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Coinfection
Detecting Mutations in the Mycobacterium tuberculosis Pyrazinamidase Gene pncA to Improve Infection Control and Decrease Drug Resistance Rates in Human Immunodeficiency Virus Coinfection.
Hypersensitivity
Expression of Mycobacterium smegmatis pyrazinamidase in Mycobacterium tuberculosis confers hypersensitivity to pyrazinamide and related amides.
Infections
Detecting Mutations in the Mycobacterium tuberculosis Pyrazinamidase Gene pncA to Improve Infection Control and Decrease Drug Resistance Rates in Human Immunodeficiency Virus Coinfection.
Leprosy
Identification of cat leprosy bacillus grown in mice.
Paratuberculosis
Biochemical characteristics of various strains of Mycobacterium paratuberculosis.
Tuberculosis
1H, 13C and 15N resonance assignments of the pyrazinamidase from Mycobacterium tuberculosis.
Tuberculosis
A new rapid and simple colorimetric method to detect pyrazinamide resistance in Mycobacterium tuberculosis using nicotinamide.
Tuberculosis
A simplified pyrazinamidase test for pyrazinamide drug susceptibility in Mycobacterium tuberculosis.
Tuberculosis
Association between pncA gene mutations, pyrazinamidase activity, and pyrazinamide susceptibility testing in Mycobacterium tuberculosis.
Tuberculosis
Biochemical Characterization and Computational Identification of Mycobacterium tuberculosis Pyrazinamidase in Some Pyrazinamide-Resistant Isolates of Iran.
Tuberculosis
Biochemical heterogeneity of Mycobacterium tuberculosis complex isolates in Guinea-Bissau.
Tuberculosis
Characterization of new mutations in pyrazinamide-resistant strains of Mycobacterium tuberculosis and identification of conserved regions important for the catalytic activity of the pyrazinamidase PncA.
Tuberculosis
Characterization of pncA Mutations and Prediction of PZA Resistance in Mycobacterium tuberculosis Clinical Isolates From Chongqing, China.
Tuberculosis
Characterization of pncA mutations in pyrazinamide-resistant Mycobacterium tuberculosis isolates from Korea and analysis of the correlation between the mutations and pyrazinamidase activity
Tuberculosis
Characterization of pncA mutations in pyrazinamide-resistant Mycobacterium tuberculosis isolates from Korea and analysis of the correlation between the mutations and pyrazinamidase activity.
Tuberculosis
Characterization of pncA mutations in pyrazinamide-resistant Mycobacterium tuberculosis.
Tuberculosis
Characterization of pncA mutations of pyrazinamide-resistant Mycobacterium tuberculosis in Turkey.
Tuberculosis
Comparative evaluation of Löwenstein-Jensen proportion method, BacT/ALERT 3D system, and enzymatic pyrazinamidase assay for pyrazinamide susceptibility testing of Mycobacterium tuberculosis.
Tuberculosis
Comparison of MGIT 960 & pyrazinamidase activity assay for pyrazinamide susceptibility testing of Mycobacterium tuberculosis.
Tuberculosis
Comparison of phenotypic and genotypic methods for pyrazinamide susceptibility testing with Mycobacterium tuberculosis.
Tuberculosis
Computational insights into pH-dependence of structure and dynamics of pyrazinamidase: A comparison of wild type and mutants.
Tuberculosis
Correlation between pyrazinamide activity and pncA mutations in Mycobacterium tuberculosis isolates in Taiwan.
Tuberculosis
Correlation of pncA sequence with pyrazinamide resistance level in BACTEC for 21 mycobacterium tuberculosis clinical isolates.
Tuberculosis
Crystal structure and mechanism of catalysis of a pyrazinamidase from Pyrococcus horikoshii.
Tuberculosis
Crystal structure of the pyrazinamidase of Mycobacterium tuberculosis: insights into natural and acquired resistance to pyrazinamide.
Tuberculosis
Cytochemical and biological properties of Mycobacterium bovis BCG.
Tuberculosis
Detecting Mutations in the Mycobacterium tuberculosis Pyrazinamidase Gene pncA to Improve Infection Control and Decrease Drug Resistance Rates in Human Immunodeficiency Virus Coinfection.
Tuberculosis
Determining the unbinding events and conserved motions associated with the pyrazinamide release due to resistance mutations of Mycobacterium tuberculosis pyrazinamidase.
Tuberculosis
Does pyrazinoic acid as an active moiety of pyrazinamide have specific activity against Mycobacterium tuberculosis?
Tuberculosis
Drug resistance mechanism of PncA in Mycobacterium tuberculosis.
Tuberculosis
Effect of pyrazinamidase activity on pyrazinamide resistance in Mycobacterium tuberculosis.
Tuberculosis
Effects of metal-ion replacement on pyrazinamidase activity: A quantum mechanical study.
Tuberculosis
Effects of sorbitol and glycerol on the structure, dynamics, and stability of Mycobacterium tuberculosis pyrazinamidase.
Tuberculosis
Esters of Pyrazinoic Acid Are Active against Pyrazinamide-Resistant Strains of Mycobacterium tuberculosis and Other Naturally Resistant Mycobacteria In Vitro and Ex Vivo within Macrophages.
Tuberculosis
Estimation of pyrazinamidase activity using a cell-free
Tuberculosis
Evaluation of BACTEC MGIT 960 PZA medium for susceptibility testing of Mycobacterium tuberculosis to pyrazinamide (PZA): compared with the results of pyrazinamidase assay and Kyokuto PZA test.
Tuberculosis
Evaluation of drug susceptibility testing methods of clinical Mycobacterium tuberculosis isolates to pyrazinamide.
Tuberculosis
Evaluation of the microscopic observation drug susceptibility assay for detection of Mycobacterium tuberculosis resistance to pyrazinamide.
Tuberculosis
Expression of Mycobacterium smegmatis pyrazinamidase in Mycobacterium tuberculosis confers hypersensitivity to pyrazinamide and related amides.
Tuberculosis
Insight into novel clinical mutants of RpsA-S324F, E325K, and G341R of Mycobacterium tuberculosis associated with pyrazinamide resistance.
Tuberculosis
Insight to the molecular mechanisms of the osmolyte effects on Mycobacterium tuberculosis pyrazinamidase stability using experimental studies, molecular dynamics simulations, and free energy calculation.
Tuberculosis
Insights into Pyrazinamidase and DNA Gyrase Protein Structures in Resistant and Susceptible Clinical Isolates of Mycobacterium tuberculosis.
Tuberculosis
Long-Chain Fatty Acyl Coenzyme A Ligase FadD2 Mediates Intrinsic Pyrazinamide Resistance in Mycobacterium tuberculosis.
Tuberculosis
Mechanistic analysis elucidating the relationship between Lys96 mutation in Mycobacterium tuberculosis pyrazinamidase enzyme and pyrazinamide susceptibility.
Tuberculosis
Metal-ion effects on the polarization of metal-bound water and infrared vibrational modes of the coordinated metal center of Mycobacterium tuberculosis pyrazinamidase via quantum mechanical calculations.
Tuberculosis
Molecular dynamics simulations suggest ligand's binding to nicotinamidase/pyrazinamidase.
Tuberculosis
Mutation in pncA is a major mechanism of pyrazinamide resistance in Mycobacterium tuberculosis.
Tuberculosis
Mutations found in the pncA gene of Mycobacterium tuberculosis in clinical pyrazinamide-resistant isolates from a local region of China.
Tuberculosis
Mutations in pncA, a gene encoding pyrazinamidase/nicotinamidase, cause resistance to the antituberculous drug pyrazinamide in tubercle bacillus.
Tuberculosis
Mutually exclusive genotypes for pyrazinamide and 5-chloropyrazinamide resistance reveal a potential resistance proofing strategy.
