3.5.1.B15	evolution	the nicotinamidase/pyrazinamidase PncA is a member of a large family of hydrolase enzymes that catalyze the deamination of nicotinamide to nicotinic acid	752683	
3.5.1.B15	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	755800	
3.5.1.B15	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	-, 757448	
3.5.1.B15	malfunction	cumulative effect of mutations and iron substitution	-, 756516	
3.5.1.B15	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	-, 757008	
3.5.1.B15	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	-, 757293	
3.5.1.B15	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	-, 757305	
3.5.1.B15	malfunction	mutations in the pncA gene cause pyrazinamide (PZA) resistance in Mycobacterium tuberculosis	-, 758499	
3.5.1.B15	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	-, 757474	
3.5.1.B15	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	757474	
3.5.1.B15	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	757474	
3.5.1.B15	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	757474	
3.5.1.B15	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	757474	
3.5.1.B15	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	757474	
3.5.1.B15	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)	-, 757007	
3.5.1.B15	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	757258	
3.5.1.B15	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	-, 756295	
3.5.1.B15	metabolism	in Mycobacterium tuberculosis the enzyme converts the nicotinamide analogue prodrug pyrazinamide into the bacteriostatic pyrazinoic acid	710862	
3.5.1.B15	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	-, 756295	
3.5.1.B15	additional information	catalytic Cys138	-, 757008	
3.5.1.B15	additional information	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)	753679	
3.5.1.B15	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	-, 757291	
3.5.1.B15	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	-, 757425	
3.5.1.B15	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	735054	
3.5.1.B15	additional information	residues Asp8, Lys96, and Cys138 form the catalytic triad. Receptor and ligand docking, molecular dynamics simulations, overview	-, 757293	
3.5.1.B15	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	-, 756937	
3.5.1.B15	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	-, 757448	
3.5.1.B15	additional information	structural modeling of the enzyme homodimer, docking study and molecular dynamics simulations, overview	-, 735324	
3.5.1.B15	additional information	structure analysis by molecular dynamics (MD) simulations, and spectroscopic methods, such as fluorescence spectroscopy and circular dichroism (CD)	-, 757007	
3.5.1.B15	additional information	structure predictions of wild-type and mutant enzymes from sequences, modeling	-, 758499	
3.5.1.B15	additional information	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	758283	
3.5.1.B15	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	-, 757445	
3.5.1.B15	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	-, 756295	
3.5.1.B15	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	-, 757474	
3.5.1.B15	additional information	wild-type and mutant PZase structures in apo and complex with pyrazinamide (PZA) are subjected to structure analysis by molecular dynamics simulations	757258	
3.5.1.B15	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	752683	
3.5.1.B15	physiological function	pyrazinamidase (PZase) is involved in degradation of pyrazinamide to ammonia and pyrazinoic acid	-, 757007	
3.5.1.B15	physiological function	pyrazinamidase (PZase), a metalloenzyme, is responsible for acidic modification of pyrazinamide (PZA), a drug used in tuberculosis treatment	-, 757445	
3.5.1.B15	physiological function	pyrazinamidase, activator for pyrazinamide, leads to resistance against the drug pyrazinamide due to mutagenicity across the world	-, 757448	
3.5.1.B15	physiological function	pyrazinamide (PZA) is a prodrug that is converted to pyrazinoic acid (PoA, active form) by the pyrazinamidase (PZase) of Mycobacterium tuberculosis	-, 757425	
3.5.1.B15	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)	757258	
3.5.1.B15	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)	-, 757293	
3.5.1.B15	physiological function	role of flap region present in PncA protein in development of resistance to the drug, molecular dynamics simulations	-, 756295	
3.5.1.B15	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	-, 757291	
3.5.1.B15	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	710862