occupied structural state that gives rise to this density is not the same as either the previously described ‘closed’ or ‘open’ states. Rather, the density suggests an even more extended conformation of the B-domain relative to the rest of the protein. Together, the most likely interpretation of the combined structural data of biotin-dependent carboxylases is that the B-domain is dynamic over a continuum of conformations, or several defined conformations.
+<scene name='76/763765/Cv/8'>Structural model</scene> of biotin and ADP binding in MTb AccA3 based on the biotin and ADP-bound ''Escherichia coli'' BDC (PDB [[3g8c]]). Substrate-bridging loop of ''MTb'' AccA3 rendered in pink and ''E. coli'' BDC in cyan.
+===[[Mycobacterium tuberculosis ArfA Rv0899]]===
 </StructureSection>