Tuberculosis
Mycobacterium tuberculosis pyrazinamide resistance determinants: a multicenter study.
Tuberculosis
Novel pncA Mutations in Pyrazinamide-Resistant Isolates of Mycobacterium tuberculosis.
Tuberculosis
Patterns of pncA mutations in drug-resistant Mycobacterium tuberculosis isolated from patients in South Korea.
Tuberculosis
Pentacyanoferrate(II) complex of pyridine-4- and pyrazine-2-hydroxamic acid as source of HNO: investigation of anti-tubercular and vasodilation activities.
Tuberculosis
Peruvian and globally reported amino acid substitutions on the Mycobacterium tuberculosis pyrazinamidase suggest a conserved pattern of mutations associated to pyrazinamide resistance.
Tuberculosis
Phenotypic characterization of pncA mutants of Mycobacterium tuberculosis.
Tuberculosis
pncA gene expression and prediction factors on pyrazinamide resistance in Mycobacterium tuberculosis.
Tuberculosis
pncA mutations as a major mechanism of pyrazinamide resistance in Mycobacterium tuberculosis: spread of a monoresistant strain in Quebec, Canada.
Tuberculosis
pncA Mutations in the Specimens from Extrapulmonary Tuberculosis.
Tuberculosis
Prediction of Mycobacterium tuberculosis pyrazinamidase function based on structural stability, physicochemical and geometrical descriptors.
Tuberculosis
Purification, gene cloning, targeted knockout, overexpression, and biochemical characterization of the major pyrazinamidase from Mycobacterium smegmatis.
Tuberculosis
Pyrazinamidase activity of Mycobacterium tuberculosis--a test of sensitivity to pyrazinamide.
Tuberculosis
Pyrazinamide Inhibits Trans-Translation in Mycobacterium tuberculosis.
Tuberculosis
Pyrazinamide is not active in vitro against Mycobacterium avium complex.
Tuberculosis
Pyrazinamide resistance among South African multidrug-resistant Mycobacterium tuberculosis isolates.
Tuberculosis
Pyrazinamide resistance and mutations L19R, R140H, and E144K in Pyrazinamidase of Mycobacterium tuberculosis.
Tuberculosis
Pyrazinamide resistance associated with pncA gene mutation in Mycobacterium tuberculosis in Japan.
Tuberculosis
Pyrazinamide resistance in multidrug-resistant Mycobacterium tuberculosis isolates in Japan.
Tuberculosis
Rapid colorimetric testing for pyrazinamide susceptibility of M. tuberculosis by a PCR-based in-vitro synthesized pyrazinamidase method.
Tuberculosis
Rapid detection of pyrazinamide-resistant Mycobacterium tuberculosis by a PCR-based in vitro system.
Tuberculosis
Rapid detection of resistance to pyrazinamide in Mycobacterium tuberculosis using the resazurin microtitre assay.
Tuberculosis
Rapid differentiation of bovine and human tubercle bacilli based on a characteristic mutation in the bovine pyrazinamidase gene.
Tuberculosis
Reduced pyrazinamidase activity and the natural resistance of Mycobacterium kansasii to the antituberculosis drug pyrazinamide.
Tuberculosis
Relationship between pyrazinamide resistance, loss of pyrazinamidase activity, and mutations in the pncA locus in multidrug-resistant clinical isolates of Mycobacterium tuberculosis.
Tuberculosis
Role of acid pH and deficient efflux of pyrazinoic acid in unique susceptibility of Mycobacterium tuberculosis to pyrazinamide.
Tuberculosis
Role of metal ions on the activity of Mycobacterium tuberculosis pyrazinamidase.
Tuberculosis
Selection of in vitro mutants of pyrazinamide-resistant Mycobacterium tuberculosis.
Tuberculosis
Structural and quantum mechanical computations to elucidate the altered binding mechanism of metal and drug with pyrazinamidase from Mycobacterium tuberculosis due to mutagenicity.
Tuberculosis
Structural dynamics behind variants in pyrazinamidase and pyrazinamide resistance.
Tuberculosis
Structural insights of catalytic mechanism in mutant pyrazinamidase of Mycobacterium tuberculosis.
Tuberculosis
Structure-Activity relationship in mutated pyrazinamidases from Mycobacterium tuberculosis.
Tuberculosis
Study of pyrazinamidase structural changes in pyrazinamide resistant and susceptible isolates of Mycobacterium tuberculosis.
Tuberculosis
Study of the structure-activity relationships for the pyrazinamidase (PncA) from Mycobacterium tuberculosis.
Tuberculosis
Surveillance of pyrazinamide susceptibility among multidrug-resistant Mycobacterium tuberculosis isolates from Siriraj Hospital, Thailand.
Tuberculosis
Susceptibility of Mycobacterium tuberculosis to pyrazinamide and its relationship to pyrazinamidase activity.
Tuberculosis
Synthesis, in vitro antibacterial activity against Mycobacterium tuberculosis, and reverse docking-based target fishing of 1,4-benzoxazin-2-one derivatives.
Tuberculosis
Systematic review of mutations in pyrazinamidase associated with pyrazinamide resistance in Mycobacterium tuberculosis clinical isolates.
Tuberculosis
Testing of susceptibility of Mycobacterium tuberculosis to pyrazinamide: comparison of Bactec method with pyrazinamidase assay.
Tuberculosis
The biodistribution of 5-[18F]fluoropyrazinamide in Mycobacterium tuberculosis-infected mice determined by positron emission tomography.
Tuberculosis
The combinatorial effects of osmolytes and alcohols on the stability of pyrazinamidase: Methanol affects the enzyme stability through hydrophobic interactions and hydrogen bonds.
Tuberculosis
The pncA gene from naturally pyrazinamide-resistant Mycobacterium avium encodes pyrazinamidase and confers pyrazinamide susceptibility to resistant M. tuberculosis complex organisms.
Tuberculosis
Use of pyrazinamidase activity on Mycobacterium tuberculosis as a rapid method for determination of pyrazinamide susceptibility.
Tuberculosis
[Determination of pyrazinamide susceptibility for Mycobacterium tuberculosis by use of Middlebrook culture media and comparison with results of pyrazinamidase test]
Tuberculosis
[Evaluation of the pyrazinamidase test for the detection of susceptibility of Mycobacterium tuberculosis to pyrazinamide]
Tuberculosis
[Pyrazinamidase activity and sensitivity to pyrazinamide in tuberculosis bacteria]
Tuberculosis, Multidrug-Resistant
Systematic Analysis of Pyrazinamide-Resistant Spontaneous Mutants and Clinical Isolates of Mycobacterium tuberculosis.
