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Functional genomics of C190T single nucleotide polymorphism in human N-acetyltransferase 2

Yuanqi Zhu1, Mark A Doll, David W Hein

  • 1Department of Pharmacology and Toxicology, University of Louisville School of Medicine, KY 40292, USA.

Biological Chemistry
|September 12, 2002
PubMed

Insights

The C190T (R64W) single nucleotide polymorphism (SNP) in N-acetyltransferase 2 (NAT2)*19 significantly reduces protein stability and enzymatic activity for both N- and O-acetylation, leading to a slow acetylator phenotype.

Area of Science:

  • Pharmacogenomics
  • Enzymology
  • Molecular Biology

Background:

  • N-acetyltransferase 2 (NAT2) is crucial for metabolizing drugs and carcinogens via N- and O-acetylation.
  • Genetic variations (polymorphisms) in NAT2 influence individual susceptibility to cancers and drug toxicity.
  • Single nucleotide polymorphisms (SNPs) in the NAT2 gene can alter enzyme function.

Purpose of the Study:

  • To investigate the functional impact of a newly identified NAT2 polymorphism, C190T (R64W), found in the NAT2*19 allele.
  • To determine how this specific SNP affects NAT2 protein stability, expression, and enzymatic activity.

Main Methods:

  • Recombinant NAT2*4 (reference) and NAT2*19 proteins were expressed in yeast (Schizosaccharomyces pombe).
  • Protein levels, mRNA levels, and transformation efficiency were assessed.
  • Enzymatic activities for N-acetylation (arylamine carcinogens, sulfonamide drug) and O-acetylation were measured.
  • Kinetic studies (Vmax, Km) were performed to characterize enzyme kinetics.

Main Results:

  • The C190T (R64W) SNP in NAT2*19 led to a substantial decrease in NAT2 protein level and stability.
  • Enzymatic activities for N-acetylation and O-acetylation were over 100-fold lower for NAT2*19 compared to NAT2*4.
  • Kinetic analysis revealed a reduced Vmax without significant changes in substrate Km for NAT2*19.
  • No significant reduction in transformation efficiency or mRNA level was observed.

Conclusions:

  • The NAT2*19 allele, characterized by the C190T (R64W) SNP, encodes a slow acetylator phenotype.
  • This slow acetylation phenotype is attributed to reduced protein amount and stability of the NAT2*19 allozyme.
  • The findings highlight the significant impact of specific NAT2 SNPs on drug and carcinogen metabolism.

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