Alternative titles; symbols
HGNC Approved Gene Symbol: SULT1A1
Cytogenetic location: 16p11.2 Genomic coordinates (GRCh38): 16:28,605,258-28,623,375 (from NCBI)
The SULT1A1 gene encodes a phenol sulfotransferase (STP, or PST) (EC 2.8.2.1), which catalyzes the sulfate conjugation of catecholamines and of phenolic drugs. There are 3 phenol-preferring SULT isoforms encoded by 3 genes, SULT1A1, SULT1A2 (601292), and SULT1A3 (600641), which have also been referred to as STP1, STP2, and STM, respectively. These genes are highly homologous and are located within a 120-kb region on chromosome 16p. SULT enzymes are widely distributed in human and animal tissues, including blood platelets (summary by Raftogianis et al., 1997).
Wilborn et al. (1993) cloned cDNAs encoding SULT1A1, which they called PPST, from a human liver cDNA library. The full-length cDNA encodes a deduced 295-amino acid protein with a calculated molecular mass of 34.1 kD. The rat and human proteins share 89% amino acid similarity. Northern blot analysis of human liver detected a 1.3-kb mRNA transcript.
Using PCR, Jones et al. (1995) cloned PPST from human platelet and liver cDNA libraries.
Dooley and Huang (1996) determined the genomic organization of the human SULT1A1, SULT1A2, and SULT1A3 genes. These 3 genes each have 8 exons with the initiator methionine in exon 2. All 3 colocalize on a single cosmid and have a high degree of sequence homology, suggesting that these 3 genes arose by gene duplication. Dooley and Huang (1996) stated that the previously identified PST gene sequences PPST, HPST, HAST1, and HAST2 are isolates of the SULT1A1 gene.
Wilborn et al. (1993) determined that SULT1A1 has 3 putative polyadenylation signal sequences.
By screening DNA samples from a human-hamster somatic cell hybrid panel by PCR using an oligonucleotide primer pair, Dooley et al. (1993) mapped the SULT1A1 gene to human chromosome 16p. PCR amplification on a human-mouse somatic cell hybrid panel containing defined portions of chromosome 16 showed that SULT1A1 is located proximal to the gene for protein kinase C, beta-1 polypeptide (176970), in the region 16p12.1-p11.2.
Her et al. (1996) identified a second thermostable phenol sulfotransferase, SULT1A2, which also maps to chromosome 16; see 601292. Raftogianis et al. (1996) found that the SULT1A1 gene is located approximately 45 kb 5-prime upstream from the SULT1A2 gene.
By interspecific backcross analysis, Dooley et al. (1993) mapped the mouse Sult1a1 gene to chromosome 7. Khan et al. (1995) also mapped the Sult1a1 gene to mouse chromosome 7.
Wilborn et al. (1993) observed significant increases in sulfotransferase activity toward 2 PST-specific substrates, minoxidil and 4-nitrophenol, in cytosol prepared from COS-7 cells transfected with human PPST. PPST appeared to function as a homodimer.
By assaying transfected Chinese hamster fibroblasts, Jones et al. (1995) showed that cytosolic human PPST sulfated 1-naphthol, 4-nitrophenol, and phenol. It showed lower activity with tyramine, dopamine, noradrenalin, and 17-alpha-ethinylestradiol, and had no activity toward dehydroepiandrosterone and estrone.
Kester et al. (1999) investigated sulfation of the prohormone T4, the active hormone T3, and the metabolites rT3 and 3,3-prime-diiodothyronine (3,3-prime-T2) by human liver and kidney cytosol sulfotransferases as well as by recombinant human SULT1A1 and SULT1A3. In all cases, the most preferred substrate was 3,3-prime-T2, followed by rT3, T3, and T4 (most preferred to least preferred, respectively). These results indicated similar substrate specificities for iodothyronine sulfation by native human liver and kidney sulfotransferases and recombinant SULT1A1 and SULT1A3. Of the latter, SULT1A1 clearly showed the highest affinity for iodothyronines, but it remained to be established whether SULT1A1 is the prominent isoenzyme for sulfation of thyroid hormone in human liver and kidney.