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evolution
-
the nicotinamidase/pyrazinamidase PncA is a member of a large family of hydrolase enzymes that catalyze the deamination of nicotinamide to nicotinic acid
malfunction
-
a nonfunctional PZase in resistant strains allows the mycobacterium to survive in the presence of pyrazinamide. Alternative or complementary mechanism of resistance may exist
malfunction
analysis of mutations in pyrazinamidase and effects of the mutations at the metal coordination site and conformational changes in PZase binding cavity on the enzyme activity, quantum mechanical calculations, overview. Iron shows weak binding with the metal coordination site of the mutant proteins due to alteration in electron transfer mechanism. The binding cavity of the mutant PZase has undergone major conformational changes as the volume of pocket increased due to bulky R-chains of mutated amino acids. These conformational changes lead to weak binding of the drug at binding cavity of PZase and reduce the drug activation mechanism leading to increased drug resistance in the bacterial strains. The template structure used is the tertiary structure of pyrazinamidase from Mycobacterium tuberculosis, PDB ID 3PL1
malfunction
cumulative effect of mutations and iron substitution
malfunction
estimation of pyrazinamidase activity using a cell-free in vitro synthesis of pncA and its association with pyrazinamide susceptibility in Mycobacterium tuberculosis, mutant phenotypes, overview
malfunction
identification and multiple analyses to unveil different mechanisms of resistance of PZase mutants L19R, R140H, and E144K, overview. The native PZase protein docking score is the maximum, showing strong binding affinity in comparison with mutants. Molecular dynamics simulations explore the effect of the variants on the biological function of PZase. Hydrogen bonding, metal ion Fe2+ deviation, and fluctuation also seem to be affected because of the mutations L19R, R140H, and E144K. The mutant variants play a significant role in PZA resistance, altering the overall activity of native PZase, including metal ion Fe2+ displacement and free energy
malfunction
mechanisms of the pyrazinamide (PZA) resistance of three pyrazinamidase mutants N11K, P69T, and D126N. In general, pyrazinoic acid (PZA) resistance is caused by three genes pncA, rpsA, and panD. Among them, the pncA gene contributes 72-99% to the resistance. The binding pocket analysis shows that mutations N11K and P69T decrease the volume of the active site and hinder the correct orientation of PZA drug in the active site. Moreover, the Patchdock score is low as compared to wild-type showing the disturbance of shape complementarity between enzyme PZase and PZA drug. These mutations N11K, P69T, and D126N disturb the position of the Fe2+ ion. Among the mutations, D126N allosterically disturbs the position of the Fe2+ ion. The mutations decrease the binding affinity toward the PZA drug
malfunction
mutations in the pncA gene cause pyrazinamide (PZA) resistance in Mycobacterium tuberculosis
malfunction
Mycobacterium abscessus is resistant to pyrazinamide due to the random mutations in the primary sequences of the pyrazinamidase. In silico structural characterizations of pyrazinamidase variants from various species of Mycobacterium
malfunction
Mycobacterium avium is resistant to pyrazinamide due to the random mutations in the primary sequences of the pyrazinamidase. In silico structural characterizations of pyrazinamidase variants from various species of Mycobacterium
malfunction
Mycobacterium bovis is resistant to pyrazinamide due to the random mutations in the primary sequences of the pyrazinamidase. In silico structural characterizations of pyrazinamidase variants from various species of Mycobacterium
malfunction
Mycobacterium kansasii is resistant to pyrazinamide due to the random mutations in the primary sequences of the pyrazinamidase. In silico structural characterizations of pyrazinamidase variants from various species of Mycobacterium
malfunction
Mycobacterium marinum is resistant to pyrazinamide due to the random mutations in the primary sequences of the pyrazinamidase. In silico structural characterizations of pyrazinamidase variants from various species of Mycobacterium
malfunction
Mycobacterium smegmatis is resistant to pyrazinamide due to the random mutations in the primary sequences of the pyrazinamidase. In silico structural characterizations of pyrazinamidase variants from various species of Mycobacterium
malfunction
pyrazinamide (PZA)-resistance in Mycobacterium tuberculosis strains is caused by point mutations in the PZase enzyme which is the activator of the prodrug pyrazinoic acid (PZA)
malfunction
the major cause of PZA-resistance is associated with mutations in the pncA gene. Several novel mutations including V131F, Q141P, R154T, A170P, and V180F in the pncA gene of PZA-resistant isolates are detectetd during PZA drug susceptibility testing followed by pncA gene sequencing. Molecular mechanism of PZA-resistance, molecular dynamics
malfunction
the residues of flap region of enzyme mutant K96R acquire more flexibility in mutant form of protein and thus move away from the active site. This leads to weak binding of the drug to the target residues which might interfere with the activation of the drug to functional form thereby giving rise to drug resistant bacterial strains
malfunction
-
Mycobacterium abscessus is resistant to pyrazinamide due to the random mutations in the primary sequences of the pyrazinamidase. In silico structural characterizations of pyrazinamidase variants from various species of Mycobacterium
-
malfunction
-
Mycobacterium abscessus is resistant to pyrazinamide due to the random mutations in the primary sequences of the pyrazinamidase. In silico structural characterizations of pyrazinamidase variants from various species of Mycobacterium
-
malfunction
-
Mycobacterium abscessus is resistant to pyrazinamide due to the random mutations in the primary sequences of the pyrazinamidase. In silico structural characterizations of pyrazinamidase variants from various species of Mycobacterium
-
malfunction
-
Mycobacterium abscessus is resistant to pyrazinamide due to the random mutations in the primary sequences of the pyrazinamidase. In silico structural characterizations of pyrazinamidase variants from various species of Mycobacterium
-
malfunction
-
Mycobacterium abscessus is resistant to pyrazinamide due to the random mutations in the primary sequences of the pyrazinamidase. In silico structural characterizations of pyrazinamidase variants from various species of Mycobacterium
-
malfunction
-
Mycobacterium abscessus is resistant to pyrazinamide due to the random mutations in the primary sequences of the pyrazinamidase. In silico structural characterizations of pyrazinamidase variants from various species of Mycobacterium
-
malfunction
-
the residues of flap region of enzyme mutant K96R acquire more flexibility in mutant form of protein and thus move away from the active site. This leads to weak binding of the drug to the target residues which might interfere with the activation of the drug to functional form thereby giving rise to drug resistant bacterial strains
-
malfunction
-
cumulative effect of mutations and iron substitution
-
malfunction
-
pyrazinamide (PZA)-resistance in Mycobacterium tuberculosis strains is caused by point mutations in the PZase enzyme which is the activator of the prodrug pyrazinoic acid (PZA)
-
malfunction
-
estimation of pyrazinamidase activity using a cell-free in vitro synthesis of pncA and its association with pyrazinamide susceptibility in Mycobacterium tuberculosis, mutant phenotypes, overview
-
malfunction
-
identification and multiple analyses to unveil different mechanisms of resistance of PZase mutants L19R, R140H, and E144K, overview. The native PZase protein docking score is the maximum, showing strong binding affinity in comparison with mutants. Molecular dynamics simulations explore the effect of the variants on the biological function of PZase. Hydrogen bonding, metal ion Fe2+ deviation, and fluctuation also seem to be affected because of the mutations L19R, R140H, and E144K. The mutant variants play a significant role in PZA resistance, altering the overall activity of native PZase, including metal ion Fe2+ displacement and free energy
-
malfunction
-
mechanisms of the pyrazinamide (PZA) resistance of three pyrazinamidase mutants N11K, P69T, and D126N. In general, pyrazinoic acid (PZA) resistance is caused by three genes pncA, rpsA, and panD. Among them, the pncA gene contributes 72-99% to the resistance. The binding pocket analysis shows that mutations N11K and P69T decrease the volume of the active site and hinder the correct orientation of PZA drug in the active site. Moreover, the Patchdock score is low as compared to wild-type showing the disturbance of shape complementarity between enzyme PZase and PZA drug. These mutations N11K, P69T, and D126N disturb the position of the Fe2+ ion. Among the mutations, D126N allosterically disturbs the position of the Fe2+ ion. The mutations decrease the binding affinity toward the PZA drug
-
malfunction
-
analysis of mutations in pyrazinamidase and effects of the mutations at the metal coordination site and conformational changes in PZase binding cavity on the enzyme activity, quantum mechanical calculations, overview. Iron shows weak binding with the metal coordination site of the mutant proteins due to alteration in electron transfer mechanism. The binding cavity of the mutant PZase has undergone major conformational changes as the volume of pocket increased due to bulky R-chains of mutated amino acids. These conformational changes lead to weak binding of the drug at binding cavity of PZase and reduce the drug activation mechanism leading to increased drug resistance in the bacterial strains. The template structure used is the tertiary structure of pyrazinamidase from Mycobacterium tuberculosis, PDB ID 3PL1
-
malfunction
-
mutations in the pncA gene cause pyrazinamide (PZA) resistance in Mycobacterium tuberculosis
-
malfunction
-
the residues of flap region of enzyme mutant K96R acquire more flexibility in mutant form of protein and thus move away from the active site. This leads to weak binding of the drug to the target residues which might interfere with the activation of the drug to functional form thereby giving rise to drug resistant bacterial strains
