University of Utah Department of Medicinal Chemistry, Salt Lake City, UT 84112, United States.
J Inorg Biochem. 2010 Mar;104(3):268-73. doi: 10.1016/j.jinorgbio.2009.12.012. Epub 2009 Dec 28.
Selective protein tyrosine phosphatase (PTP) inhibition is often difficult to achieve owing to the high degree of similarity of the catalytic domains of this family of enzymes. Selective inhibitors of the lymphoid specific tyrosine phosphatase, LYP, are of great interest due to the involvement of LYP in several autoimmune disorders. This manuscript describes a study into the mechanistic details of selective LYP inhibition by a Au(I)-phosphine complex. The complex, [Au((CH(2)CH(2)CN)(2)PPh)Cl], selectively inhibits LYP activity both in vitro and in cells, but does not inhibit other T-cell derived PTPs including the highly homologous PTP-PEST. The mode of inhibition was probed by investigating inhibition of LYP, the LYP mutant C129/231S, and PTP-PEST. Inhibition of LYP and PTP-PEST was competitive, while the LYP double mutant appeared mixed. Wild-type LYP was inhibited more potently than LYP C129/231S, indicating an important role for at least one of these residues in Au(I) binding. Coordination of Au(I) by both the active site cysteine residue as well as either Cys129 or 231 is suggested as a potential mechanism for LYP selective inhibition.
由于该酶家族的催化结构域具有高度相似性，因此选择性蛋白酪氨酸磷酸酶（PTP）抑制通常难以实现。由于淋巴特异性酪氨酸磷酸酶 LYP 参与了多种自身免疫性疾病，因此对 LYP 的选择性抑制剂的研究具有重要意义。本文描述了一种通过 Au（I）-膦配合物对选择性 LYP 抑制的机制细节研究。该配合物 [Au((CH(2)CH(2)CN)(2)PPh)Cl]，在体外和细胞内均能选择性地抑制 LYP 活性，但不能抑制其他 T 细胞衍生的 PTP，包括高度同源的 PTP-PEST。通过研究 LYP、LYP 突变体 C129/231S 和 PTP-PEST 的抑制作用，探测了抑制作用的模式。对 LYP 和 PTP-PEST 的抑制是竞争性的，而 LYP 双突变体则表现出混合性。野生型 LYP 的抑制作用比 LYP C129/231S 更强，这表明至少有一个残基在 Au（I）结合中起重要作用。Au（I）与活性位点半胱氨酸残基以及 Cys129 或 231 的配位被认为是 LYP 选择性抑制的潜在机制。
