GLYCOBIOLOGY OF SULFATED GLYCOCONJUGATES IN CANCER

最近，与癌症相关的糖脂和糖蛋白含有 硫酸盐残留物引起了人们的极大关注。他的存在 在这些硫酸化的糖偶联物中产生了一些非常重要的和 有趣的问题：异常的硫酸盐化是某些 恶性肿瘤；哪些类型的磺基转移酶参与了 这些磺基糖偶联物的表达？这项提案的中心是 磺糖的糖生物学，以寻求这些问题的答案 问题。我们最感兴趣的是生化方面，以及 这些研究所需的碳水化合物结构的合成。我们 建议研究不同的磺基转移酶，例如：(A)半乳糖3-O- 磺基转移酶，作用于Ga1beta1yeels3Ga1Nacalpha产生连锁的 化合物。我们已经证明了这种酶的存在 人卵巢组织和人脾的活性。(B)磺基转移酶 能够作用于Ga1beta1产生4G1cNAc和Ga1beta1产生3G1cNAc到 分别给予SE-3Ga1beta1yeelds4G1cNAc和SE-3Ga1beta1yeelds6G1cNAc。 人体结肠组织中含有这种酶。(C)6-O-磺基转移酶 参与组装6‘-磺化的Lewis(X)部分[NeuAcalpha2 得3(SE-6Ga1)Beta1得4(欧几里得3)G1cNAc]。(D) 作用于G1cNAcbeta1的磺基转移酶产生3Ga1beta1，产生一些 给SE-6G1cNAcbeta1yeelds3Ga1beta1yeeldsOMe。 我们对利用不同的肿瘤细胞系感兴趣，而且两者都是正常的 和癌变的人体组织作为筛查和 证明了磺基转移酶的存在。在这些来源中， 那些表现出明显活动的人将成为进一步 学习。我们的合成糖的硫酸盐位于不同的位置 位置(异构体硫化糖)将特别有用，因为 用于表征和分析的参比化合物 磺基转移酶产物。 磺基转移酶活性的鉴定将为我们提供新的线索 糖偶联物的生物合成途径，特别是那些 含有硫酸盐、岩藻糖和唾液酸的糖偶联物。这些研究 将为细胞的靶配体的合成提供信息- 黏附(选择素)分子。建议的成功结果 该计划将为其他重要调查开辟各种途径。

Recently, cancer-associated glycolipids and glycoproteins containing sulfate residue (or residues) have attracted much attention. The presence of these sulfated glycoconjugates raises some very important and interesting questions: Is aberrant sulfation a characteristic of certain malignancies; What type of sulfotransferases are involved in the expression of these sulfoglycoconjugates? This proposal centers at the glycobiology of sulfosaccharides in order to seek answers to these questions. Our prime interest is in the biochemical aspects, and in the synthesis of carbohydrate structures required for these studies. We propose to study different sulfotransferases such as; (a) Galactose 3-O- sulfotransferase, which acts upon Ga1beta1yields3Ga1NAcalpha yields linked compounds. We have already demonstrated the existence of this enzyme activity in human ovarian tissues and human spleen. (b) Sulfotransferase capable of acting on Ga1beta1 yields 4G1cNAc and Ga1beta1yields3G1cNAc to give SE-3Ga1beta1yields4G1cNAc and SE-3Ga1beta1yields6G1cNAc, respectively. Human colon tissues contain this enzyme. (c) 6-O-Sulfotransferase involved in the assembly of the 6'-sulfated Lewis (x) moiety [NeuAcalpha2 yields 3 (SE-6Ga1)beta1 yields4(Eucalpha1 yields 3) G1cNAc]. (d) Sulfotransferase which acts on G1cNAcbeta1 yields 3 Ga1beta1yields OMe to give SE-6G1cNAcbeta1yields3Ga1beta1yieldsOMe. We are interested in utilizing different tumor cell lines and both normal and cancerous human tissues a source material for screening and demonstrating the existence of sulfotransferase. Among these sources, those displaying appreciable activity will become candidates for further study. Our synthetic saccharides having sulfate situated at different positions (isomeric sulfated saccharides) will be particularly useful as reference compounds for the characterization and analysis of sulfotransferase product. The identification of sulfotransferase activities will shed new light on the biosynthetic pathways of glycoconjugates, especially those glycoconjugates containing sulfate, fucose and sialic acid. These studies will provide information toward the synthesis of target ligands for cell- adhesion (selectin) molecules. A successful outcome of the proposed program will open various avenues for other important investigations.