-
malfunction
-
cumulative effect of mutations and iron substitution
-
malfunction
-
pyrazinamide (PZA)-resistance in Mycobacterium tuberculosis strains is caused by point mutations in the PZase enzyme which is the activator of the prodrug pyrazinoic acid (PZA)
-
malfunction
-
estimation of pyrazinamidase activity using a cell-free in vitro synthesis of pncA and its association with pyrazinamide susceptibility in Mycobacterium tuberculosis, mutant phenotypes, overview
-
malfunction
-
identification and multiple analyses to unveil different mechanisms of resistance of PZase mutants L19R, R140H, and E144K, overview. The native PZase protein docking score is the maximum, showing strong binding affinity in comparison with mutants. Molecular dynamics simulations explore the effect of the variants on the biological function of PZase. Hydrogen bonding, metal ion Fe2+ deviation, and fluctuation also seem to be affected because of the mutations L19R, R140H, and E144K. The mutant variants play a significant role in PZA resistance, altering the overall activity of native PZase, including metal ion Fe2+ displacement and free energy
-
malfunction
-
mechanisms of the pyrazinamide (PZA) resistance of three pyrazinamidase mutants N11K, P69T, and D126N. In general, pyrazinoic acid (PZA) resistance is caused by three genes pncA, rpsA, and panD. Among them, the pncA gene contributes 72-99% to the resistance. The binding pocket analysis shows that mutations N11K and P69T decrease the volume of the active site and hinder the correct orientation of PZA drug in the active site. Moreover, the Patchdock score is low as compared to wild-type showing the disturbance of shape complementarity between enzyme PZase and PZA drug. These mutations N11K, P69T, and D126N disturb the position of the Fe2+ ion. Among the mutations, D126N allosterically disturbs the position of the Fe2+ ion. The mutations decrease the binding affinity toward the PZA drug
-
malfunction
-
analysis of mutations in pyrazinamidase and effects of the mutations at the metal coordination site and conformational changes in PZase binding cavity on the enzyme activity, quantum mechanical calculations, overview. Iron shows weak binding with the metal coordination site of the mutant proteins due to alteration in electron transfer mechanism. The binding cavity of the mutant PZase has undergone major conformational changes as the volume of pocket increased due to bulky R-chains of mutated amino acids. These conformational changes lead to weak binding of the drug at binding cavity of PZase and reduce the drug activation mechanism leading to increased drug resistance in the bacterial strains. The template structure used is the tertiary structure of pyrazinamidase from Mycobacterium tuberculosis, PDB ID 3PL1
-
malfunction
-
mutations in the pncA gene cause pyrazinamide (PZA) resistance in Mycobacterium tuberculosis
-
metabolism
-
in Mycobacterium tuberculosis the enzyme converts the nicotinamide analogue prodrug pyrazinamide into the bacteriostatic pyrazinoic acid
metabolism
pyrazinamide (PZA), a derivative of nicotinamide is one of the most imperative first-line drug treatments against tuberculosis. PZA is significantly used in MDR tuberculosis in combination with isoniazid, rifampicin and ethambutol in regimens. The most potent action of the drug is against the semi-dormant bacilli in an acidic environment, which cannot be treated with most other drugs and thus helps in shortening the chemotherapy period
metabolism
-
pyrazinamide (PZA), a derivative of nicotinamide is one of the most imperative first-line drug treatments against tuberculosis. PZA is significantly used in MDR tuberculosis in combination with isoniazid, rifampicin and ethambutol in regimens. The most potent action of the drug is against the semi-dormant bacilli in an acidic environment, which cannot be treated with most other drugs and thus helps in shortening the chemotherapy period
-
metabolism
-
pyrazinamide (PZA), a derivative of nicotinamide is one of the most imperative first-line drug treatments against tuberculosis. PZA is significantly used in MDR tuberculosis in combination with isoniazid, rifampicin and ethambutol in regimens. The most potent action of the drug is against the semi-dormant bacilli in an acidic environment, which cannot be treated with most other drugs and thus helps in shortening the chemotherapy period
-
physiological function
-
the reaction product pyrazinoic acid inhibits Mycobacterium tuberculosis type I fatty acid synthase, represses mycolic acid biosynthesis, and appears to affect membrane energetics and acidification of the cytoplasm
physiological function
-
nicotinamidase/pyrazinamidase PncA catalyzes the deamination of nicotinamide to nicotinic acid (EC 3.5.1.19). PncA also functions as a pyrazinamidase in a wide variety of eubacteria and is an essential coenzyme in many cellular redox reactions in living systems
physiological function
pyrazinamidase (PZase) is involved in degradation of pyrazinamide to ammonia and pyrazinoic acid
physiological function
pyrazinamidase (PZase), a metalloenzyme, is responsible for acidic modification of pyrazinamide (PZA), a drug used in tuberculosis treatment
physiological function
pyrazinamidase, activator for pyrazinamide, leads to resistance against the drug pyrazinamide due to mutagenicity across the world
physiological function
pyrazinamide (PZA) is a prodrug that is converted to pyrazinoic acid (PoA, active form) by the pyrazinamidase (PZase) of Mycobacterium tuberculosis
physiological function
pyrazinamide (PZA) is an important component of first-line anti-tuberculosis (anti-TB) drugs. The anti-TB agent is activated into an active form, pyrazinoic acid, by Mycobacterium tuberculosis (MTB) pncA gene encoding pyrazinamidase (PZase)
physiological function
pyrazinamide (PZA) is an important component of first-line antituberculosis drugs activated by Mycobacterium tuberculosis pyrazinamidase (PZase) into its active form pyrazinoic acid (PZA)
physiological function
role of flap region present in PncA protein in development of resistance to the drug, molecular dynamics simulations
physiological function
the mycobacterial enzyme pyrazinamidase (PZase), is the target of pyrazinamide (PZA), one of the first-line medications for treatment of tuberculosis. PZA is a prodrug catalyzed to its active form pyrazinoic acid (POA) by enzyme PZase. POA is pumped out of the cell slowly and converts to its conjugate acid form to easily diffuse inwards and accumulates
physiological function
-
role of flap region present in PncA protein in development of resistance to the drug, molecular dynamics simulations
-
physiological function
-
pyrazinamidase (PZase) is involved in degradation of pyrazinamide to ammonia and pyrazinoic acid
-
physiological function
-
the mycobacterial enzyme pyrazinamidase (PZase), is the target of pyrazinamide (PZA), one of the first-line medications for treatment of tuberculosis. PZA is a prodrug catalyzed to its active form pyrazinoic acid (POA) by enzyme PZase. POA is pumped out of the cell slowly and converts to its conjugate acid form to easily diffuse inwards and accumulates
-
physiological function
-
pyrazinamide (PZA) is an important component of first-line antituberculosis drugs activated by Mycobacterium tuberculosis pyrazinamidase (PZase) into its active form pyrazinoic acid (PZA)
-
physiological function
-
pyrazinamide (PZA) is a prodrug that is converted to pyrazinoic acid (PoA, active form) by the pyrazinamidase (PZase) of Mycobacterium tuberculosis
-
physiological function
-
pyrazinamidase (PZase), a metalloenzyme, is responsible for acidic modification of pyrazinamide (PZA), a drug used in tuberculosis treatment
-
physiological function
-
pyrazinamidase, activator for pyrazinamide, leads to resistance against the drug pyrazinamide due to mutagenicity across the world
-
physiological function
-
role of flap region present in PncA protein in development of resistance to the drug, molecular dynamics simulations
-
physiological function
-
pyrazinamidase (PZase) is involved in degradation of pyrazinamide to ammonia and pyrazinoic acid
-
physiological function
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the mycobacterial enzyme pyrazinamidase (PZase), is the target of pyrazinamide (PZA), one of the first-line medications for treatment of tuberculosis. PZA is a prodrug catalyzed to its active form pyrazinoic acid (POA) by enzyme PZase. POA is pumped out of the cell slowly and converts to its conjugate acid form to easily diffuse inwards and accumulates
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physiological function
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pyrazinamide (PZA) is an important component of first-line antituberculosis drugs activated by Mycobacterium tuberculosis pyrazinamidase (PZase) into its active form pyrazinoic acid (PZA)
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physiological function
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pyrazinamide (PZA) is a prodrug that is converted to pyrazinoic acid (PoA, active form) by the pyrazinamidase (PZase) of Mycobacterium tuberculosis
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physiological function
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pyrazinamidase (PZase), a metalloenzyme, is responsible for acidic modification of pyrazinamide (PZA), a drug used in tuberculosis treatment
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physiological function
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pyrazinamidase, activator for pyrazinamide, leads to resistance against the drug pyrazinamide due to mutagenicity across the world
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additional information
protein conformational changes after ligand dissociation, molecular dynamics simulation methods are performed to investigate the unbinding process of nicotinamide using the enzyme's crystal structure. PDB ID 2WT9
additional information
structural modeling of the enzyme homodimer, docking study and molecular dynamics simulations, overview
additional information
catalytic Cys138
additional information
