Human catecholamine sulfotransferase (SULT1A3) pharmacogenetics: functional genetic polymorphism.
Sulfotransferase (SULT) 1A3 catalyzes the sulfate conjugation of catecholamines and structurally related drugs. As a step toward studies of the possible contribution of inherited variation in SULT1A3 to the pathophysiology of human disease and/or variation in response to drugs related to catecholamines, we have resequenced all seven coding exons, three upstream non-coding exons, exon-intron splice junctions and the 5'-flanking region of SULT1A3 using DNA samples from 60 African-American (AA) and 60 Caucasian-American (CA) subjects. Eight single nucleotide polymorphisms (SNPs) were observed in AA and five in CA subjects, including one non-synonymous cSNP (Lys234Asn) that was observed only in AA subjects with an allele frequency of 4.2%. This change in amino acid sequence resulted in only 28 +/- 4.5% (mean +/- SEM) of the enzyme activity of the wild-type (WT) sequence after transient expression in COS-1 cells, with a parallel decrease (54 +/- 2.2% of WT) in level of SULT1A3 immunoreactive protein. Substrate kinetic studies failed to show significant differences in apparent Km values of the two allozymes for either dopamine (10.5 versus 10.2 micro m for WT and variant, respectively) or the cosubstrate 3'-phosphoadenosine 5'-phosphosulfate (0.114 versus 0.122 micro m, respectively). The decrease in level of immunoreactive protein in response to this single change in amino acid sequence was due, at least in part, to accelerated SULT1A3 degradation through a proteasome-mediated process. These observations raise the possibility of ethnic-specific inherited alterations in catecholamine sulfation in humans.
Thomae
Bianca A
BA
Department of Molecular Pharmacology & Experimental Therapeutics, Mayo Medical School-Mayo Clinic, Rochester, Minnesota 55905, USA.
Rifki
Oktay F
OF
Theobald
Michelle A
MA
Eckloff
Bruce W
BW
Wieben
Eric D
ED
Weinshilboum
Richard M
RM
D001741:Black or African American / Q000235:genetics; D000818:Animals; D015239:Arylsulfotransferase; D001483:Base Sequence; D019556:COS Cells; D002395:Catecholamines / Q000378:metabolism; D002474:Cell-Free System; D018360:Crystallography, X-Ray; D004789:Enzyme Activation / Q000235:genetics; D015870:Gene Expression; D005787:Gene Frequency; D008040:Genetic Linkage; D006239:Haplotypes; D006801:Humans; D007438:Introns / Q000235:genetics; D008969:Molecular Sequence Data; D011110:Polymorphism, Genetic / Q000235:genetics*; D017422:Sequence Analysis, DNA; D015238:Sulfotransferases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D044465:White People / Q000235:genetics
D002395:Catecholamines; D015238:Sulfotransferases; D015239:Arylsulfotransferase; C403170:monoamine-sulfating phenol sulfotransferase