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Chemical probes of protein tyrosine phosphatase activity.

机译：蛋白酪氨酸磷酸酶活性的化学探针。

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摘要

Chemical probes of PTP activity are needed to gain a more complete understanding of their involvement in many physiological pathways and disease states. Two examples of inhibitory chemical probes for PTPs are Pmp, phosphonomethylphenylalanine, and F2Pmp, phosphono(difluoromethyl)phenylalanine. These mimics were synthesized by novel routes so that they were appropriately protected for solid phase peptide synthesis. Pmp was incorporated into two peptides for CD45 and HePTP inhibition studies. F2Pmp was incorporated into nine peptides for crystallization experiments. A very useful chemical probe of PTP activity, called pCAP, was synthesized, incorporated into peptides and used as a substrate to determine PTP subsite specificity in multiply phosphorylated peptide sequences. All three of the above mentioned probes are mimics of phosphotyrosine. Nitrosylating reagents are extremely useful inhibitory chemical probes that are not based on phosphotyrosine. Sodium nitroprusside (SNP) and a peptide-based homocysteine-S-nitroso-thiol (14merHCys-NO) were found to inhibit LYP with low micromolar IC50 values. SNP inhibited by nitrosylating multiple cysteine residues while 14merHCys-NO appeared to only nitrosylate the active site cysteine residue. Due to the importance of reactive oxygen species and reactive nitrogen species in many biological processes, three chemical probes were designed and synthesized to detect these species based on a coumarin scaffold. Two probes contained boron based reporters and were effective at detecting hydrogen peroxide as well as nitric oxide, while the third contained a diamine reporter that was not effective at detecting any oxidant. The boron based probes will be useful in imaging cellular oxidants. All of these chemical probes have aided in gaining a better understanding of the regulation and activity of PTPs.
机译：需要使用PTP活性的化学探针来更全面地了解其参与许多生理途径和疾病状态。用于PTP的抑制性化学探针的两个例子是Pmp（膦酰基甲基苯丙氨酸）和F2Pmp（膦酰基（二氟甲基）苯丙氨酸）。这些模拟物是通过新颖的途径合成的，因此可以适当保护它们进行固相肽合成。将Pmp掺入两个用于CD45和HePTP抑制研究的肽中。将F2Pmp掺入九种肽中进行结晶实验。合成了一种非常有用的PTP活性化学探针pCAP，将其掺入肽中并用作确定多重磷酸化肽序列中PTP亚位特异性的底物。上述所有三种探针都是磷酸酪氨酸的模拟物。亚硝酰化试剂是非常有用的抑制化学探针，它不是基于磷酸酪氨酸的。发现硝普钠（SNP）和基于肽的高半胱氨酸-S-亚硝基硫醇（14merHCys-NO）可以抑制LYP，其微摩尔IC50值低。 SNP被亚硝化多个半胱氨酸残基抑制，而14merHCys-NO似乎仅亚硝化了活性位点的半胱氨酸残基。由于活性氧和活性氮在许多生物过程中的重要性，因此设计并合成了三种化学探针以基于香豆素支架来检测这些物种。两个探针包含基于硼的报告分子，可有效检测过氧化氢和一氧化氮，而第三个探针则包含对检测任何氧化剂均无效的二胺报告分子。硼基探针将对细胞氧化剂成像有用。所有这些化学探针都有助于更好地了解PTP的调控和活性。

著录项

  • 作者

    Hubbard, Caitlin E.;

  • 作者单位

    University of Southern California.;

  • 授予单位 University of Southern California.;
  • 学科 Chemistry Biochemistry.;Chemistry Organic.
  • 学位 Ph.D.
  • 年度 2009
  • 页码 143 p.
  • 总页数 143
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 生物化学;有机化学;
  • 关键词

  • 入库时间 2022-08-17 11:38:24

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