Aggresome formation and pharmacogenetics: sulfotransferase 1A3 as a model system.

A common cause for pharmacogenetic alteration in drug response is genetic variation in encoded amino acid sequence. We have used the catecholamine and drug-metabolizing enzyme sulfotransferase (SULT)1A3 to create an artificial model system to study mechanisms-especially possible aggresome formation-by which genetic alteration in amino acid sequence might influence function. Specifically, we created a double variant SULT1A3 allozyme that included the naturally occurring Asn234 polymorphism plus an additional Trp172Arg mutation.

Human estrogen sulfotransferase (SULT1E1) pharmacogenomics: gene resequencing and functional genomics.

1. Estrogens are used as drugs and estrogen exposure is a risk factor for hormone-dependent diseases such as breast cancer. Sulfate conjugation is an important pathway for estrogen metabolism.

Pharmacogenetics of human 3'-phosphoadenosine 5'-phosphosulfate synthetase 1 (PAPSS1): gene resequencing, sequence variation, and functional genomics.

3'-Phosphoadenosine 5'-phosphosulfate (PAPS) is the high-energy "sulfate donor" for reactions catalyzed by sulfotransferase (SULT) enzymes. The strict requirement of SULTs for PAPS suggests that PAPS synthesis might influence the rate of sulfate conjugation. In humans, PAPS is synthesized from ATP and SO(4)(2-) by two isoforms of PAPS synthetase (PAPSS): PAPSS1 and PAPSS2.

Canine red blood cell thiopurine S-methyltransferase: companion animal pharmacogenetics.

Thiopurine S-methyltransferase (TPMT) plays an important role in the metabolism of thiopurine drugs. In humans, a common genetic polymorphism for TPMT is a major factor responsible for individual variation in the toxicity and therapeutic efficacy of these drugs. Dogs (Canis familiaris) are also treated with thiopurine drugs and, similar to humans, they display large individual variations in thiopurine toxicity and efficacy.

Human sulfotransferase SULT2A1 pharmacogenetics: genotype-to-phenotype studies.

SULT2A1 catalyzes the sulfate conjugation of dehydroepiandrosterone (DHEA) as well as other steroids. As a step toward pharmacogenetic studies, we have 'resequenced' SULT2A1 using 60 DNA samples from African-American and 60 samples from Caucasian-American subjects. All exons, splice junctions and approximately 370 bp located 5' of the site of transcription initiation were sequenced.

Catecholestrogen sulfation: possible role in carcinogenesis.

A growing body of evidence supports the hypothesis that estrogens can be carcinogens as a result of their conversion to genotoxins after biotransformation to form the catecholestrogens (CEs) 2-hydroxyestrone (2-OHE1), 2-hydroxyestradiol (2-OHE2), 4-hydroxyestrone (4-OHE1) and 4-hydroxyestradiol (4-OHE2). CEs can then undergo further metabolism to form quinones that interact with DNA to form either stable or depurinating adducts. These events could potentially be interrupted by the sulfate conjugation of both the parent estrogens and/or the CEs.

Human 3'-phosphoadenosine 5'-phosphosulfate synthetase 2 (PAPSS2) pharmacogenetics: gene resequencing, genetic polymorphisms and functional characterization of variant allozymes.

3'-Phosphoadenosine 5'-phosphosulfate (PAPS) is the sulfate donor cosubstrate for all sulfotransferase (SULT) enzymes. SULTs catalyze the sulfate conjugation of many endogenous and exogenous compounds, including drugs and other xenobiotics. In humans, PAPS is synthesized from adenosine 5'-triphosphate (ATP) and inorganic sulfate (SO2-4) by two isoforms, PAPSS1 and PAPSS2.

Histamine N-methyltransferase pharmacogenetics: association of a common functional polymorphism with asthma.

Histamine is involved in the pathophysiology of asthma, and histamine N-methyltransferase (HNMT) plays the dominant role in histamine metabolism in human bronchial epithelium. Levels of HNMT activity in human tissues are controlled, in part, by inheritance. A common C314T polymorphism within the HNMT gene results in a Thr105Ile change in encoded amino acid, and the T314 allele is associated with decreased levels of both HNMT enzymatic activity and immunoreactive protein.

Human indolethylamine N-methyltransferase: cDNA cloning and expression, gene cloning, and chromosomal localization.

Indolethylamine N-methyltransferase (INMT) catalyzes the N-methylation of tryptamine and structurally related compounds. We recently cloned and characterized the rabbit INMT cDNA and gene as a step toward cloning the cDNA and gene for this enzyme in humans. We have now used a PCR-based approach to clone a human INMT cDNA that had a 792-bp open reading frame that encoded a 263-amino-acid protein 88% identical in sequence to rabbit INMT.

Human nicotinamide N-methyltransferase pharmacogenetics: gene sequence analysis and promoter characterization.

Nicotinamide N-methyltransferase (NNMT) catalyses the N-methylation of nicotinamide and structurally related pyridines. NNMT enzymatic activity in human liver varies over a five-fold range with a bimodal frequency distribution - raising the possibility of regulation by a genetic polymorphism. We set out to characterize molecular genetic mechanisms that might be involved in the regulation of individual variation in human liver NNMT activity.

Human phenol sulfotransferases SULT1A2 and SULT1A1: genetic polymorphisms, allozyme properties, and human liver genotype-phenotype correlations.

Phenol sulfotransferases (PSTs or phenol SULTs) catalyze the sulfate conjugation of phenolic drugs, xenobiotics, and monoamines. Two human PST isoforms have been defined biochemically, a thermostable (TS), or phenol-preferring, and a thermolabile (TL), or monoamine-preferring form. Pharmacogenetic studies showed that levels of both TS PST activity and TS PST thermal stability (an indirect measure of variation in amino acid sequence) in the platelet were regulated by genetic polymorphisms.

