Effects of single nucleotide polymorphisms on human N-acetyltransferase 2 structure and dynamics by molecular...

Area of Science:

• Biochemistry
• Structural Biology
• Pharmacogenomics

Background:

• Arylamine N-acetyltransferase 2 (NAT2) metabolizes drugs and carcinogens.
• NAT2 exhibits population-specific polymorphisms, leading to 'slow acetylator' phenotypes.
• Slow acetylators are linked to adverse drug reactions and cancer risk.

Purpose of the Study:

• To elucidate the structural and dynamical basis for reduced catalytic activity in NAT2 slow acetylator mutants.
• To investigate the effects of specific NAT2 polymorphisms on protein structure and function.

Main Methods:

• Multiple molecular dynamics simulations were performed on wild-type NAT2 and seven functional mutants (R64Q, I114T, D122N, L137F, Q145P, R197Q, G286E).
• Simulations analyzed structural and dynamical changes in key functional regions: catalytic triad, cofactor binding site, and substrate binding pocket.

Main Results:

• Mutations did not cause protein unfolding but reduced flexibility in specific regions (inter-domain, domain 3, 17-residue insert).
• Structural effects propagated, altering the conformation of the catalytic triad, cofactor binding site, and substrate pocket.
• All mutants exhibited similar dynamical property changes and altered electrostatic potentials compared to wild-type NAT2.

Conclusions:

• The study provides a structural explanation for the experimentally observed reduced catalytic activity and protein levels in NAT2 slow acetylator variants.
• Dynamical and structural alterations in key functional sites of NAT2 mutants underlie their impaired enzymatic function.
• Findings contribute to understanding the molecular basis of pharmacogenetic variations in drug metabolism and disease susceptibility.