Human phenol sulfotransferase pharmacogenetics: STP1 * gene cloning and structural characterization

Rebecca B. Raftogianis, Chengtao Her, Richard M Weinshilboum

Research output: Contribution to journalArticle

44 Citations (Scopus)

Abstract

Sulfate conjugation catalysed by phenol sulfotransferase (PST) is an important pathway in the metabolism of many drugs. Two isoforms of PST have been characterized biochemically in human tissues - a thermostable (TS), or phenol-metabolizing (P) and a thermolabile (TL), or monoamine-metabolizing (M) form. Pharmacogenetic studies of TS and TL PST activities in the human blood platelet showed that the activities of these two isoforms were regulated by separate genetic polymorphisms. Subsequently, a series of TS PST cDNAs were cloned, and, based on sequence homology, those cDNAs could be classified as members of two separate subgroups, designated here as 'TS PST1' and 'TS PST2' - indicating the existence of three rather than two PST isoforms; TS PST1, TS PST2 and TL PST. The genes encoding TS PST2, STP2, and TL PST, STM, have been cloned, structurally characterized and mapped to chromosome 16 - the same chromosome on which the TS PST1 gene, STP1, is localized. As a step toward molecular pharmacogenetic studies of sulfate conjugation in humans, we set out to clone and structurally characterize STP1, the remaining uncharacterized human PST gene. We found that STP1 spanned approximately 4.4 kb and contained 9 exons. The first two exons, IA and IB, were identified by performing 5′-rapid amplification of cDNA ends (RACE) with human liver cDNA as template. Exons IA and IB were noncoding and represented two different cDNA 5′-untranslated region sequences. No canonical TATA box sequences were present within the 5′-flanking regions of the gene, i.e. regions flanking exons IA and IB. Finally, use of the long polymerase chain reaction made it possible to determine that STP1 is located approximately 45 kb 5′-upstream from STP2 on the short arm of human chromosome 16. Cloning and structural characterization of STP1, when combined with knowledge of the structures of STP2 and STM, will make it possible to study the molecular basis for the genetic regulation of PST activity in human tissue.

Original languageEnglish (US)
Pages (from-to)473-487
Number of pages15
JournalPharmacogenetics
Volume6
Issue number6
StatePublished - 1996

Fingerprint

Arylsulfotransferase
Pharmacogenetics
Organism Cloning
Genes
Complementary DNA
Exons
Chromosomes, Human, Pair 16
Protein Isoforms
Human Activities
Sulfates
TATA Box
5' Flanking Region
5' Untranslated Regions
Human Chromosomes
Genetic Polymorphisms
Sequence Homology
Phenol
Molecular Biology
Blood Platelets
Clone Cells

Keywords

  • Gene cloning
  • Phenol sulfotransferase
  • STP1
  • Structural characterization

ASJC Scopus subject areas

  • Genetics
  • Pharmacology, Toxicology and Pharmaceutics(all)

Cite this

Human phenol sulfotransferase pharmacogenetics : STP1 * gene cloning and structural characterization. / Raftogianis, Rebecca B.; Her, Chengtao; Weinshilboum, Richard M.

In: Pharmacogenetics, Vol. 6, No. 6, 1996, p. 473-487.

Research output: Contribution to journalArticle

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AB - Sulfate conjugation catalysed by phenol sulfotransferase (PST) is an important pathway in the metabolism of many drugs. Two isoforms of PST have been characterized biochemically in human tissues - a thermostable (TS), or phenol-metabolizing (P) and a thermolabile (TL), or monoamine-metabolizing (M) form. Pharmacogenetic studies of TS and TL PST activities in the human blood platelet showed that the activities of these two isoforms were regulated by separate genetic polymorphisms. Subsequently, a series of TS PST cDNAs were cloned, and, based on sequence homology, those cDNAs could be classified as members of two separate subgroups, designated here as 'TS PST1' and 'TS PST2' - indicating the existence of three rather than two PST isoforms; TS PST1, TS PST2 and TL PST. The genes encoding TS PST2, STP2, and TL PST, STM, have been cloned, structurally characterized and mapped to chromosome 16 - the same chromosome on which the TS PST1 gene, STP1, is localized. As a step toward molecular pharmacogenetic studies of sulfate conjugation in humans, we set out to clone and structurally characterize STP1, the remaining uncharacterized human PST gene. We found that STP1 spanned approximately 4.4 kb and contained 9 exons. The first two exons, IA and IB, were identified by performing 5′-rapid amplification of cDNA ends (RACE) with human liver cDNA as template. Exons IA and IB were noncoding and represented two different cDNA 5′-untranslated region sequences. No canonical TATA box sequences were present within the 5′-flanking regions of the gene, i.e. regions flanking exons IA and IB. Finally, use of the long polymerase chain reaction made it possible to determine that STP1 is located approximately 45 kb 5′-upstream from STP2 on the short arm of human chromosome 16. Cloning and structural characterization of STP1, when combined with knowledge of the structures of STP2 and STM, will make it possible to study the molecular basis for the genetic regulation of PST activity in human tissue.

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