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Biochemical Characterization of FIKK...

Osman, Khan Tanjid.

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Biochemical Characterization of FIKK Kinase from Cryptosporidium parvum and Discovery of Potent Inhibitors.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Biochemical Characterization of FIKK Kinase from Cryptosporidium parvum and Discovery of Potent Inhibitors./
Author:	Osman, Khan Tanjid.
Published:	Ann Arbor : ProQuest Dissertations & Theses, : 2016,
Description:	117 p.
Notes:	Source: Dissertation Abstracts International, Volume: 78-08(E), Section: B.
Contained By:	Dissertation Abstracts International78-08B(E).
Subject:	Biochemistry. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=10195073
ISBN:	9781369674033

Biochemical Characterization of FIKK Kinase from Cryptosporidium parvum and Discovery of Potent Inhibitors.
Osman, Khan Tanjid.

Biochemical Characterization of FIKK Kinase from Cryptosporidium parvum and Discovery of Potent Inhibitors. - Ann Arbor : ProQuest Dissertations & Theses, 2016 - 117 p.

Source: Dissertation Abstracts International, Volume: 78-08(E), Section: B.

Thesis (Ph.D.)--University of Toronto (Canada), 2016.

Cryptosporidium parasites cause serious human and animal diseases and affect millions of children worldwide. Drug discovery attempts against the parasites are insufficient and new drug targets are necessary. C. parvum harbors some unique protein kinases including one called FIKK kinase. FIKKs are parasite-specific protein kinases with distinctive sequence motifs and restricted to phylum Apicomplexa. The biochemistry and biology of the evolutionarily conserved members of the FIKK family have not been elucidated before this project. I explored the biochemical nature of the most conserved FIKK members in C. parvum and malaria causing P. falciparum, known as CpFIKK and PfFIKK8, respectively. I have identified the soluble domain boundary of the proteins and their substrate preferences, and characterized their activity in vitro. FIKKs need a &sim;40 residue extension to the predicted kinase domain to be soluble. They prefer Ser as phosphoacceptor residue flanked by Arg at the -3 and +3 positions in the substrate. Because their biological roles have not been completely elucidated, potent, selective and cell permeable inhibitors would be useful to understand the biological roles of FIKKs in parasites. Here, I report the first Cryptosporidium FIKK (CpFIKK) inhibitor and its selectivity profile. I systematically explored the structure activity relationship for CpFIKK inhibition and for selectivity against CpCDPK1. I identified 4b as a potent (IC50 = 0.2 nM) inhibitor of CpFIKK catalytic activity, and confirmed CpFIKK binding using a thermal melt assay. Minor variations of inhibitor structure led to significant change in selectivity profiles against CpCDPK1 and identified CpCDPK1 selective as well as dually acting C. parvum FIKK-CDPK1 inhibitors from the same structural class of compounds. I evaluated these CpFIKK inhibitors for inhibition of parasite growth in vitro. The observed effect in parasite growth did not correlate with CpFIKK inhibition.

ISBN: 9781369674033Subjects--Topical Terms:

518028
Biochemistry.

Biochemical Characterization of FIKK Kinase from Cryptosporidium parvum and Discovery of Potent Inhibitors.
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500 $a Source: Dissertation Abstracts International, Volume: 78-08(E), Section: B.
500 $a Advisers: Aled M. Edwards; Frank Sicheri.
502 $a Thesis (Ph.D.)--University of Toronto (Canada), 2016.
520 $a Cryptosporidium parasites cause serious human and animal diseases and affect millions of children worldwide. Drug discovery attempts against the parasites are insufficient and new drug targets are necessary. C. parvum harbors some unique protein kinases including one called FIKK kinase. FIKKs are parasite-specific protein kinases with distinctive sequence motifs and restricted to phylum Apicomplexa. The biochemistry and biology of the evolutionarily conserved members of the FIKK family have not been elucidated before this project. I explored the biochemical nature of the most conserved FIKK members in C. parvum and malaria causing P. falciparum, known as CpFIKK and PfFIKK8, respectively. I have identified the soluble domain boundary of the proteins and their substrate preferences, and characterized their activity in vitro. FIKKs need a &sim;40 residue extension to the predicted kinase domain to be soluble. They prefer Ser as phosphoacceptor residue flanked by Arg at the -3 and +3 positions in the substrate. Because their biological roles have not been completely elucidated, potent, selective and cell permeable inhibitors would be useful to understand the biological roles of FIKKs in parasites. Here, I report the first Cryptosporidium FIKK (CpFIKK) inhibitor and its selectivity profile. I systematically explored the structure activity relationship for CpFIKK inhibition and for selectivity against CpCDPK1. I identified 4b as a potent (IC50 = 0.2 nM) inhibitor of CpFIKK catalytic activity, and confirmed CpFIKK binding using a thermal melt assay. Minor variations of inhibitor structure led to significant change in selectivity profiles against CpCDPK1 and identified CpCDPK1 selective as well as dually acting C. parvum FIKK-CDPK1 inhibitors from the same structural class of compounds. I evaluated these CpFIKK inhibitors for inhibition of parasite growth in vitro. The observed effect in parasite growth did not correlate with CpFIKK inhibition.
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