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Literature summary for 1.11.1.21 extracted from

  • Marney, M.W.; Metzger, R.P.; Hecht, D.; Valafar, F.
    Modeling the structural origins of drug resistance to isoniazid via key mutations in Mycobacterium tuberculosis catalase-peroxidase, KatG (2018), Tuberculosis, 108, 155-162 .
    View publication on PubMed
Search for more literature for 1.11.1.21

Protein Variants

Protein Variants Comment Organism
A110V naturally occuring mutation in KatG which does not cause INH resistance Mycobacterium tuberculosis
D387G naturally occuring mutation in KatG which causes INH resistance to a very high level Mycobacterium tuberculosis
G273C site-directed mutagenesis near the heme center, the mutation causes a decrease in the the volume of the catalytic center Mycobacterium tuberculosis
G316S naturally occuring mutation in KatG which does not cause INH resistance Mycobacterium tuberculosis
H97R/L200Q site-directed mutagenesis near the heme center, the mutation causes a decrease in the the volume of the catalytic center Mycobacterium tuberculosis
L499M naturally occuring mutation in KatG which does not cause INH resistance Mycobacterium tuberculosis
L587P naturally occuring mutation in KatG which does not cause INH resistance Mycobacterium tuberculosis
additional information enzyme mutants' tertiary structures analysis, detailed overview Mycobacterium tuberculosis
R385W naturally occuring mutation in KatG which causes INH resistance to a very high level Mycobacterium tuberculosis
R463L naturally occuring mutation in KatG which does not cause INH resistance Mycobacterium tuberculosis
S315G site-directed mutagenesis near the heme center, the mutation causes a decrease in the the volume of the catalytic center Mycobacterium tuberculosis
S315I site-directed mutagenesis near the heme center, the mutation causes a decrease in the the volume of the catalytic center Mycobacterium tuberculosis
S315N site-directed mutagenesis near the heme center, the mutation causes a decrease in the the volume of the catalytic center Mycobacterium tuberculosis
S315R site-directed mutagenesis near the heme center, the mutation causes a decrease in the the volume of the catalytic center Mycobacterium tuberculosis
S315T naturally occuring mutation in KatG which restricts a pathway into a catalytic heme center in the active site causing INH resistance Mycobacterium tuberculosis
S315T site-directed mutagenesis near the heme center, the mutation causes a decrease in the the volume of the catalytic center Mycobacterium tuberculosis

Metals/Ions

Metals/Ions Comment Organism Structure
Fe2+ in the heme group Mycobacterium tuberculosis

Natural Substrates/ Products (Substrates)

Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
2 H2O2 Mycobacterium tuberculosis
-
 O2 + 2 H2O
-
 ?
2 H2O2 Mycobacterium tuberculosis H37Rv
-
 O2 + 2 H2O
-
 ?
2 H2O2 Mycobacterium tuberculosis ATCC 25618
-
 O2 + 2 H2O
-
 ?
isoniazid + H2O2 Mycobacterium tuberculosis pro-drug activation ?
-
 ?
isoniazid + H2O2 Mycobacterium tuberculosis H37Rv pro-drug activation ?
-
 ?
isoniazid + H2O2 Mycobacterium tuberculosis ATCC 25618 pro-drug activation ?
-
 ?

Organism

Organism UniProt Comment Textmining
Mycobacterium tuberculosis P9WIE5
-
-
Mycobacterium tuberculosis ATCC 25618 P9WIE5
-
-
Mycobacterium tuberculosis H37Rv P9WIE5
-
-

Substrates and Products (Substrate)

Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
2 H2O2
-
 Mycobacterium tuberculosis O2 + 2 H2O
-
 ?
2 H2O2
-
 Mycobacterium tuberculosis H37Rv O2 + 2 H2O
-
 ?
2 H2O2
-
 Mycobacterium tuberculosis ATCC 25618 O2 + 2 H2O
-
 ?
isoniazid + H2O2
-
 Mycobacterium tuberculosis ?
-
 ?
isoniazid + H2O2 pro-drug activation Mycobacterium tuberculosis ?
-
 ?
isoniazid + H2O2
-
 Mycobacterium tuberculosis H37Rv ?
-
 ?
isoniazid + H2O2 pro-drug activation Mycobacterium tuberculosis H37Rv ?
-
 ?
isoniazid + H2O2
-
 Mycobacterium tuberculosis ATCC 25618 ?
-
 ?
isoniazid + H2O2 pro-drug activation Mycobacterium tuberculosis ATCC 25618 ?
-
 ?

Synonyms

Synonyms Comment Organism
KatG
-
 Mycobacterium tuberculosis
Rv1908c
-
 Mycobacterium tuberculosis

Cofactor

Cofactor Comment Organism Structure
heme
-
 Mycobacterium tuberculosis

General Information

General Information Comment Organism
malfunction resistance to INH is primarily caused by key mutations of the catalase-peroxidase, KatG, and/or promoter mutations in the inhA gene. The most frequently observed mutation involving an amino acid substitution conferring INH resistance (KatG S315T) is believed to restrict a pathway into a catalytic heme center in the active site. Effects of several mutations on the tertiary structure of KatG, focusing on conformational changes in the three channels in the protein structure, molecular dynamics study. The mutations sufficiently restrict one or more of these access channels, thus potentially preventing INH from reaching the catalytic heme, structure-based origins of INH resistance Mycobacterium tuberculosis
additional information enzyme structure homology modelling using the KtG structure (PDB ID 2CCA) as template, overview Mycobacterium tuberculosis
physiological function isoniazid (INH) is a pro-drug, that becomes activated by the endogenoous catalase-peroxidase enzyme KAtG in Mycobacterium tuberculosis. Once taken up by Mycobacterium tuberculosis, INH serves as a substrate, along with NAD+, for the KatG-catalyzed formation of nitric oxide (NO) and isonicotinyl-NAD Isonicotinyl-NAD binds to the active site of enoyl acyl carrier protein reductase, blocking fatty acid synthesis in general and the synthesis of mycolic acids, which are components of the Mycobacterium tuberculosis cell wall, in particular Mycobacterium tuberculosis