Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
1998-10-07
2001-07-24
Prouty, Rebecca E. (Department: 1652)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C536S023100, C435S193000
Reexamination Certificate
active
06265561
ABSTRACT:
TECHNICAL FIELD
The invention relates to sulfotransferase nucleic acid sequence variants.
STATEMENT AS TO FEDERALLY SPONSORED RESEARCH
Funding for the work described herein was provided by the federal government, which has certain rights in the invention.
BACKGROUND OF THE INVENTION
Pharmacogenetics is the study of the role of inheritance in variation of drug response, a variation that often results from individual differences in drug metabolism. Sulfation is an important pathway in the metabolism of many neurotransmitters, hormones, drugs and other xenobiotics. Sulfate conjugation is catalyzed by members of a gene superfamily of cytosolic sulfotransferase enzymes. It was recently agreed that “SULT” will be used as an abbreviation for these enzymes. These enzymes also are known as “PSTs” in the literature. Included among the nine cytosolic SULTs presently known to be expressed in human tissues are three phenol SULTs, SULT1A1, 1A2 and 1A3, which catalyze the sulfate conjugation of many phenolic drugs and other xenobiotics.
Biochemical studies of human phenol SULTs led to the identification of two isoforms that were defined on the basis of substrate specificities, inhibitor sensitivities and thermal stabilities. A thermostable (TS), or phenol-preferring form, and a thermolabile (TL), or monoamine-preferring form, were identified. “TS PST” preferentially catalyzed the sulfation at micromolar concentrations of small planar phenols such as 4-nitrophenol and was sensitive to inhibition by 2,6-dichloro-4-nitrophenol (DCNP). “TL PST” preferentially catalyzed the sulfation of micromolar concentration of phenolic monoamines such as dopamine and was relatively insensitive to DCNP inhibition. Weinshilboum, R. M.
Fed. Proc
., 45:2223 (1986). Both of these biochemically-defined activities were expressed in a variety of human tissues including liver, brain, jejunum and blood platelets. Human platelet TS PST displayed wide individual variations, not only in level of activity, but also in thermal stability. Segregation analysis of data from family studies of human platelet TS PST showed that levels of this activity as well as individual variations in its thermal stability were controlled by genetic variation. Price, P. A. et al.,
Genetics
, 122:905-914 (1989).
Molecular genetic experiments indicated that there are three “PST genes” in the human genome, two of which, SULT1A1 (STP1) and SULT1A2 (STP2), encode proteins with TS PST-like activity, SULT1A1 (TS PST1) and SULT1A2 (TS PST2), respectively. The remaining gene, SULT1A3 (STM), encodes a protein with TL PST-like activity, SULT1A3 (TL PST). DNA sequences and structures of the genes for these enzymes are highly homologous, and all three map to a phenol SULT gene complex on the short arm of human chromosome 16. Weinshilboum, R. et al.,
FASEB J
., 11(1):3-14 (1997).
SUMMARY OF THE INVENTION
The invention is based on the discovery of several common SULT1A1 and SULT1A2 alleles encoding enzymes that differ functionally and are associated with individual differences in phenol SULT properties in platelets and liver. In addition, the invention is based on the discovery of SULT1A3 sequence variants. These discoveries permit use of SULT genomic and biochemical pharmacogenetic data to better understand the possible contribution of inheritance to individual differences in the sulfate conjugation of drugs and other xenobiotics in humans. Thus, the identification of SULT allozymes and alleles allows sulfonator status of a subject to be assessed. The information and insight obtained thereby allows tailoring of particular treatment regimens in the subject. In addition, risk estimates for hormone dependent diseases can be determined.
The invention features an isolated nucleic acid molecule including a SULT1A3 nucleic acid sequence. The sulfotransferase nucleic acid sequence includes a nucleotide sequence variant and nucleotides flanking the sequence variant. A nucleic acid construct that includes such sulfotransferase nucleic acid sequences is also described. The SULT1A3 sulfotransferase nucleic acid sequence can encode a sulfotransferase polypeptide including an amino acid sequence variant. SULT1A3 nucleotide sequence variants can be within an intron. For example, introns 4 and 6 each can include an adenine at nucleotide 69. Intron 7 can include a thymine at nucleotide 113. SULT1A3 nucleotide sequence variants can include insertion of nucleotides within intron sequences. The nucleotide sequence 5′-CAGT-3′ can be inserted, for example, within intron 3. A SULT1A3 nucleotide sequence variant also can include a guanine at nucleotide 105 of the coding sequence.
The invention also features SULT1A1 and SULT1A2 nucleotide sequence variants. The SULT1A1 nucleotide sequence variants can include, for example, a cytosine at nucleotide 138 of intron 1A or a thymine at nucleotide 34 of intron 5. A SULT1A1 variant also can include, for example, an adenine at nucleotide 57, 110, or 645 of the SULT1A1 coding sequence. The SULT1AL nucleic acid sequence can encode a sulfotransferase polypeptide having, for example, a glutamine at amino acid 37. SULT1A2 nucleotide sequence variants can include a thymine at nucleotide 78 of intron 5 or a thymine at nucleotide 9 of intron 7. The coding sequence of SULT1A2 can include a thymine of nucleotide 550. The SULT1A2 nucleic acid sequence can encode, for example a cysteine at amino acid 184.
In another aspect, the invention features a method for determining a risk estimate of a hormone disease in a patient. The method includes detecting the presence or absence of a sulfotransferase nucleotide sequence variant in a patient, and determining the risk estimate based, at least in part, on presence or absence of the variant in the patient. The hormone dependent disease can be, for example, breast cancer, prostate cancer or ovarian cancer.
The invention also features a method for determining sulfonator status in a subject. The method includes detecting the presence or absence of a sulfotransferase allozyme or nucleotide sequence variant in a subject, and determining the sulfonator status based, at least in part, on said determination.
An antibody having specific binding affinity for a sulfotransferase polypeptide is also described.
The invention also features isolated nucleic acid molecules that include a sulfotransferase nucleic acid sequence that encode a sulfotransferase allozyme. The allozyme can be selected from the group consisting of SULT1A1*4, SULT1A2*4, SULT1A2*5, and SULT1A2*6. Sulfotransferase nucleic acid sequences that include sulfotransferase alleles selected from the group consisting of SULT1A1*1, SULT1A1*2, SULT1A1*3A, SULT1A1*3B and SULT1A1*4 also are featured. In particular, the SULT1A1*1 allele can be SULT1A1*1A to SULT1A1*1K. The SULT1A2 allele can be SULT1A2*1A-1D, SULT1A2*2A-2C, SULT1A2*3A-3C or SULT1A2*4-*6.
The invention also relates to an article of manufacture that includes a substrate and an array of different sulfotransferase nucleic acid molecules immobilized on the substrate. Each of the different sulfotransferase nucleic acid molecules includes a different sulfotransferase nucleotide sequence variant and nucleotides flanking the sequence variant. The array of different sulfotransferase nucleic acid molecules can include at least two nucleotide sequence variants of SULT1A1, SULT1A2, or SULT1A3.
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used to practice the invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.
Other features and advantages of the i
Otterness Diane M.
Raftogianis Rebecca B.
Weinshilboum Richard M.
Wood Thomas C.
Fish & Richardson P.C.
Mayo Foundation for Medical Education and Research
Prouty Rebecca E.
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