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Targeting the arginine phosphatase YwlE with a catalytic redox-based inhibitor.

Abstract：

:Protein phosphatases are critical regulators of cellular signaling in both eukaryotes and prokaryotes. The majority of protein phosphatases dephosphorylate phosphoserine/phosphothreonine or phosphotyrosine residues. Recently, however, YwlE, a member of the low-molecular weight protein tyrosine phosphatase (LMW-PTP) family, was shown to efficiently target phosphoarginine. YwlE shares several sequence motifs with this family including the C(X)4 CR(S/T) motif that is crucial for catalysis and redox regulation of the enzyme. Herein we confirm that Cys9 and Cys14 play important roles in YwlE catalysis and regulation. On the basis of these observations, we designed and synthesized a YwlE inhibitor, denoted cyc-SeCN-amidine, that irreversibly inhibits YwlE (kinact/KI = 310 M(-1) min(-1)) by inducing disulfide bond formation between the two active site cysteine residues. Interestingly, inactivation appears to be catalytic, since the compound is neither destroyed nor altered after enzyme inhibition. Although the exact mechanism of disulfide induction remains elusive, we propose several potential mechanisms accounting for the cyc-SeCN-amidine mediated inhibition of YwlE. These findings could stimulate the design of similar selenium-based compounds targeting other redox-sensitive enzymes.

journal_name

ACS Chem Biol

journal_title

ACS chemical biology

authors

Fuhrmann J,Subramanian V,Thompson PR

doi

10.1021/cb4001469

subject

Has Abstract

pub_date

2013-09-20 00:00:00

pages

2024-32

issue

9

eissn

1554-8929

issn

1554-8937

journal_volume

8

pub_type

杂志文章

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