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Development of neutral phosphotyrosine memetics as a protein tyrosine phosphatase inhibitor and studies on its inhibition mechanism

Park, Junguk
http://rave.ohiolink.edu/etdc/view?acc_num=osu1133278132

Abstract Details

2005, Doctor of Philosophy, Ohio State University, Chemistry.
Reversible phosphorylation of proteins on tyrosyl residues is one of the most important processes in various cellular signaling pathways. A proper level of phosphorylation is controlled by the opposing actions of protein tyrosine kinases (PTKs), and protein tyrosine phosphatases (PTPs). Thus far, a great deal of efforts was focused on development of the specific PTP inhibitor not only because it would be a useful tool for studying the physiological role of this enzyme, but also because inhibitors against PTPs could provide potential therapeutic agents. Almost all PTP inhibitors developed so far contain a negatively-charged nonhydrolyzable pY mimetic as the inhibitor core structure, although it may impede their membrane permeability. This dissertation describes the development of neutral pY mimetics as PTP inhibitors and their inhibition mechanisms. First, we have shown that peptidylaldehydes act as reversible, slow-binding inhibitors with modest potency against classical PTPs and DSPs (VH1 and VHR). The mechanism of inhibition was investigated by 1H-13C HSQC spectroscopy using Cinn-GEE specifically labeled with 13C at the aldehyde carbon and the wild type/mutant PTP1B. It was revealed that the aldehyde group of the inhibitor formed an imine/enamine adduct with the guanidine group of Arg-221 in the PTP1B active site, resulting in loss of its activity. Based on this information, we tested peptidylaldehydes aginst SH2 domains, which also contain Arg in their pY binding site. Biochemical as well as spectroscopic data showed that peptidylaldehydes also bind to SH2 domains with the same inhibition mechanism. These results strongly suggested that these aldehydes should provide a general, neutral core structure for the further development of potent, specific, and membrane permeable inhibitors against PTPs and SH2 domains.
Dehua Pei (Advisor)
Chemistry, Biochemistry
PTPs; Cinn-GEE; PTP1B; SH2; TBNS; SH2 domains; INHIBITOR

Recommended Citations

Citations

  • Park, J. (2005). Development of neutral phosphotyrosine memetics as a protein tyrosine phosphatase inhibitor and studies on its inhibition mechanism [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1133278132

    APA Style (7th edition)

  • Park, Junguk. Development of neutral phosphotyrosine memetics as a protein tyrosine phosphatase inhibitor and studies on its inhibition mechanism. 2005. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1133278132.

    MLA Style (8th edition)

  • Park, Junguk. "Development of neutral phosphotyrosine memetics as a protein tyrosine phosphatase inhibitor and studies on its inhibition mechanism." Doctoral dissertation, Ohio State University, 2005. http://rave.ohiolink.edu/etdc/view?acc_num=osu1133278132

    Chicago Manual of Style (17th edition)

osu1133278132
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© 2005, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.