The HS3ST3A1/B1 genes encode two homologous 3-O-sulfotransferases involved in the late modification step during heparan sulfate (HS) biosynthesis. In addition to the single nucleotide polymorphisms (SNPs) rs28470223 (C > T) in the promoter region of both HS3ST3A1 and rs62636623 (Gly/Arg) in the stem region of HS3ST3B1, three missense mutations (rs62056073, rs61729712 and rs9906590) located within the catalytic sulfotransferase domain of 3-OST-B1 are linked and associated to Plasmodium falciparum parasitaemia. To ascertain the functional effects of these SNP associations, we investigated the regulatory effect of rs28470223 and characterized the enzymatic activity of the missense SNP rs61729712 (Ser279Asn) localized at proximity of the substrate binding cleft. The SNP rs28470223 results in decreased promoter activity of HS3ST3A1 in K562 cells, suggesting a reduced in vivo transcription activity of the target gene. A comparative kinetic analysis of wt HS3ST3B1 and the Ser269Asn variant (rs61729712) using a HS-derived oligosaccharide substrate reveals a slightly higher catalytic activity for the SNP variant. These genetic and enzymatic studies suggest that genetic variations in enzymes responsible of HS 3-O-sulfation can modulate their promoter and enzymatic activities and may influence P. falciparum parasitaemia.

中文翻译：

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遗传和3-酶促表征ö具有相关联的SNP磺基恶性疟原虫寄生虫血症

所述HS3ST3A1 / B1的基因编码两种同源3- ö -sulfotransferases参与硫酸乙酰肝素（HS）的生物合成过程中晚期改性步骤。除了HS3ST3B1的茎干区域中HS3ST3A1和rs62636623（Gly / Arg）的启动子区域中的单核苷酸多态性（SNP）rs28470223（C> T）之外，还有三个错义突变（rs62056073，rs61729712和rs9906590） 3-OST-B1的催化磺基转移酶结构域与恶性疟原虫连接并缔合寄生虫血症。为了确定这些SNP关联的功能作用，我们调查了rs28470223的调节作用，并表征了位于底物结合裂隙附近的错义SNP rs61729712（Ser279Asn）的酶活性。SNP rs28470223导致K562细胞中HS3ST3A1的启动子活性降低，表明靶基因的体内转录活性降低。使用HS衍生的寡糖底物对wt HS3ST3B1和Ser269Asn变体（rs61729712）进行比较动力学分析，发现该SNP变体的催化活性略高。这些遗传学和酶学研究表明，负责HS 3- O-的酶的遗传变异硫酸化可以调节其启动子和酶活性，并可能影响恶性疟原虫寄生虫血症。