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dc.contributor.advisorLangeland, James A., 1964-
dc.contributor.advisorStevens-Truss, Regina, 1960-
dc.contributor.authorJackson, Philip
dc.description33 p.en_US
dc.description.abstractExcess nitric oxide (NO), synthesized from L-arginine by nitric oxide synthase (NOS), has been linked to a number of pathological conditions. Inhibition of NOS is, therefore, currently a target for drug design. NOS requires binding of calmodulin (CaM), a calcium binding protein ubiquitously expressed in eukaryotes, for activity. The CaM binding site serves as an excellent target for selective inhibition of NOS because studies have demonstrated that the three isoforms of NOS, endothelial (eNOS), neuronal (nNOS), and inducible (iNOS), vary in the orientation and nature by which they bind CaM. Previous studies with wild type CaM showed that suramin, a polysulfonated naphthylurea, inhibits iNOS at lower concentrations than nNOS indicating that it discriminates among calmodulin-binding sites of NOS. This study further investigates the nature of nNOS and iNOS inhibition by suramin by testing it in the presence of CaM with mutations at calcium binding sites 1 and 3 (1Q mutant and 3Q mutant). Kinetic analysis demonstrated that the half-maximal inhibitory constant, IC 50, of suramin for iNOS with wild type CaM and 2.6 µM and 41 µM, in the presence and absence of 1 mM EDTA respectively, and with 1Q mutant CaM, was 6.9 µM and 63 µM. IC 50 of nNOS with wild type CaM was 81 µM and with 3Q mutant CaM, was 48 µM. Moreover, western analyses of nNOS and iNOS in the presence of all three CaM variations indicated that suramin disrupts NOS-CaM binding. These data suggest that suramin selectively inhibits iNOS over nNOS and that inhibition occurs by way of competition for the CaM binding site.en_US
dc.description.sponsorshipKalamazoo College Department of Chemistry. Kalamazoo, Michigan.
dc.publisherKalamazoo Collegeen_US
dc.relation.ispartofKalamazoo College Biology Senior Individualized Projects Collection
dc.relation.ispartofseriesSenior Individualized Projects. Biology;
dc.rightsU.S. copyright laws protect this material. Commercial use or distribution of this material is not permitted without prior written permission of the copyright holder.
dc.titleSuramin Selectivity Inhibits Inducible Nitric Oxide Synthase at the Calmodulin Binding Siteen_US
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  • Biology Senior Individualized Projects [1489]
    This collection includes Senior Individualized Projects (SIP's) completed in the Biology Department. Abstracts are generally available to the public, but PDF files are available only to current Kalamazoo College students, faculty, and staff.

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