N-acetyl transferase 2 polymorphisms associated with isoniazid pharmacodynamics: molecular features for ligand interaction.
BACKGROUND
Isoniazid is mainly metabolized by arylamine N-acetyltransferase 2 (NAT2). Rapid acetylator types have NAT2*4/*4 alleles. Intermediate acetylator types have any of the following alleles: NAT2*4/*5, *4/*6, or *4/*7. Slow acetylator types do not have the NAT2*4 allele. We examined molecular features of these NAT2 molecules.


METHODS
Structures of NAT2*5, *6, and *7 were constructed based on X-ray data of human NAT2*4 using a molecular modeling technique.


RESULTS
The NAT2*4 molecule mostly occupied a positive electrostatic potential field. Ile(114) and Arg(197), which are mutation sites of NAT2*4 to NAT2*5 and NAT2*6, were located in the peripheral part of the positive field. Gly(286), the mutation site from NAT2*4 to NAT2*7, was located near coenzyme A (CoA) in the boundary of the positive and negative fields.


CONCLUSIONS
Nonbinding energies between NAT2s and isoniazid were larger than those of CoA. Molecular polymorphism appears to influence the reactivity between NAT2 and the external ligand.
Ohkura
Kazuto
K
Faculty of Pharmacy, Chiba Institute of Science, 3 Shiomi-cho, Choshi, Chiba 288-0025, Japan. kohkura@sag.bekkoame.ne.jp
Fukino
Katsumi
K
Shinohara
Yasuo
Y
Hori
Hitoshi
H
D000595:Amino Acid Sequence; D000995:Antitubercular Agents / Q000494:pharmacology*; D001191:Arylamine N-Acetyltransferase / Q000737:chemistry / Q000235:genetics*; D005838:Genotype; D006801:Humans; D007538:Isoniazid / Q000494:pharmacology*; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011110:Polymorphism, Genetic; D055672:Static Electricity
D000995:Antitubercular Agents; D008024:Ligands; D001191:Arylamine N-Acetyltransferase; C478900:NAT2 protein, human; D007538:Isoniazid