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cAMP signaling and regulation by ph...

Laxman, Sunil.

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cAMP signaling and regulation by phosphodiesterases in trypanosomes.

紀錄類型:	書目-語言資料,印刷品 : Monograph/item
正題名/作者:	cAMP signaling and regulation by phosphodiesterases in trypanosomes./
作者:	Laxman, Sunil.
面頁冊數:	162 p.
附註:	Adviser: Joseph A. Beavo.
Contained By:	Dissertation Abstracts International67-11B.
標題:	Biology, Molecular. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3241917
ISBN:	9780542978906

cAMP signaling and regulation by phosphodiesterases in trypanosomes.
Laxman, Sunil.

cAMP signaling and regulation by phosphodiesterases in trypanosomes. - 162 p.

Adviser: Joseph A. Beavo.

Thesis (Ph.D.)--University of Washington, 2006.

Trypanosomes (T. brucei and T. cruzi) are unicellular, eukaryotic parasites causing major human diseases (sleeping sickness and Chagas disease respectively). The mechanism of cAMP signaling and regulation by phosphodiesterases is relatively unknown in these organisms. Both species appear to express two cAMP-specific Class I phosphodiesterases (PDEs) of the PDEB family. The first section of this study shows that the T. brucei TbrPDEB2 binds cAMP with high affinity and selectivity through its GAF-A domain. Additionally, binding of cAMP to the holoenzyme shows strong positive cooperativity. Point mutation of a key predicted binding site residue results in a complete loss of high affinity cAMP binding, and increases the apparent Km of the mutant enzyme for substrate, suggesting that cAMP binding to the GAF-A domain can regulate TbrPDEB2 by allowing the full activity of the enzyme to be expressed.

ISBN: 9780542978906Subjects--Topical Terms:

1017719
Biology, Molecular.

cAMP signaling and regulation by phosphodiesterases in trypanosomes.
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245 1 0 $a cAMP signaling and regulation by phosphodiesterases in trypanosomes.
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502 $a Thesis (Ph.D.)--University of Washington, 2006.
520 $a Trypanosomes (T. brucei and T. cruzi) are unicellular, eukaryotic parasites causing major human diseases (sleeping sickness and Chagas disease respectively). The mechanism of cAMP signaling and regulation by phosphodiesterases is relatively unknown in these organisms. Both species appear to express two cAMP-specific Class I phosphodiesterases (PDEs) of the PDEB family. The first section of this study shows that the T. brucei TbrPDEB2 binds cAMP with high affinity and selectivity through its GAF-A domain. Additionally, binding of cAMP to the holoenzyme shows strong positive cooperativity. Point mutation of a key predicted binding site residue results in a complete loss of high affinity cAMP binding, and increases the apparent Km of the mutant enzyme for substrate, suggesting that cAMP binding to the GAF-A domain can regulate TbrPDEB2 by allowing the full activity of the enzyme to be expressed.
520 $a The second section of this study identifies and characterizes orthologs of the T. brucei PDEB family in T. cruzi (TcrPDEB1 and TcrPDEB2). These enzymes were also found to be cAMP specific, and resistant to mammalian PDE inhibitors. Both the T. cruzi and the T. brucei PDEB2s showed significant flagellar localization. The N-terminus+GAF A domains of TcrPDEBs also bound cAMP, with differences in their binding affinity and selectivity for cAMP and cGMP compared to TbrPDEB2. Fluorescent cAMP analogs were found to be substrates for TcrPDEB and TbrPDEB, opening the possibility of using MANT-cAMP in fluorescence based PDE assays for the study of trypanosomal PDEs.
520 $a In the third section of this study we reinvestigated a putative role of cAMP in trypanosome differentiation from proliferating long forms to non-dividing stumpy forms. Using cell membrane permeable analogs of cAMP, we showed that 5'AMP/adenosine analogs are potently anti-proliferative and cause the transformation of dividing bloodstream form trypanosomes into non-dividing stumpy forms. Non-hydrolyzable cAMP analogs do not cause this same effect. This data suggests that slender to stumpy transformation in trypanosomes may not be caused by cAMP, provides future directions in understanding the signal and mechanism for this transformation, and suggests the use of similar analogs as anti-trypanosomal drugs.
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