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CHEMICAL PROBES OF PROTEIN
TYROSINE PHOSPHATASE ACTIVITY
by
Caitlin E. Hubbard
A Dissertation Presented to the
FACULTY OF THE GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(CHEMISTRY)
August 2009
Copyright 2009 Caitlin E. Hubbard
Object Description
| Title | Chemical probes of protein tyrosine phosphatase activity |
| Author | Hubbard, Caitlin E. |
| Author email | caitlinh@usc.edu; cehubbard@gmail.com |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Chemistry |
| School | College of Letters, Arts and Sciences |
| Date defended/completed | 2009-06-23 |
| Date submitted | 2009 |
| Restricted until | Unrestricted |
| Date published | 2009-07-13 |
| Advisor (committee chair) | Qin, Peter |
| Advisor (committee member) |
Prakash, G. K. Surya Langen, Ralf Barrios, Amy |
| Abstract | Chemical probes of PTP activity are needed to gain a more complete understanding of their involvement in many physiological pathways and disease states. Two examples of inhibitory chemical probes for PTPs are Pmp, phosphonomethylphenylalanine, and F2Pmp, phosphono(difluoromethyl)phenylalanine. These mimics were synthesized by novel routes so that they were appropriately protected for solid phase peptide synthesis. Pmp was incorporated into two peptides for CD45 and HePTP inhibition studies. F2Pmp was incorporated into nine peptides for crystallization experiments. A very useful chemical probe of PTP activity, called pCAP, was synthesized, incorporated into peptides and used as a substrate to determine PTP subsite specificity in multiply phosphorylated peptide sequences. All three of the above mentioned probes are mimics of phosphotyrosine. Nitrosylating reagents are extremely useful inhibitory chemical probes that are not based on phosphotyrosine. Sodium nitroprusside (SNP) and a peptide-based homocysteine-S-nitroso-thiol (14merHCys-NO) were found to inhibit LYP with low micromolar IC50 values. SNP inhibited by nitrosylating multiple cysteine residues while 14merHCys-NO appeared to only nitrosylate the active site cysteine residue. Due to the importance of reactive oxygen species and reactive nitrogen species in many biological processes, three chemical probes were designed and synthesized to detect these species based on a coumarin scaffold. Two probes contained boron based reporters and were effective at detecting hydrogen peroxide as well as nitric oxide, while the third contained a diamine reporter that was not effective at detecting any oxidant. The boron based probes will be useful in imaging cellular oxidants. All of these chemical probes have aided in gaining a better understanding of the regulation and activity of PTPs. |
| Keyword | protein tyrosine phosphatases; phosphonomethyl phenylalanine; phosphono(difluoromethyl) phenylalanine; pCAP; reactive oxygen species; reactive nitrogen species; nitrosylation; LYP; PTPN22; ITAMs; phosphotyrosine mimics |
| Language | English |
| Part of collection | University of Southern California dissertations and theses |
| Publisher (of the original version) | University of Southern California |
| Place of publication (of the original version) | Los Angeles, California |
| Publisher (of the digital version) | University of Southern California. Libraries |
| Provenance | Electronically uploaded by the author |
| Type | texts |
| Legacy record ID | usctheses-m2355 |
| Rights | Hubbard, Caitlin E. |
| Repository name | Libraries, University of Southern California |
| Repository address | Los Angeles, California |
| Repository email | http://www.usc.edu/isd/libraries/services/ask_a_librarian/email/ |
| Filename | etd-Hubbard-3110 |
| Archival file | uscthesesreloadpub_Volume17/etd-Hubbard-3110.pdf |
Description
| Title | Page 1 |
| Full text | CHEMICAL PROBES OF PROTEIN TYROSINE PHOSPHATASE ACTIVITY by Caitlin E. Hubbard A Dissertation Presented to the FACULTY OF THE GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY (CHEMISTRY) August 2009 Copyright 2009 Caitlin E. Hubbard |
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