Analysis of Regulatory and Interaction Networks from Clusters of Co-expressed Genes - Clustering Challenges in Biological Network - page 76

tory response. A second plausible method used to interfere with the inflammatory
response would be to intervene at the level of protein-mediated enzymatic ac-
tivity. To do this, the idea of competitive inhibition could be utilized, wherein
a secondary inhibitor protein would bind to the same active site as the normal
enzyme substrate, without undergoing a reaction. This would then decrease the
total concentration of active enzymatic protein, and decrease the overall pathway
which the reaction is involved in. One example of this approach is the use of
IkB Kinase beta inhibitor to block nuclear factor kappaB-mediated inflammatory
response processes [91]. A third possible means of inhibiting inflammatory re-
sponse at the protein level, would be to implement the idea of protein suicide
inhibition. In this approach, an enzyme binds a substrate analogue and forms a
complex with it during the “normal” catalysis reaction. The catalytic step will
generate one of three reactive groups on the substrate analogue that will allow for
the irreversible inhibition: an α -or β -haloketone, a βγ unsaturated carbon, or a
βγ acetylenic carbon. Thus, as opposed to merely blocking the active site in a
reversible manner like that in competitive inhibition, this process is irreversible,
and hence makes a protein completely inactive once bound to the substrate analog.
An example of this approach is the use of petrosaspongiolides which have been
shown to have an in vitro and in vivo potent anti-inflammatory activity, mediated
by specific inhibition of secretory phospholipase A(2) (sPLA(2) enzymes) [92].

Acknowledgements

The authors acknowledge support from the National Science Foundation under
the grant NSF-BES 0519563 and the Environmental Protection Agency under the
grant EPA-GAD R 832721-010. The authors would also like to acknowledge
the critical input of Prof. F. Berthiaume (Center for Engineering in Medicine,
Harvard Medical School) and Professors R.R. Almon, D. Dubois and W.J. Jusko
(Department of Biological Sciences, SUNY Buffalo)

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