Isoniazid (isonicotinic acid hydrazide, INH) is a first-line antitubercular drug. A catalase-peroxidase (KatGII) in M. tuberculosis oxidizes INH, generating radical intermediates. These form NAD adducts that inhibit the inhA gene product, an enzyme critical for chain elongation in mycolic acid biosynthesis, which disrupts cell wall formation. Other adducts inhibit dihydrofolate reductase, which is critical for nucleotide biosynthesis (Argyrou et al., 2006). Nitric oxide is also generated and confers antimycobaterial activity as well (Timmins, 2004).
Biodegradation of isoniazid occurs in three principle branches: acetylation, hydrolysis, and deamination. Simple acetylation occurs in Pseudomonas aeruginosa, Mycobacterium smegmatis, and Mycobacterium tuberculosis (Westwood et al., 2005). Subsequent hydrolysis by amidase has been demonstrated in rabbits (Sarich et al., 1999), but not yet in microbes. Hydrazinolysis into isonicotinate and hydrazine is carried out by Pseudomonas, Bacillus sp., and Sarcina sp. Deamination occurs in Mycobacterium bovis BCG via a catalase-peroxidase (KatG1).
Both hydrazinolysis and deamination liberate isonicotinate. Hydrazine or ammonia (Kang et al., 2005) are the respective coproducts. Hydrazine can be anaerobically degraded to dinitrogen gas in anammoxosome-containing bacteria such as Candidata brocadia anammoxidans (van Niftrik et al., 2004; Jetten et al., 2001). Isonicotinate itself is hydroxylated by Mycobacterium INA1 or Achromobacter sp. to form citrazinate (Schrader et al., 1998). Several branches may then occur. Sarcina sp. carries out a hydrolysis pathway going to aconitamide, whereby deamination leads into common intermediary metabolism (RC Gupta and OP Shukla (1979) J. Biosci. (India), 1: 223-234.). Alternatively, succinic acid semialdehyde can form via ring cleavage of citrazinate by Achromobacter D (Kaiser et al., 1996). Another branch by the same species, as well as Achromobacter 4C1, cleaves the citrazinate ring into maleamate. Pseudomonas and Arthrobacter oxydans indirectly form maleamate from citrazinate via hydroxylation to trihydroxyisonicotinate, decarboxylation to 2,3,6-trihydroxypyridine, and finally ring cleavage (Kaiser et al., 1996).
Peroxidation occurs via the catalase-peroxidase enzymes found in Mycobacterium sp. (Pierattelli et al., 2004). The radical intermediates can form at least six different NAD and NADP adducts that are not depicted in this pathway, or may stabilize into isonicotinamide or isonicotinate (Argyrou et al., 2006). There is some uncertainty regarding the catalase peroxidase enzymes, KatGI and KatGII; it is not currently agreed whether they are two subunits of one enzyme, or two separate enzymes (Menendez et al., 1997). The position of the KatG genes on the bacterial genome makes them amenable to mutation, resulting in various structure homologies. This also contributes to isoniazid resistance.
The following is a text-format isoniazid pathway map. Organisms which can initiate the pathway are given, but other organisms may also carry out later steps. Follow the links for more information on compounds or reactions. This map is also available in graphic (17k) format.
Isoniazid Isoniazid Isoniazid Isoniazid
Pseudomonas aeruginosa Pseudomonas aeruginosa PA012 Mycobacterium bovis BCG 1173P2 Mycobacterium tuberculosis H37Rv
Mycobacterium smegmatis Bacillus spp. Mycobacterium fortuitum Mycobacterium fortuitum
Mycobacterium tuberculosis Sarcina sp. | |
| | | catalase | catalase
| | | peroxidase v peroxidase
| | | |
| | isonicotinic v v
| arylamine | acid hydrazide Isonicotinamide Pyridine-4-
| N-acetyltransferase | hydrolase | carboxaldehyde
| | | acylamide
| | | amidohydrolase
| | |
| +---------------------------------+
| |
| |
| |
| |
v v
N-Acetylisoniazid Isonicotinate
|
|
|
|
| isonicotinate
| dehydrogenase
|
|
|
v
2-Hydroxyisonicotinate
|
|
|
|
| 2-hydroxy-
| isonicotinate
| dehydrogenase
|
|
citrazinate |
dehydrogenase v A
2,3,6-Trihydroxy- <----------------- Citrazinate ----------------->---------------+
isonicotinate | \ |
| | \____________ |
| | \ |
| 2,3,6-trihydroxy- | | |
| isonicotinate v B | citrazinate |
| decarboxylase | | hydrolase |
| | | |
| | | |
v C v v v
2,3,6-Trihydroxypyridine -------->-------> Maleamate cis-Aconitamide Succinic
| | | semialdehyde
| | | |
| | | |
| | | cis-aconitamide |
| | | amidase |
| | | |
| | | |
v v v v
to the Intermediary cis-Aconitate Intermediary
Nicotine Metabolism | Metabolism
Pathway (KEGG) | (KEGG)
|
|
v
Intermediary
Metabolism
(KEGG)
Page Author(s): Edward LaBelle
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