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catalytic Cys138
additional information
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combined whole-cell high-throughput functional screening for identification of nicotinamidases/pyrazinamidases in metagenomic/polygenomic libraries, screening of mesophilic marine bacteria (MB) polygenomic library. Development of two whole-cell methods using the chemical property of one of the products formed in the enzymatic reaction (pyrazinoic or NA) to form colored complexes with stable iron salts, such as ammonium ferrous sulfate or sodium nitroprusside (SNP), optimization of the assay. A fosmid polygenomic expression library obtained from deep-sea mesophilic bacteria is screened, discovering several positive clones with the ammonium ferrous sulfate method. Quantitative rescreening with the SNP method allowing the finding of the first nicotinamidase with balanced catalytic efficiency toward nicotinamidase activity (EC 3.5.1.19) and pyrazinamide (pyrazinamidase activity)
additional information
computational insights into pH-dependence of structure and dynamics of pyrazinamidase, comparison of wild-type and mutant enzymes, molecular dynamics simulations using the wild-type structure, PDB ID 3PL1, detailed overview. The 51-71 flap region exhibits a drastic displacement leading to enlargement of binding cavity, especially at the lower pH. Residues D8, K96, and C138 comprise an active site
additional information
development and validation of a simplified pyrazinamidase test by modifying Wayne's pyrazinamidase test for pyrazinamide drug susceptibility in Mycobacterium tuberculosis using a total of 120 complex strains/isolates, including 118 clinical isolates, and also Myycobacetrium bovis strain BCG (Tokyo substrain) and strain H37Rv, overview
additional information
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development and validation of a simplified pyrazinamidase test by modifying Wayne's pyrazinamidase test for pyrazinamide drug susceptibility in Mycobacterium tuberculosis using a total of 120 complex strains/isolates, including 118 clinical isolates, and also Myycobacetrium bovis strain BCG (Tokyo substrain) and strain H37Rv, overview
additional information
residues Asp8, Lys96, and Cys138 form the catalytic triad. Receptor and ligand docking, molecular dynamics simulations, overview
additional information
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residues Asp8, Lys96, and Cys138 form the catalytic triad. Receptor and ligand docking, molecular dynamics simulations, overview
additional information
stability and structure of recombinant pyrazinamidase (PZase) from Mycobacterium tuberculosis are analyzed in the presence of stabilizing osmolytes sorbitol, sucrose and glycerol, and alcohols methanol, ethanol, isopropanol and n-propanol, overview
additional information
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stability and structure of recombinant pyrazinamidase (PZase) from Mycobacterium tuberculosis are analyzed in the presence of stabilizing osmolytes sorbitol, sucrose and glycerol, and alcohols methanol, ethanol, isopropanol and n-propanol, overview
additional information
structural and quantum mechanical computations to elucidate the altered binding mechanism of metal and drug with Mycobacterium tuberculosis pyrazinamidase due to mutagenicity. Residues Asp8, Lys96, and Cys138 play a pivotal role in catalysis
additional information
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structural and quantum mechanical computations to elucidate the altered binding mechanism of metal and drug with Mycobacterium tuberculosis pyrazinamidase due to mutagenicity. Residues Asp8, Lys96, and Cys138 play a pivotal role in catalysis
additional information
structure analysis by molecular dynamics (MD) simulations, and spectroscopic methods, such as fluorescence spectroscopy and circular dichroism (CD)
additional information
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structure analysis by molecular dynamics (MD) simulations, and spectroscopic methods, such as fluorescence spectroscopy and circular dichroism (CD)
additional information
structure predictions of wild-type and mutant enzymes from sequences, modeling
additional information
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structure predictions of wild-type and mutant enzymes from sequences, modeling
additional information
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the active site residues are Asp8, Lys96, and Cys138, structure-function relationship and catalytic mechanism, overview. Homology structure modeling of wild-type and mutant enzymes, molecular substrate docking and molecular dynamics simulations, overview
additional information
the coordination of metal cofactors Ni2+, Co2+, or Fe2+ to PZase facilitates the deprotonation of coordinates water molecules to generate a nucleophile that catalyzes the enzymatic reaction
additional information
the most important catalytically important binding residues are Asp 8, Phe13, IIe133, Ala134 and Cys138 of native and mutant structures, substrate binding cavity structure analysis, and protein-ligand interaction analysis and hydrophobic interaction patterns, docking and molecular dynamics simulations of the docked complexes, overview
additional information
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the most important catalytically important binding residues are Asp 8, Phe13, IIe133, Ala134 and Cys138 of native and mutant structures, substrate binding cavity structure analysis, and protein-ligand interaction analysis and hydrophobic interaction patterns, docking and molecular dynamics simulations of the docked complexes, overview
additional information
the substrate binding site involves residues D8, F13, D49, K96, I133, A135, H137, and C138, binding sites architectures and GATE analysis, molecular dynamics simulations, overview
additional information
the substrate binding site involves residues D8, F13, D49, K96, I133, A135, H137, and C138, binding sites architectures and GATE analysis, molecular dynamics simulations, overview
additional information
the substrate binding site involves residues D8, F13, D49, K96, I133, A135, H137, and C138, binding sites architectures and GATE analysis, molecular dynamics simulations, overview
additional information
the substrate binding site involves residues D8, F13, D49, K96, I133, A135, H137, and C138, binding sites architectures and GATE analysis, molecular dynamics simulations, overview
additional information
the substrate binding site involves residues D8, F13, D49, K96, I133, A135, H137, and C138, binding sites architectures and GATE analysis, molecular dynamics simulations, overview
additional information
the substrate binding site involves residues D8, F13, D49, K96, I133, A135, H137, and C138, binding sites architectures and GATE analysis, molecular dynamics simulations, overview
additional information
wild-type and mutant PZase structures in apo and complex with pyrazinamide (PZA) are subjected to structure analysis by molecular dynamics simulations
additional information
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wild-type and mutant PZase structures in apo and complex with pyrazinamide (PZA) are subjected to structure analysis by molecular dynamics simulations
additional information
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the substrate binding site involves residues D8, F13, D49, K96, I133, A135, H137, and C138, binding sites architectures and GATE analysis, molecular dynamics simulations, overview
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additional information
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the substrate binding site involves residues D8, F13, D49, K96, I133, A135, H137, and C138, binding sites architectures and GATE analysis, molecular dynamics simulations, overview
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additional information
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the substrate binding site involves residues D8, F13, D49, K96, I133, A135, H137, and C138, binding sites architectures and GATE analysis, molecular dynamics simulations, overview
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additional information
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the substrate binding site involves residues D8, F13, D49, K96, I133, A135, H137, and C138, binding sites architectures and GATE analysis, molecular dynamics simulations, overview
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additional information
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the substrate binding site involves residues D8, F13, D49, K96, I133, A135, H137, and C138, binding sites architectures and GATE analysis, molecular dynamics simulations, overview
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additional information
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the substrate binding site involves residues D8, F13, D49, K96, I133, A135, H137, and C138, binding sites architectures and GATE analysis, molecular dynamics simulations, overview
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additional information
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structural modeling of the enzyme homodimer, docking study and molecular dynamics simulations, overview
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additional information
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the most important catalytically important binding residues are Asp 8, Phe13, IIe133, Ala134 and Cys138 of native and mutant structures, substrate binding cavity structure analysis, and protein-ligand interaction analysis and hydrophobic interaction patterns, docking and molecular dynamics simulations of the docked complexes, overview
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additional information
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stability and structure of recombinant pyrazinamidase (PZase) from Mycobacterium tuberculosis are analyzed in the presence of stabilizing osmolytes sorbitol, sucrose and glycerol, and alcohols methanol, ethanol, isopropanol and n-propanol, overview
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additional information
