Author ORCID Identifier
https://orcid.org/0000-0002-2956-9781 : James W. Gauld
Document Type
Article
Publication Date
2015
Publication Title
ACS Catalysis
Volume
5
First Page
2195
Keywords
enzyme catalysis, quantum mechanic/molecular mechanics (QM/MM), molecular dynamics (MD) simulations, sulfenic acid, sulfenyl-amide, amide−iminol tutomerization, S···N noncovalent interaction
Last Page
2202
DOI
10.1021/cs501707h
Recommended Citation
Dokainish, Hisham Mohammed Mohammed and Gauld, James. (2015). Formation of a Stable Iminol Intermediate in the Redox Regulation Mechanism of Protein Tyrosine Phosphatase 1B (PTP1B). ACS Catalysis, 5, 2195-2202.
https://scholar.uwindsor.ca/chemistrybiochemistrypub/110
Comments
Protein tyrosine phosphatase 1B (PTP1B) is a key enzyme in a variety of physiological processes including insulin and leptin signaling. Experimentally it has been previously suggested to form an enzyme-derived sulfenylamide intermediate as a means of protecting an active site cysteinyl against overoxidation. In this study, key aspects of the mechanism by which PTP1B mediates against overoxidation of its active site cysteinyl has been examined via multiscale computational enzymology (e.g., molecular dynamics simulations and high-level hybrid quantum mechanics/molecular mechanics). Several possible initial reactive complexes containing an active site sulfenic acid (oxidized cysteinyl) were considered, as well as possible reaction pathways and intermediates. Importantly, the only enzymatically feasible mechanism for formation of a putative sulfenyl-amide intermediate occurs via a stepwise pathway. The only feasible mechanism was found to occur in a stepwise fashion, in which a stable iminol intermediate is formed. This step has an activation energy of 48.6 kJ mol−1 . Later, a much more stable iminol intermediate is formed in which a noncovalent electrostatic interaction of the sulfenic acid sulfur antibonding orbital with the iminol nitrogen lone pair was found to occur. Subsequently, a cyclic sulfenyl-amide is formed with a concomitant proton transfer from Glu115 to the sulfenic acid oxygen. Our results suggest that Glu115 and His214 play a crucial role in the mechanism. These results could contribute to the discovery of PTP1B inhibitors and the stabilization of the enzyme oxidized form.