Functional effects of single nucleotide polymorphisms in the coding region of human N-acetyltransferase 1

Yusheng Zhu, D. W. Hein

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Genetic variants of human N-acetyltransferase 1 (NAT1) are associated with cancer and birth defects. N- and O-acetyltransferase catalytic activities, Michaelis-Menten kinetic constants (Km and Vmax) and steady-state expression levels of NAT1-specific mRNA and protein were determined for the reference NAT1*4 and variant human NAT1 haplotypes possessing single nucleotide polymorphisms (SNPs) in the open reading frame. Although none of the SNPs caused a significant effect on steady-state levels of NAT1-specific mRNA, C97T(R33stop), C190T(R64W), C559T (R187stop) and A752T(D251V) each reduced NAT1 protein level and/or N- and O-acetyltransferase catalytic activities to levels below detection. G560A(R187Q) substantially reduced NAT1 protein level and catalytic activities and increased substrate Km. The G445A(V149I), G459A(synonymous) and T640G(S214A) haplotype present in NAT1*11 significantly (P<0.05) increased NAT1 protein level and catalytic activity. Neither T21G(synonymous), T402C(synonymous), A613G(M205V), T777C(synonymous), G781A(E261K) nor A787G(I263V) significantly affected Km, catalytic activity, mRNA or protein level. These results suggest heterogeneity among slow NAT1 acetylator phenotypes.

Original languageEnglish (US)
Pages (from-to)339-348
Number of pages10
JournalPharmacogenomics Journal
Volume8
Issue number5
DOIs
StatePublished - Oct 3 2008

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Single Nucleotide Polymorphism
Acetyltransferases
Proteins
Messenger RNA
Haplotypes
N-acetyltransferase 1
Open Reading Frames
Phenotype

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Genetics
  • Pharmacology

Cite this

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title = "Functional effects of single nucleotide polymorphisms in the coding region of human N-acetyltransferase 1",
abstract = "Genetic variants of human N-acetyltransferase 1 (NAT1) are associated with cancer and birth defects. N- and O-acetyltransferase catalytic activities, Michaelis-Menten kinetic constants (Km and Vmax) and steady-state expression levels of NAT1-specific mRNA and protein were determined for the reference NAT1*4 and variant human NAT1 haplotypes possessing single nucleotide polymorphisms (SNPs) in the open reading frame. Although none of the SNPs caused a significant effect on steady-state levels of NAT1-specific mRNA, C97T(R33stop), C190T(R64W), C559T (R187stop) and A752T(D251V) each reduced NAT1 protein level and/or N- and O-acetyltransferase catalytic activities to levels below detection. G560A(R187Q) substantially reduced NAT1 protein level and catalytic activities and increased substrate Km. The G445A(V149I), G459A(synonymous) and T640G(S214A) haplotype present in NAT1*11 significantly (P<0.05) increased NAT1 protein level and catalytic activity. Neither T21G(synonymous), T402C(synonymous), A613G(M205V), T777C(synonymous), G781A(E261K) nor A787G(I263V) significantly affected Km, catalytic activity, mRNA or protein level. These results suggest heterogeneity among slow NAT1 acetylator phenotypes.",
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Functional effects of single nucleotide polymorphisms in the coding region of human N-acetyltransferase 1. / Zhu, Yusheng; Hein, D. W.

In: Pharmacogenomics Journal, Vol. 8, No. 5, 03.10.2008, p. 339-348.

Research output: Contribution to journalArticle

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