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structure analysis by molecular dynamics (MD) simulations, and spectroscopic methods, such as fluorescence spectroscopy and circular dichroism (CD)
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additional information
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catalytic Cys138
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additional information
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computational insights into pH-dependence of structure and dynamics of pyrazinamidase, comparison of wild-type and mutant enzymes, molecular dynamics simulations using the wild-type structure, PDB ID 3PL1, detailed overview. The 51-71 flap region exhibits a drastic displacement leading to enlargement of binding cavity, especially at the lower pH. Residues D8, K96, and C138 comprise an active site
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additional information
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residues Asp8, Lys96, and Cys138 form the catalytic triad. Receptor and ligand docking, molecular dynamics simulations, overview
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additional information
-
development and validation of a simplified pyrazinamidase test by modifying Wayne's pyrazinamidase test for pyrazinamide drug susceptibility in Mycobacterium tuberculosis using a total of 120 complex strains/isolates, including 118 clinical isolates, and also Myycobacetrium bovis strain BCG (Tokyo substrain) and strain H37Rv, overview
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additional information
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the coordination of metal cofactors Ni2+, Co2+, or Fe2+ to PZase facilitates the deprotonation of coordinates water molecules to generate a nucleophile that catalyzes the enzymatic reaction
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additional information
-
structural and quantum mechanical computations to elucidate the altered binding mechanism of metal and drug with Mycobacterium tuberculosis pyrazinamidase due to mutagenicity. Residues Asp8, Lys96, and Cys138 play a pivotal role in catalysis
-
additional information
-
structure predictions of wild-type and mutant enzymes from sequences, modeling
-
additional information
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the most important catalytically important binding residues are Asp 8, Phe13, IIe133, Ala134 and Cys138 of native and mutant structures, substrate binding cavity structure analysis, and protein-ligand interaction analysis and hydrophobic interaction patterns, docking and molecular dynamics simulations of the docked complexes, overview
-
additional information
-
stability and structure of recombinant pyrazinamidase (PZase) from Mycobacterium tuberculosis are analyzed in the presence of stabilizing osmolytes sorbitol, sucrose and glycerol, and alcohols methanol, ethanol, isopropanol and n-propanol, overview
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additional information
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structure analysis by molecular dynamics (MD) simulations, and spectroscopic methods, such as fluorescence spectroscopy and circular dichroism (CD)
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additional information
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catalytic Cys138
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additional information
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computational insights into pH-dependence of structure and dynamics of pyrazinamidase, comparison of wild-type and mutant enzymes, molecular dynamics simulations using the wild-type structure, PDB ID 3PL1, detailed overview. The 51-71 flap region exhibits a drastic displacement leading to enlargement of binding cavity, especially at the lower pH. Residues D8, K96, and C138 comprise an active site
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additional information
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residues Asp8, Lys96, and Cys138 form the catalytic triad. Receptor and ligand docking, molecular dynamics simulations, overview
-
additional information
-
development and validation of a simplified pyrazinamidase test by modifying Wayne's pyrazinamidase test for pyrazinamide drug susceptibility in Mycobacterium tuberculosis using a total of 120 complex strains/isolates, including 118 clinical isolates, and also Myycobacetrium bovis strain BCG (Tokyo substrain) and strain H37Rv, overview
-
additional information
-
the coordination of metal cofactors Ni2+, Co2+, or Fe2+ to PZase facilitates the deprotonation of coordinates water molecules to generate a nucleophile that catalyzes the enzymatic reaction
-
additional information
-
structural and quantum mechanical computations to elucidate the altered binding mechanism of metal and drug with Mycobacterium tuberculosis pyrazinamidase due to mutagenicity. Residues Asp8, Lys96, and Cys138 play a pivotal role in catalysis
-
additional information
-
structure predictions of wild-type and mutant enzymes from sequences, modeling
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A143T
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site-directed mutagenesis, the mutation decreases the Km and kcat values of the enzyme
A143T/T168A/E173K
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site-directed mutagenesis, the mutation decreases the Km and kcat values of the enzyme, the mutant shows reduced thermostability compared to wild-type
A146V
naturally occuring mutation, the mutant shows 72% reduced activity compared to wild-type, resistant strain
C138Y
site-directed mutagenesis
D126N
site-directed mutagenesis, the mutation causes pyrazinamide resistance, the mutation is located outside of active site and has an allosteric affect
D136G
site-directed mutagenesis, the mutation highly reduces the mutant activity compared to wild-type
D63A
naturally occuring mutation, susceptible strain
E144K
naturally occuring mutation from PZA-resistant isolate, analysis of the resistance mechanism of the mutant strain
F94L
site-directed mutagenesis
G24D
site-directed mutagenesis
G97D
naturally occuring mutation, the mutant shows 90% reduced activity compared to wild-type, resistant strain
H51P
naturally occuring mutation, inactive mutant, resistant strain
H51Q
site-directed mutagenesis
I5T
naturally occuring mutation, the mutant shows 88% reduced activity compared to wild-type, resistant strain
I6L
naturally occuring mutation, susceptible strain
K96R
naturally occurring mutation in the PncA catalytic region, binding cavity analysis shows an increase of 762.3 A3 in the volume of the mutant protein. Docking studies reveal that pyrazinamide (PZA) has a greater binding affinity for the wild-type protein in comparison to the mutant protein. The residues of flap region acquire more flexibility in mutant form of protein and thus move away from the active site. This leads to weak binding of the drug to the target residues. The mutation leads to a substantial increase in the binding cavity. This prohibits the enzyme from holding the drug properly and therefore pyrazinoic acid (PZA) cannot take its active form
L116P
site-directed mutagenesis
L151S
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site-directed mutagenesis, the mutant has a weakened binding affinity for pyrazinamide and reduced thermostability compared to the wild-type
L19R
naturally occuring mutation from PZA-resistant isolate
L85P
naturally occuring mutation, resistant strain
L85R
naturally occuring mutation, inactive mutant, resistant strain
M175V
naturally occuring mutation, susceptible strain
N11K
site-directed mutagenesis, the active site mutation causes pyrazinamide resistance, destabilization of the Fe2+ binding site
P62T
naturally occuring mutation, susceptible strain
P69T
site-directed mutagenesis, the active site mutation causes pyrazinamide resistance, destabilization of the Fe2+ binding site
P77L/V131G
naturally occuring mutation, susceptible strain
R140H
naturally occuring mutation from PZA-resistant isolate
R140S
naturally occuring mutation, susceptible strain
S67P
site-directed mutagenesis
T167I
naturally occuring mutation, susceptible strain
T47A
naturally occuring mutation, susceptible strain
T47P
naturally occuring mutation, inactive mutant, resistant strain
T87M
site-directed mutagenesis, active mutant, susceptible strain
T92C
the naturally occuring mutation causes an increase in distance from metal ion position to enzyme active site, but it is considered as a polymorphism
V155G
naturally occuring mutation, resistant strain
V7A
naturally occuring mutation, susceptible strain
V9A
naturally occuring mutation, the mutant shows 73% reduced activity compared to wild-type, resistant strain
V9G
naturally occuring mutation, the mutant shows 99% reduced activity compared to wild-type, resistant strain
W68G
naturally occuring mutation, resistant strain
Y64D
naturally occuring mutation, susceptible strain
Y99S
naturally occuring mutation, susceptible strain
D126N
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site-directed mutagenesis, the mutation causes pyrazinamide resistance, the mutation is located outside of active site and has an allosteric affect
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D63A
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naturally occuring mutation, susceptible strain
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E144K
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naturally occuring mutation from PZA-resistant isolate, analysis of the resistance mechanism of the mutant strain
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G78C
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site-directed mutagenesis, the mutation highly reduces the mutant activity compared to wild-type and has a deleterious effect on the metal binding mechanism of PZase
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H51Q
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site-directed mutagenesis
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H57D
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site-directed mutagenesis
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K96R
