Human 3′-phosphoadenosine-5′-phosphosulfate synthetase2 (PAPSS2) pharmacogenetics

Gene cloning, resequencing and single nucleotide polymorphisms, (SNPs)

Research output: Contribution to journalArticle

Abstract

PAPS is the co-substrate for all sulfotransferase (SULT) enzymes. These enzymes catalyze the sulfate conjugation of many endogenous and exogenous compounds, including drugs and other xenobiotics. In humans, PAPS is synthesized from ATP and SO4 2- by two bifunctional PAPSS isoforms. A rare inactivating mutation within PAPSS2 results in major skeletal deformity in humans. To determine whether less striking "pharmacogenomic" variations in the PAPSS2 gene might be one factor responsible for individual differences in sulfate conjugation, we cloned PAPSS2 and "resequenced" all exons and splice junctions, as well as the core promoter using 90 Coriell Polymorphism Discovery Resource DNA samples. A total of 1 Mb of sequence was analyzed. Twenty-two SNPs were seen, including 4 non-synonymous cSNPs which altered the following amino acids: Glu10Lys, Met281Leu, Val291Met, and Arg432Lys. We also observed 4 insertions/deletions, and one sample was homozygous for an 81 bp deletion in the core promoter region. The functional significance of these polymorphisms will now be assessed by site-directed mutagenesis and transient expression.

Original languageEnglish (US)
JournalClinical Pharmacology and Therapeutics
Volume69
Issue number2
StatePublished - 2001

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Phosphoadenosine Phosphosulfate
Pharmacogenetics
Single Nucleotide Polymorphism
Organism Cloning
Sulfates
Genes
Sulfotransferases
Xenobiotics
Enzymes
Site-Directed Mutagenesis
Genetic Promoter Regions
Individuality
Exons
Protein Isoforms
Adenosine Triphosphate
Amino Acids
Mutation
DNA
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Pharmacology

Cite this

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title = "Human 3′-phosphoadenosine-5′-phosphosulfate synthetase2 (PAPSS2) pharmacogenetics: Gene cloning, resequencing and single nucleotide polymorphisms, (SNPs)",
abstract = "PAPS is the co-substrate for all sulfotransferase (SULT) enzymes. These enzymes catalyze the sulfate conjugation of many endogenous and exogenous compounds, including drugs and other xenobiotics. In humans, PAPS is synthesized from ATP and SO4 2- by two bifunctional PAPSS isoforms. A rare inactivating mutation within PAPSS2 results in major skeletal deformity in humans. To determine whether less striking {"}pharmacogenomic{"} variations in the PAPSS2 gene might be one factor responsible for individual differences in sulfate conjugation, we cloned PAPSS2 and {"}resequenced{"} all exons and splice junctions, as well as the core promoter using 90 Coriell Polymorphism Discovery Resource DNA samples. A total of 1 Mb of sequence was analyzed. Twenty-two SNPs were seen, including 4 non-synonymous cSNPs which altered the following amino acids: Glu10Lys, Met281Leu, Val291Met, and Arg432Lys. We also observed 4 insertions/deletions, and one sample was homozygous for an 81 bp deletion in the core promoter region. The functional significance of these polymorphisms will now be assessed by site-directed mutagenesis and transient expression.",
author = "Xu, {Z. H.} and Robert Freimuth and B. Eckloff and Wieben, {Eric D} and Weinshilboum, {Richard M}",
year = "2001",
language = "English (US)",
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journal = "Clinical Pharmacology and Therapeutics",
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TY - JOUR

T1 - Human 3′-phosphoadenosine-5′-phosphosulfate synthetase2 (PAPSS2) pharmacogenetics

T2 - Gene cloning, resequencing and single nucleotide polymorphisms, (SNPs)

AU - Xu, Z. H.

AU - Freimuth, Robert

AU - Eckloff, B.

AU - Wieben, Eric D

AU - Weinshilboum, Richard M

PY - 2001

Y1 - 2001

N2 - PAPS is the co-substrate for all sulfotransferase (SULT) enzymes. These enzymes catalyze the sulfate conjugation of many endogenous and exogenous compounds, including drugs and other xenobiotics. In humans, PAPS is synthesized from ATP and SO4 2- by two bifunctional PAPSS isoforms. A rare inactivating mutation within PAPSS2 results in major skeletal deformity in humans. To determine whether less striking "pharmacogenomic" variations in the PAPSS2 gene might be one factor responsible for individual differences in sulfate conjugation, we cloned PAPSS2 and "resequenced" all exons and splice junctions, as well as the core promoter using 90 Coriell Polymorphism Discovery Resource DNA samples. A total of 1 Mb of sequence was analyzed. Twenty-two SNPs were seen, including 4 non-synonymous cSNPs which altered the following amino acids: Glu10Lys, Met281Leu, Val291Met, and Arg432Lys. We also observed 4 insertions/deletions, and one sample was homozygous for an 81 bp deletion in the core promoter region. The functional significance of these polymorphisms will now be assessed by site-directed mutagenesis and transient expression.

AB - PAPS is the co-substrate for all sulfotransferase (SULT) enzymes. These enzymes catalyze the sulfate conjugation of many endogenous and exogenous compounds, including drugs and other xenobiotics. In humans, PAPS is synthesized from ATP and SO4 2- by two bifunctional PAPSS isoforms. A rare inactivating mutation within PAPSS2 results in major skeletal deformity in humans. To determine whether less striking "pharmacogenomic" variations in the PAPSS2 gene might be one factor responsible for individual differences in sulfate conjugation, we cloned PAPSS2 and "resequenced" all exons and splice junctions, as well as the core promoter using 90 Coriell Polymorphism Discovery Resource DNA samples. A total of 1 Mb of sequence was analyzed. Twenty-two SNPs were seen, including 4 non-synonymous cSNPs which altered the following amino acids: Glu10Lys, Met281Leu, Val291Met, and Arg432Lys. We also observed 4 insertions/deletions, and one sample was homozygous for an 81 bp deletion in the core promoter region. The functional significance of these polymorphisms will now be assessed by site-directed mutagenesis and transient expression.

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