Rabbit lung indolethylamine N-methyltransferase. cDNA and gene cloning and characterization.

Indolethylamine N-methyltransferase (INMT) catalyzes the N-methylation of tryptamine and structurally related compounds. This reaction has been studied because of its possible role in the in vivo synthesis of psychoactive compounds or neurotoxins and has been characterized biochemically in preparations of rabbit lung. Therefore, we set out to purify rabbit lung INMT, to clone and express its cDNA, and to clone and structurally characterize its gene as steps toward understanding the function and regulation of this enzyme.

Human hydroxysteroid sulfotransferase SULT2B1: two enzymes encoded by a single chromosome 19 gene.

We have cloned and characterized cDNAs that encode two human hydroxysteroid sulfotransferase (SULT) enzymes, SULT2B1a and SULT2B1b, as well as the single gene that encodes both of these enzymes. The two cDNAs differed at their 5'-termini and had 1050- and 1095-bp open reading frames that encoded 350 and 365 amino acids, respectively. The amino acid sequences encoded by these cDNAs included "signature sequences" that are conserved in all known cytosolic SULTs.

Mouse nicotinamide N-methyltransferase gene: molecular cloning, structural characterization, and chromosomal localization.

Nicotinamide N-methyltransferase (NNMT) catalyzes the N-methylation of nicotinamide and structurally related compounds. There are large strain-dependent variations in the expression of NNMT activity in mouse liver during growth and development, raising the possibility of developmental regulation of the gene. Therefore, we set out to clone and structurally characterize the mouse NNMT gene, Nnmt.

Human thiopurine methyltransferase pharmacogenetics. Kindred with a terminal exon splice junction mutation that results in loss of activity.

Thiopurine methyltransferase (TPMT) catalyzes S-methylation of thiopurine drugs such as 6-mercaptopurine. Large variations in levels of TPMT activity in human tissue can result from a common genetic polymorphism with a series of alleles for low activity. This polymorphism is an important factor responsible for large individual variations in thiopurine toxicity and therapeutic efficacy.

Mouse liver nicotinamide N-methyltransferase: cDNA cloning, expression, and nucleotide sequence polymorphisms.

Nicotinamide N-methyltransferase (NNMT) catalyzes the N-methylation of nicotinamide and structurally related compounds. We cloned mouse liver NNMT cDNA to make it possible to test the hypothesis that large differences among strains in levels of hepatic NNMT activity might be associated with strain-dependent variation in NNMT amino acid sequence. Mouse liver NNMT cDNA was 1015 nucleotides in length with a 792 nucleotide open reading frame (ORF) that was 83% identical to the nucleotide sequence of the human liver NNMT cDNA ORF.

Phenol sulfotransferase pharmacogenetics in humans: association of common SULT1A1 alleles with TS PST phenotype.

The phenol sulfotransferases (PSTs) catalyze the sulfation of both small planar phenols and phenolic monoamines. Three highly homologous PST genes, SULT1A1, SULT1A2, and SULT1A3, are known to exist in humans. The prototypic biochemical phenotype associated with the enzyme encoded by SULT1A1 is the thermal stable (TS) sulfation of 4 microM 4-nitrophenol (TS PST activity).

Human thiopurine methyltransferase pharmacogenetics: gene sequence polymorphisms.

Thiopurine methyltransferase (TPMT) catalyzes the S-methylation of thiopurine drugs. TPMT activity is regulated by a common genetic polymorphism that is associated with large individual variations in thiopurine toxicity and efficacy. We previously cloned the functional gene for human TPMT and reported a common variant allele for low enzyme activity, TPMT*3A, that contains point mutations at cDNA nucleotides 460 and 719.

Human sulfotransferase SULT1C1: cDNA cloning, tissue-specific expression, and chromosomal localization.

We have isolated and sequenced a cDNA that encodes an apparent human orthologue of a rat sulfotransferase (ST) cDNA that has been referred to as "ST1C1"-although it was recently recommended that sulfotransferase proteins and cDNAs be abbreviated "SULT." The new human cDNA was cloned from a fetal liver-spleen cDNA library and had an 888-bp open reading frame. The amino acid sequence of the protein encoded by the cDNA was 62% identical with that encoded by the rat ST1C1 cDNA and included signature sequences that are conserved in all cytosolic SULT enzymes.

Sulfation and sulfotransferases 1: Sulfotransferase molecular biology: cDNAs and genes.

Sulfotransferase (ST) enzymes catalyze the sulfate conjugation of many hormones, neurotransmitters, drugs, and xenobiotic compounds. These reactions result in enhanced renal excretion of the sulfate-conjugated reaction products, but they can also lead to the formation of "bioactivated" metabolites. ST enzymes are members of an emerging gene superfamily that presently includes phenol ST (PST), hydroxysteroid ST (HSST), and, in plants, flavonol ST (FST) "families," members of which share at least 45% amino acid sequence identity.

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

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.

Human dehydroepiandrosterone sulfotransferase pharmacogenetics: quantitative Western analysis and gene sequence polymorphisms.

Dehydroepiandrosterone sulfotransferase (DHEA ST) catalyzes the sulfation of DHEA and other hydroxysteroids. DHEA ST enzymatic activity in individual human liver biopsy samples has been shown to vary over a five-fold range, and frequency distribution histograms are bimodal, with approximately 25% of subjects included in a high activity subgroup. We set out to characterize the molecular basis for variation in human liver DHEA ST activity.