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naturally occurring mutation in the PncA catalytic region, binding cavity analysis shows an increase of 762.3 A3 in the volume of the mutant protein. Docking studies reveal that pyrazinamide (PZA) has a greater binding affinity for the wild-type protein in comparison to the mutant protein. The residues of flap region acquire more flexibility in mutant form of protein and thus move away from the active site. This leads to weak binding of the drug to the target residues. The mutation leads to a substantial increase in the binding cavity. This prohibits the enzyme from holding the drug properly and therefore pyrazinoic acid (PZA) cannot take its active form
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L19R
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naturally occuring mutation from PZA-resistant isolate
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L85P
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naturally occuring mutation, resistant strain
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N11K
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site-directed mutagenesis, the active site mutation causes pyrazinamide resistance, destabilization of the Fe2+ binding site
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P69T
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site-directed mutagenesis, the active site mutation causes pyrazinamide resistance, destabilization of the Fe2+ binding site
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R140H
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naturally occuring mutation from PZA-resistant isolate
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R140S
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naturally occuring mutation, susceptible strain
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T47A
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naturally occuring mutation, susceptible strain
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T92C
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the naturally occuring mutation causes an increase in distance from metal ion position to enzyme active site, but it is considered as a polymorphism
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V155G
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naturally occuring mutation, resistant strain
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V9A
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naturally occuring mutation, the mutant shows 73% reduced activity compared to wild-type, resistant strain
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W68G
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naturally occuring mutation, resistant strain
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D126N
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site-directed mutagenesis, the mutation causes pyrazinamide resistance, the mutation is located outside of active site and has an allosteric affect
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D63A
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naturally occuring mutation, susceptible strain
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E144K
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naturally occuring mutation from PZA-resistant isolate, analysis of the resistance mechanism of the mutant strain
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G78C
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site-directed mutagenesis, the mutation highly reduces the mutant activity compared to wild-type and has a deleterious effect on the metal binding mechanism of PZase
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H51Q
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site-directed mutagenesis
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H57D
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site-directed mutagenesis
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K96R
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naturally occurring mutation in the PncA catalytic region, binding cavity analysis shows an increase of 762.3 A3 in the volume of the mutant protein. Docking studies reveal that pyrazinamide (PZA) has a greater binding affinity for the wild-type protein in comparison to the mutant protein. The residues of flap region acquire more flexibility in mutant form of protein and thus move away from the active site. This leads to weak binding of the drug to the target residues. The mutation leads to a substantial increase in the binding cavity. This prohibits the enzyme from holding the drug properly and therefore pyrazinoic acid (PZA) cannot take its active form
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L19R
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naturally occuring mutation from PZA-resistant isolate
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L85P
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naturally occuring mutation, resistant strain
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N11K
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site-directed mutagenesis, the active site mutation causes pyrazinamide resistance, destabilization of the Fe2+ binding site
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P69T
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site-directed mutagenesis, the active site mutation causes pyrazinamide resistance, destabilization of the Fe2+ binding site
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R140H
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naturally occuring mutation from PZA-resistant isolate
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R140S
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naturally occuring mutation, susceptible strain
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T47A
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naturally occuring mutation, susceptible strain
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T92C
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the naturally occuring mutation causes an increase in distance from metal ion position to enzyme active site, but it is considered as a polymorphism
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V155G
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naturally occuring mutation, resistant strain
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V9A
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naturally occuring mutation, the mutant shows 73% reduced activity compared to wild-type, resistant strain
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W68G
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naturally occuring mutation, resistant strain
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H57D
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site-directed mutagenesis, inactive mutant
D12A
site-directed mutagenesis
D12A
site-directed mutagenesis, the mutation highly reduces the mutant activity compared to wild-type
D12G
site-directed mutagenesis
D12G
site-directed mutagenesis, the mutation highly reduces the mutant activity compared to wild-type
D49N
site-directed mutagenesis
D49N
site-directed mutagenesis, the mutation highly reduces the mutant activity compared to wild-type and has a deleterious effect on the metal binding mechanism of PZase
G78C
site-directed mutagenesis
G78C
site-directed mutagenesis, the mutation highly reduces the mutant activity compared to wild-type and has a deleterious effect on the metal binding mechanism of PZase
H51R
naturally occuring mutation, inactive mutant, resistant strain
H51R
site-directed mutagenesis, the mutation highly reduces the mutant activity compared to wild-type and has a deleterious effect on the metal binding mechanism of PZase
H57D
site-directed mutagenesis
H57D
naturally occuring mutation, inactive mutant, resistant strain
T135P
site-directed mutagenesis
T135P
site-directed mutagenesis, the mutation highly reduces the mutant activity compared to wild-type
T142R
naturally occuring mutation, inactive mutant, resistant strain
T142R
naturally occuring mutation, resistant strain
D12A
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site-directed mutagenesis, the mutation highly reduces the mutant activity compared to wild-type
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D12A
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site-directed mutagenesis
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D12G
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site-directed mutagenesis, the mutation highly reduces the mutant activity compared to wild-type
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D12G
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site-directed mutagenesis
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D49N
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site-directed mutagenesis, the mutation highly reduces the mutant activity compared to wild-type and has a deleterious effect on the metal binding mechanism of PZase
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D49N
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site-directed mutagenesis
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D12A
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site-directed mutagenesis, the mutation highly reduces the mutant activity compared to wild-type
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D12A
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site-directed mutagenesis
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D12G
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site-directed mutagenesis, the mutation highly reduces the mutant activity compared to wild-type
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D12G
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site-directed mutagenesis
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D49N
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site-directed mutagenesis, the mutation highly reduces the mutant activity compared to wild-type and has a deleterious effect on the metal binding mechanism of PZase
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D49N
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site-directed mutagenesis
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additional information
