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Literature summary for 3.5.1.B15 extracted from

  • Vats, C.; Dhanjal, J.; Goyal, S.; Gupta, A.; Bharadvaja, N.; Grover, A.
    Mechanistic analysis elucidating the relationship between Lys96 mutation in Mycobacterium tuberculosis pyrazinamidase enzyme and pyrazinamide susceptibility (2015), BMC Genomics, 16(Suppl 2), S14 .
    View publication on PubMedView publication on EuropePMC
Search for more literature for 3.5.1.B15

Protein Variants

Protein Variants Comment Organism
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 Mycobacterium tuberculosis

Metals/Ions

Metals/Ions Comment Organism Structure
Fe2+ the enzyme contains a Fe2+ ion surrounded by one aspartate and three histidines in the substrate binding cavity along with three water molecules Mycobacterium tuberculosis

Natural Substrates/ Products (Substrates)

Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
pyrazinamide + H2O Mycobacterium tuberculosis
-
 pyrazinoic acid + NH3
-
 ?
pyrazinamide + H2O Mycobacterium tuberculosis H37Rv
-
 pyrazinoic acid + NH3
-
 ?
pyrazinamide + H2O Mycobacterium tuberculosis ATCC 25618
-
 pyrazinoic acid + NH3
-
 ?

Organism

Organism UniProt Comment Textmining
Mycobacterium tuberculosis I6XD65
-
-
Mycobacterium tuberculosis ATCC 25618 I6XD65
-
-
Mycobacterium tuberculosis H37Rv I6XD65
-
-

Substrates and Products (Substrate)

Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
pyrazinamide + H2O
-
 Mycobacterium tuberculosis pyrazinoic acid + NH3
-
 ?
pyrazinamide + H2O enzyme protein ligand interaction, docking study using the wild-type PncA protein structure (PDB ID 3PL1), overview Mycobacterium tuberculosis pyrazinoic acid + NH3
-
 ?
pyrazinamide + H2O
-
 Mycobacterium tuberculosis H37Rv pyrazinoic acid + NH3
-
 ?
pyrazinamide + H2O enzyme protein ligand interaction, docking study using the wild-type PncA protein structure (PDB ID 3PL1), overview Mycobacterium tuberculosis H37Rv pyrazinoic acid + NH3
-
 ?
pyrazinamide + H2O
-
 Mycobacterium tuberculosis ATCC 25618 pyrazinoic acid + NH3
-
 ?
pyrazinamide + H2O enzyme protein ligand interaction, docking study using the wild-type PncA protein structure (PDB ID 3PL1), overview Mycobacterium tuberculosis ATCC 25618 pyrazinoic acid + NH3
-
 ?

Synonyms

Synonyms Comment Organism
PncA
-
 Mycobacterium tuberculosis

General Information

General Information Comment Organism
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 Mycobacterium tuberculosis
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 Mycobacterium tuberculosis
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 Mycobacterium tuberculosis
physiological function role of flap region present in PncA protein in development of resistance to the drug, molecular dynamics simulations Mycobacterium tuberculosis