Crystal Structure
Gamage et al. (2003) solved the crystal structure of SULT1A1 to 1.9-angstrom resolution. They found that, like other SULTs, SULT1A1 formed a central 5-stranded parallel beta sheet surrounded on either side by helices. The L-shaped substrate-binding site was highly hydrophobic and accommodated 2 p-nitrophenol molecules. Kinetic analysis revealed a slight deviation from Michaelis-Menten kinetics at low concentrations of p-nitrophenol, suggestive of positive cooperativity, although higher concentrations resulted in substrate inhibition. The substrate-binding site accepted a single T2 molecule, with the 2 phenyl rings of T2 occupying each of the 2 p-nitrophenol-binding sites. The substrate 17-beta-estradiol caused a conformational change in the SULT1A1 substrate-binding site, suggesting that this rearrangement underlies the low affinity SULT1A1 shows toward this sterol.
Using molecular modeling, site-directed mutagenesis, and kinetic analysis, Barnett et al. (2004) showed that phe247 of SULT1A1 interacted with both p-nitrophenol molecules in the active site and was required for substrate inhibition.
Evidence that inheritance contributes to differences in levels of the 2 forms of the SULT1A1 enzyme in Caucasians was presented by Reveley et al. (1982), Price et al. (1988), and Van Loon and Weinshilboum (1984).
Anderson and Jackson (1984) showed that the mean basal level of platelet thermostable PST (TS PST) activity in American blacks is significantly higher than the mean basal level in whites, whereas the average platelet thermolabile PST activity does not differ significantly between the 2 groups. Anderson et al. (1988) suggested that the findings are a first step toward testing the hypothesis that inheritance may be a factor in the regulation of basal levels of activity and thermostability of platelet PST.
Raftogianis et al. (1997) identified a common variant allele of the SULT1A1 gene, termed SULT1A1*2 (rs9282861), that was uniformly associated with both very low TS PST activity and low thermal stability. The variant allele, 638G-A transition in exon 7, resulted in an arg213-to-his (R213H) substitution. The allele frequency of SULT1A1*2 in a population sample of 150 Caucasian blood donors was 0.31 (31%), indicating that approximately 9% of this population would be homozygous for that allele. Overall, Raftogianis et al. (1997) identified 13 SULT1A1 alleles encoding 4 allozymes.
Coughtrie et al. (1999) found the variant SULT1A1*2 allele at frequencies of 0.321 and 0.269 in 293 U.K. Caucasian and 52 Nigerian African individuals, respectively. This allele codes for an allozyme with low enzyme activity and stability compared to the wildtype (SULT1A1*1) enzyme. Therefore, the SULT1A1 genotype may influence susceptibility to mutagenicity following exposure to heterocyclic amines and other environmental toxins. Accordingly, Coughtrie et al. (1999) found an age-related difference in SULT1A1 genotype within the Caucasian population, with increasing incidence of SULT1A1*1 homozygosity and decreasing incidence of SULT1A1*2 homozygosity with increasing age. These findings suggested a possible association of SULT1A1*1 allozyme with protection against cell or tissue damage during aging.
Bamber et al. (2001) compared the frequency of the most common SULT1A1 alleles in 226 colorectal cancer patients and 293 previously described control patients. There was no significant difference in allele frequency between the control and cancer patient populations, nor was there a significant association with any of the clinical parameters studied, including Duke classification, differentiation, site, nodal involvement, and survival. However, when the age-related difference in allele frequency was considered, a significantly reduced risk of colorectal cancer was associated with homozygosity for SULT1A1*1 (odds ratio = 0.47) in subjects under the age of 80 years. These results suggested that the high activity SULT1A1*1 alloallele protects against dietary and/or environmental chemicals involved in the pathogenesis of colorectal cancer.