in silico structural characterizations of pyrazinamidase variants from various species of Mycobacterium
additional information
in silico structural characterizations of pyrazinamidase variants from various species of Mycobacterium
additional information
in silico structural characterizations of pyrazinamidase variants from various species of Mycobacterium
additional information
analysis of the specific pyrazinamidase (PZase) activity of PncA mutants via PCR-based in vitro-synthesized-PZase assay and correlation of the results to the pyrazinamide (PZA) susceptibility phenotype determined by culture in acidic agar medium at pH 6.0. A set of 23 clinical isolates displaying mutated pncA genes (11 PZA-resistant and 12 PZA-susceptible) and 55 PZA-susceptible clinical strains displaying a wild-type pncA gene are tested. Among the 23 mutants tested, 4 corresponded to mutations not reported before (I5T, Y99S, T142R, and P77L/V131G). Of the 11 PncA mutants expressed from PZA-resistant clinical isolates, 9 are expressed in vitro at yields above 50% relative to the wild-type enzyme. Among them, 6 enzymes (T47P, H51P, H51R, H57D, L85R and T142R) show no detectable activity, while the relative activities for the 3 others, V9A, G97D, and A146V, are low compared to the wild-type PZase. The remaining two mutants, I5T and V9G, presented very low relative expression (5%) and relative activities values of 12 and 1%, respectively. Twelve mutants are expressed from PZA-susceptible isolates. Their expression arte is similar to the wild-type enzyme, and they behave as active pyrazinamidase with specific relative activities ranging from 34 to 314%. Finally, discrepant results are observed for two mutants, V7A and P62T
additional information
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analysis of the specific pyrazinamidase (PZase) activity of PncA mutants via PCR-based in vitro-synthesized-PZase assay and correlation of the results to the pyrazinamide (PZA) susceptibility phenotype determined by culture in acidic agar medium at pH 6.0. A set of 23 clinical isolates displaying mutated pncA genes (11 PZA-resistant and 12 PZA-susceptible) and 55 PZA-susceptible clinical strains displaying a wild-type pncA gene are tested. Among the 23 mutants tested, 4 corresponded to mutations not reported before (I5T, Y99S, T142R, and P77L/V131G). Of the 11 PncA mutants expressed from PZA-resistant clinical isolates, 9 are expressed in vitro at yields above 50% relative to the wild-type enzyme. Among them, 6 enzymes (T47P, H51P, H51R, H57D, L85R and T142R) show no detectable activity, while the relative activities for the 3 others, V9A, G97D, and A146V, are low compared to the wild-type PZase. The remaining two mutants, I5T and V9G, presented very low relative expression (5%) and relative activities values of 12 and 1%, respectively. Twelve mutants are expressed from PZA-susceptible isolates. Their expression arte is similar to the wild-type enzyme, and they behave as active pyrazinamidase with specific relative activities ranging from 34 to 314%. Finally, discrepant results are observed for two mutants, V7A and P62T
additional information
cumulative effect of mutations and iron substitution
additional information
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cumulative effect of mutations and iron substitution
additional information
molecular dynamics simulations coupled with essential dynamics and binding pocket analysis at neutral (pH = 7) and acidic (pH = 4) ambient conditions, detailed overview. Computational insights into pH-dependence of structure and dynamics of pyrazinamidase, comparison of wild-type and mutant enzymes
additional information
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molecular modeling and substrate docking reveals that the wild-type has much stronger binding affinity to PZA than the mutants whereas mutant L151S has the weakest binding affinity. Molecular dynamics simulations and the essential dynamics results illustrate that the positions of the 51st to 71st residues are more dynamics in mutant L151S as compared to the other atoms in PZase. Kinetics of activation and half-life of wild-type and mutant PZases
additional information
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mutational statistics, especially mutations in the promoter region of pncA, Analysis of methods of phenotypic determination and genotype-phenotype evaluation for diagnostics in clinical drug studies and MIC determinations, overview. For diagnostics, individual mutations (or any subset) are not sufficiently sensitive. Assuming similar error profiles of the 5 phenotyping platforms included in the study, the entire enzyme and its promoter provide a combined estimated sensitivity of 83%. Molecular diagnostics of PZA resistance
additional information
-
cumulative effect of mutations and iron substitution
-
additional information
-
analysis of the specific pyrazinamidase (PZase) activity of PncA mutants via PCR-based in vitro-synthesized-PZase assay and correlation of the results to the pyrazinamide (PZA) susceptibility phenotype determined by culture in acidic agar medium at pH 6.0. A set of 23 clinical isolates displaying mutated pncA genes (11 PZA-resistant and 12 PZA-susceptible) and 55 PZA-susceptible clinical strains displaying a wild-type pncA gene are tested. Among the 23 mutants tested, 4 corresponded to mutations not reported before (I5T, Y99S, T142R, and P77L/V131G). Of the 11 PncA mutants expressed from PZA-resistant clinical isolates, 9 are expressed in vitro at yields above 50% relative to the wild-type enzyme. Among them, 6 enzymes (T47P, H51P, H51R, H57D, L85R and T142R) show no detectable activity, while the relative activities for the 3 others, V9A, G97D, and A146V, are low compared to the wild-type PZase. The remaining two mutants, I5T and V9G, presented very low relative expression (5%) and relative activities values of 12 and 1%, respectively. Twelve mutants are expressed from PZA-susceptible isolates. Their expression arte is similar to the wild-type enzyme, and they behave as active pyrazinamidase with specific relative activities ranging from 34 to 314%. Finally, discrepant results are observed for two mutants, V7A and P62T
-
additional information
-
molecular dynamics simulations coupled with essential dynamics and binding pocket analysis at neutral (pH = 7) and acidic (pH = 4) ambient conditions, detailed overview. Computational insights into pH-dependence of structure and dynamics of pyrazinamidase, comparison of wild-type and mutant enzymes
-
additional information
-
cumulative effect of mutations and iron substitution
-
additional information
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analysis of the specific pyrazinamidase (PZase) activity of PncA mutants via PCR-based in vitro-synthesized-PZase assay and correlation of the results to the pyrazinamide (PZA) susceptibility phenotype determined by culture in acidic agar medium at pH 6.0. A set of 23 clinical isolates displaying mutated pncA genes (11 PZA-resistant and 12 PZA-susceptible) and 55 PZA-susceptible clinical strains displaying a wild-type pncA gene are tested. Among the 23 mutants tested, 4 corresponded to mutations not reported before (I5T, Y99S, T142R, and P77L/V131G). Of the 11 PncA mutants expressed from PZA-resistant clinical isolates, 9 are expressed in vitro at yields above 50% relative to the wild-type enzyme. Among them, 6 enzymes (T47P, H51P, H51R, H57D, L85R and T142R) show no detectable activity, while the relative activities for the 3 others, V9A, G97D, and A146V, are low compared to the wild-type PZase. The remaining two mutants, I5T and V9G, presented very low relative expression (5%) and relative activities values of 12 and 1%, respectively. Twelve mutants are expressed from PZA-susceptible isolates. Their expression arte is similar to the wild-type enzyme, and they behave as active pyrazinamidase with specific relative activities ranging from 34 to 314%. Finally, discrepant results are observed for two mutants, V7A and P62T
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additional information
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molecular dynamics simulations coupled with essential dynamics and binding pocket analysis at neutral (pH = 7) and acidic (pH = 4) ambient conditions, detailed overview. Computational insights into pH-dependence of structure and dynamics of pyrazinamidase, comparison of wild-type and mutant enzymes
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additional information
in silico structural characterizations of pyrazinamidase variants from various species of Mycobacterium
additional information
in silico structural characterizations of pyrazinamidase variants from various species of Mycobacterium
additional information
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in silico structural characterizations of pyrazinamidase variants from various species of Mycobacterium
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additional information
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in silico structural characterizations of pyrazinamidase variants from various species of Mycobacterium
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additional information
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in silico structural characterizations of pyrazinamidase variants from various species of Mycobacterium
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additional information
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in silico structural characterizations of pyrazinamidase variants from various species of Mycobacterium
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additional information
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in silico structural characterizations of pyrazinamidase variants from various species of Mycobacterium
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additional information
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in silico structural characterizations of pyrazinamidase variants from various species of Mycobacterium
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additional information
in silico structural characterizations of pyrazinamidase variants from various species of Mycobacterium
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