Gold(I) phosphine mediated selective inhibition of lymphoid tyrosine phosphatase.
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.
Karver
Mark R
MR
University of Utah Department of Medicinal Chemistry, Salt Lake City, UT 84112, United States.
Krishnamurthy
Divya
D
Bottini
Nunzio
N
Barrios
Amy M
AM
D000595:Amino Acid Sequence; D000818:Animals; D020134:Catalytic Domain; D003545:Cysteine / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D019169:Jurkat Cells; D008024:Ligands; D008969:Molecular Sequence Data; D015394:Molecular Structure; D050607:Organogold Compounds / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011487:Protein Conformation; D054594:Protein Tyrosine Phosphatase, Non-Receptor Type 12 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment
D004791:Enzyme Inhibitors; D008024:Ligands; D050607:Organogold Compounds; C549114:bis(cyanoethyl)phenylphosphine-Au(I)Cl; D054594:Protein Tyrosine Phosphatase, Non-Receptor Type 12; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22; D003545:Cysteine