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J Pharmacol Ther Res 2017 Volume 1 Issue 2
allied
academies
November 02-03, 2017 Chicago, USA
4
th
International Congress on
International Conference and Exhibition on
Drug Discovery, Designing and Development
Biochemistry, Molecular Biology: R&D
&
A
large number of studies of protein tyrosine phosphatases
(PTPases) have been directed towards drug design for
therapeutic intervention because of their critical roles in
homeostasis and disorders of metabolism. In contrast to
protein tyrosine kinases, virtually all inhibitors tested against
PTPases exhibit only competitive behavior because of
their consensus, active site sequence H/V-C-X5-R-S/T, a
condition leading to low specificity. Having identified protein
tyrosine phosphatase-1B (PTP1B) as the target enzyme of the
vanadyl (VO2+) chelate bis(acetylacetonato)oxidovanadium(IV)
[VO(acac)2 ] in cultured 3T3-L1 adipocytes [Ou et al. (2005)
J. Biol. Inorg. Chem. 10, 874-886], we have investigated the
basis of inhibition by the VO2+-chelate through steady-state
kinetic investigations of the recombinant human enzyme
(residues 1– 321). Our results differ from investigations by
others because we compared the influence of the chelate in the
presence of the synthetic substrate p-nitrophenylphosphate
(pNPP) and the phosphotyrosine-containing undecapeptide
DADEpYLIPQQG mimicking residues 988 – 998 of the epidermal
growth factor receptor, a physiologically relevant substrate. We
also compared the inhibitory behavior of VO(acac)2 to that of
two other VO2+-chelates similarly known for their capacity to
enhance cellular uptake of glucose as insulin mimetics. The
results indicate that VO(acac)2 acts as a classical uncompetitive
inhibitor in the presence of DADEpYLIPQQG but exhibits only
apparent competitive inhibition with pNPP as substrate. Because
uncompetitive inhibitors are more potent pharmacologically than
competitive inhibitors, structural characterization of the site of
uncompetitive binding of VO(acac)2 toPTP1B may provide a new
approach to design of inhibitors of high specificity for therapeutic
purposes.
Speaker Biography
Over the past 40 years at the University of Chicago, research in the Makinen lab has
been directed towards the structural basis of enzyme action. Earlier research was
focused on metalloenzymes and the application of magnetic resonance methods to
characterize active site structure and stereochemical relationships of substrate atoms
to catalytic residues in the active site in true reaction intermediates. More recent
studies have been carried out to identify the target enzymes of metal-chelates that
enhance the cellular uptake of glucose. Because some metal-chelates are associated
with the capacity to enhance preferential uptake of glucose into xenograft tumors in
small laboratory animal models, present research has been directed towards testing
their potential as pharmacologic reagents to increase sensitivity of detection of
malignant lesions by PET imaging.
e:
makinen@uchicago.eduMarvin W Makinen
The University of Chicago, USA
Inhibition of protein tyrosine phosphatase 1B
in vitro
and
in vivo