PMID- 15554709
OWN - NLM
STAT- MEDLINE
DCOM- 20050111
LR  - 20151119
IS  - 0006-2960 (Print)
IS  - 0006-2960 (Linking)
VI  - 43
IP  - 47
DP  - 2004 Nov 30
TI  - trans-Beta-nitrostyrene derivatives as slow-binding inhibitors of protein 
      tyrosine phosphatases.
PG  - 15014-21
AB  - Protein tyrosine phosphatases (PTPs) catalyze the hydrolysis of phosphotyrosyl 
      (pY) proteins to produce tyrosyl proteins and inorganic phosphate. Specific PTPs 
      inhibitors provide useful tools for studying PTP function in signal transduction 
      processes and potential treatment for human diseases such as diabetes, 
      inflammation, and cancer. In this work, trans-beta-nitrostyrene (TBNS) and its 
      derivatives are found to be slow-binding inhibitors against protein tyrosine 
      phosphatases PTP1B, SHP-1, and Yop with moderate potencies (K(I*) = 1-10 microM). 
      Competition experiments with a substrate (pNPP) and iodoacetate indicate that 
      TBNS is active site-directed. The mechanism of inhibition was investigated by 
      UV-vis absorption spectroscopy, (1)H-(13)C heteronuclear single-quantum 
      correlation NMR spectroscopy, and site-directed mutagenesis. These studies 
      suggested a mechanism in which TBNS acts a pY mimetic and binds to the PTP active 
      site to form an initial noncovalent E.I complex, followed by nucleophilic attack 
      on the TBNS nitro group by Cys-215 of PTP1B to form a reversible, covalent adduct 
      as the tighter E.I* complex. TBNS derivatives represent a new class of neutral pY 
      mimetic inhibitors of PTPs.
FAU - Park, Junguk
AU  - Park J
AD  - Department of Chemistry and Ohio State Biochemistry Program, The Ohio State 
      University, 100 West 18th Avenue, Columbus, Ohio 43210, USA.
FAU - Pei, Dehua
AU  - Pei D
LA  - eng
GR  - GM62820/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Biochemistry
JT  - Biochemistry
JID - 0370623
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Styrenes)
RN  - 5287E3OUAV (beta-nitrostyrene)
RN  - EC 3.1.3.48 (Protein Tyrosine Phosphatases)
SB  - IM
MH  - Binding Sites
MH  - Binding, Competitive/drug effects
MH  - Enzyme Inhibitors/*pharmacology
MH  - Kinetics
MH  - Models, Chemical
MH  - Molecular Structure
MH  - Mutagenesis, Insertional
MH  - Nuclear Magnetic Resonance, Biomolecular
MH  - Protein Binding
MH  - Protein Tyrosine Phosphatases/*antagonists & inhibitors/chemistry
MH  - Styrenes/chemistry/*metabolism/*pharmacology
MH  - Substrate Specificity
EDAT- 2004/11/24 09:00
MHDA- 2005/01/12 09:00
CRDT- 2004/11/24 09:00
PHST- 2004/11/24 09:00 [pubmed]
PHST- 2005/01/12 09:00 [medline]
PHST- 2004/11/24 09:00 [entrez]
AID - 10.1021/bi0486233 [doi]
PST - ppublish
SO  - Biochemistry. 2004 Nov 30;43(47):15014-21. doi: 10.1021/bi0486233.