Using a quantitative multiplex PCR assay, Hebbring et al. (2007) found that 17 (4.7%) of 362 Caucasian American individuals had 1 copy of the SULT1A1 gene (i.e., a deletion) and 26% had 3 or more copies. Among 99 African Americans tested, 62 (62.6%) had 3 or more copies. The variability in the level of enzyme activity among 23 human platelet and 267 human liver samples was best explained by gene copy number differences when all sources of genetic variability, including the SULT1A1*2 allele, were considered (p less than 0.0001). Overall, these results indicated that the presence of SULT1A1 gene deletions and duplications represent the major source of variability in the metabolic activity of this enzyme.
Early studies showed the existence of 2 phenol SULT isoforms based on biochemical studies: a thermolabile, or monoamine-metabolizing (SULT1A3; 600641), form and a thermostable, or phenol-metabolizing, form (SULT1A1) (summary by Raftogianis et al., 1997).
Anderson, R. J., Jackson, B. L., Liebentritt, D. K. Human platelet thermostable phenol sulfotransferase from blacks and whites: biochemical properties and variations in thermal stability. J. Lab. Clin. Med. 112: 773-783, 1988. [PubMed: 3193032]
Anderson, R. J., Jackson, B. L. Human platelet phenol sulfotransferase: stability of two forms of the enzyme with time and presence of a racial difference. Clin. Chim. Acta 138: 186-196, 1984.
Bamber, D. E., Fryer, A. A., Strange, R. C., Elder, J. B., Deakin, M., Rajagopal, R., Fawole, A., Gilissen, R. A. H. J., Campbell, F. C., Coughtrie, M. W. H. Phenol sulphotransferase SULT1A1*1 genotype is associated with reduced risk of colorectal cancer. Pharmacogenetics 11: 679-685, 2001. [PubMed: 11692076] [Full Text: https://doi.org/10.1097/00008571-200111000-00006]
Barnett, A. C., Tsvetanov, S., Gamage, N., Martin, J. L., Duggleby, R. G., McManus, M. E. Active site mutations and substrate inhibition in human sulfotransferase 1A1 and 1A3. J. Biol. Chem. 279: 18799-18805, 2004. [PubMed: 14871892] [Full Text: https://doi.org/10.1074/jbc.M312253200]
Coughtrie, M. W. H., Gilissen, R. A. H. J., Shek, B., Strange, R. C., Fryer, A. A., Jones, P. W., Bamber, D. E. Phenol sulphotransferase SULT1A1 polymorphism : molecular diagnosis and allele frequencies in Caucasian and African populations. Biochem. J. 337: 45-49, 1999. [PubMed: 9854023]
Dooley, T. P., Huang, Z. Genomic organization and DNA sequences of two human phenol sulfotransferase genes (STP1 and STP2) on the short arm of chromosome 16. Biochem. Biophys. Res. Commun. 228: 134-140, 1996. [PubMed: 8912648] [Full Text: https://doi.org/10.1006/bbrc.1996.1628]
Dooley, T. P., Obermoeller, R. D., Leiter, E. H., Chapman, H. D., Falany, C. N., Deng, Z., Siciliano, M. J. Mapping of the phenol sulfotransferase gene (STP) to human chromosome 16p12.1-p11.2 and to mouse chromosome 7. Genomics 18: 440-443, 1993. [PubMed: 8288252] [Full Text: https://doi.org/10.1006/geno.1993.1494]
Gamage, N. U., Duggleby, R. G., Barnett, A. C., Tresillian, M., Latham, C. F., Liyou, N. E., McManus, M. E., Martin, J. L. Structure of a human carcinogen-converting enzyme, SULT1A1: structural and kinetic implications of substrate inhibition. J. Biol. Chem. 278: 7655-7662, 2003. [PubMed: 12471039] [Full Text: https://doi.org/10.1074/jbc.M207246200]
