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Physiological and non-physiological ...

Sempertegui Plaza, Tito S.

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Physiological and non-physiological regulation of indoleamine-2,3-dioxygenase.

紀錄類型:	書目-語言資料,印刷品 : Monograph/item
正題名/作者:	Physiological and non-physiological regulation of indoleamine-2,3-dioxygenase./
作者:	Sempertegui Plaza, Tito S.
面頁冊數:	188 p.
附註:	Source: Dissertation Abstracts International, Volume: 74-11(E), Section: B.
Contained By:	Dissertation Abstracts International74-11B(E).
標題:	Chemistry, Analytical. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3571430
ISBN:	9781303227967

Physiological and non-physiological regulation of indoleamine-2,3-dioxygenase.
Sempertegui Plaza, Tito S.

Physiological and non-physiological regulation of indoleamine-2,3-dioxygenase. - 188 p.

Source: Dissertation Abstracts International, Volume: 74-11(E), Section: B.

Thesis (Ph.D.)--Florida Atlantic University, 2013.

The heme enzyme indoleamine 2,3-dioxygenase (IDO) catalyses L-tryptophan (LTrp) oxidation along the kynurenine pathway and is a key regulator of the mammalian immune system. It's unknown if the enzyme is under redox control and the use of new potent inhibitors of IDO represents a novel therapeutic approach.

ISBN: 9781303227967Subjects--Topical Terms:

586156
Chemistry, Analytical.

Physiological and non-physiological regulation of indoleamine-2,3-dioxygenase.
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245 1 0 $a Physiological and non-physiological regulation of indoleamine-2,3-dioxygenase.
300 $a 188 p.
500 $a Source: Dissertation Abstracts International, Volume: 74-11(E), Section: B.
500 $a Adviser: Andrew Terentis.
502 $a Thesis (Ph.D.)--Florida Atlantic University, 2013.
520 $a The heme enzyme indoleamine 2,3-dioxygenase (IDO) catalyses L-tryptophan (LTrp) oxidation along the kynurenine pathway and is a key regulator of the mammalian immune system. It's unknown if the enzyme is under redox control and the use of new potent inhibitors of IDO represents a novel therapeutic approach.
520 $a We showed that H2O2 activates the peroxidase function of IDO, which induces protein oxidation. Exposure of IDO-expressing cells or recombinant human IDO (rIDO) to H2O2 inhibited dioxygenase activity, and was correlated with H2O2 consumption, compound I-mediated formation of protein-centered radicals, and altered protein structure,. All of these changes were inhibited by cyanide or free radical scavengers, and also by the presence of L-Trp which was oxidized to oxindolylalanine and kynurenine. Compound II-type, ferryl-oxo heme was detected. Peroxidase substrates enhanced rIDOmediated H2O2 consumption and attenuated protein oxidation. Also, rIDO consumed nitric oxide (NO) in the presence of H2O2. All of these reactions were inhibited by presence of L-Trp. IDO was identified as a heme peroxidase that self-inactivates dioxygenase activity by protein oxidation. Also, L-Trp protected against dioxygenase inactivation by reacting with compound I.
520 $a We demonstrated that the drug ebselen is a potent IDO inhibitor. Exposure of IDO-expressing cells and rIDO to ebselen inhibited IDO. Optical and resonance Raman spectroscopy showed that ebselen altered the heme of rIDO. Ebselen enhanced L-Trp binding and altered protein secondary structure and stability. Thiol labeling and mass spectrometry revealed that ebselen reacted covalently with cysteines and removal of ebselen with dithiothreitol reversed the effects on the heme and significantly restored activity.
520 $a It was also shown that ebselen inhibition of IDO is irreversible under experimental conditions, and that complete inactivation of IDO was achieved by addition of ebselen to all cysteine residues of IDO. Ebselen-induced protein structural changes were cumulative and time dependent. L-Trp slowed the onset of ebselen effects on IDO, and concurrent presence of cyanide and L-Trp prevented changes at the active site. The current study also identified that ebselen phenyl-substituted analogs are potent irreversible inactivators of IDO and that replacement of the phenyl group in ebselen had major effects on IDO inactivation.
590 $a School code: 0119.
650 4 $a Chemistry, Analytical. $3 586156
650 4 $a Chemistry, Biochemistry. $3 1017722
650 4 $a Biology, Physiology. $3 1017816
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710 2 $a Florida Atlantic University. $b Chemistry and Biochemistry. $3 2104659
773 0 $t Dissertation Abstracts International $g 74-11B(E).
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791 $a Ph.D.
792 $a 2013
793 $a English
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3571430