Hebbring, S. J., Adjei, A. A., Baer, J. L., Jenkins, G. D., Zhang, J., Cunningham, J. M., Schaid, D. J., Weinshilboum, R. M., Thibodeau, S. N. Human SULT1A1 gene: copy number differences and functional implications. Hum. Molec. Genet. 16: 463-470, 2007. [PubMed: 17189289] [Full Text: https://doi.org/10.1093/hmg/ddl468]
Her, C., Raftogianis, R., Weinshilboum, R. M. Human phenol sulfotransferase STP2 gene: molecular cloning, structural characterization, and chromosomal localization. Genomics 33: 409-420, 1996. [PubMed: 8661000] [Full Text: https://doi.org/10.1006/geno.1996.0216]
Jones, A. L., Hagen, M., Coughtrie, M. W. H., Roberts, R. C., Glatt, H. Human platelet phenolsulfotransferases: cDNA cloning, stable expression in V79 cells and identification of a novel allelic variant of the phenol-sulfating form. Biochem. Biophys. Res. Commun. 208: 855-862, 1995. [PubMed: 7695643] [Full Text: https://doi.org/10.1006/bbrc.1995.1414]
Kester, M. H. A., Kaptein, E., Roest, T. J., van Dijk, C. H., Tibboel, D., Meinl, W., Glatt, H., Coughtrie, M. W. H., Visser, T. J. Characterization of human iodothyronine sulfotransferases. J. Clin. Endocr. Metab. 84: 1357-1364, 1999. [PubMed: 10199779] [Full Text: https://doi.org/10.1210/jcem.84.4.5590]
Khan, A. S., Taylor, B. R., Filie, J. D., Ringer, D. P., Kozak, C. A. Rat phenol-preferring sulfotransferase genes (Stp and Stp2): localization to mouse chromosomes 7 and 17. Genomics 26: 417-419, 1995. [PubMed: 7601475] [Full Text: https://doi.org/10.1016/0888-7543(95)80233-c]
Price, R. A., Cox, N. J., Spielman, R. S., Van Loon, J., Maidak, B. L., Weinshilboum, R. M. Inheritance of human platelet thermolabile phenol sulfotransferase (TL PST) activity. Genet. Epidemiol. 5: 1-15, 1988. [PubMed: 3162891] [Full Text: https://doi.org/10.1002/gepi.1370050102]
Raftogianis, R. B., Her, C., Weinshilboum, R. M. Human phenol sulfotransferase pharmacogenetics: STP1 gene cloning and structural characterization. Pharmacogenetics 6: 473-487, 1996. [PubMed: 9014197] [Full Text: https://doi.org/10.1097/00008571-199612000-00001]
Raftogianis, R. B., Wood, T. C., Otterness, D. M., Van Loon, J. A., Weinshilboum, R. M. Phenol sulfotransferase pharmacogenetics in humans: association of common SULT1A1 alleles with TS PST phenotype. Biochem. Biophys. Res. Commun. 239: 298-304, 1997. [PubMed: 9345314] [Full Text: https://doi.org/10.1006/bbrc.1997.7466]
Reveley, A. M., Bonham Carter, S. M., Reveley, M. A., Sandler, M. A genetic study of platelet phenolsulphotransferase activity in normal and schizophrenic twins. J. Psychiat. Res. 17: 303-307, 1982. [PubMed: 6964793] [Full Text: https://doi.org/10.1016/0022-3956(82)90009-7]
Van Loon, J., Weinshilboum, R. M. Human platelet phenol sulfotransferase: familial variation in the thermal stability of the TS form. Biochem. Genet. 22: 997-1014, 1984. [PubMed: 6597720] [Full Text: https://doi.org/10.1007/BF00499627]
Wilborn, T. W., Comer, K. A., Dooley, T. P., Reardon, I. M., Heinrikson, R. L., Falany, C. N. Sequence analysis and expression of the cDNA for the phenol-sulfating form of human liver phenol sulfotransferase. Molec. Pharm. 43: 70-77, 1993. [PubMed: 8423770]