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Redox modification of the chaperonins.

Khor, Hui Koon.

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Redox modification of the chaperonins.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Redox modification of the chaperonins./
Author:	Khor, Hui Koon.
Description:	159 p.
Notes:	Source: Dissertation Abstracts International, Volume: 66-08, Section: B, page: 4206.
Contained By:	Dissertation Abstracts International66-08B.
Subject:	Chemistry, Biochemistry. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3185173
ISBN:	0542267500

Redox modification of the chaperonins.
Khor, Hui Koon.

Redox modification of the chaperonins. - 159 p.

Source: Dissertation Abstracts International, Volume: 66-08, Section: B, page: 4206.

Thesis (Ph.D.)--The University of Kansas, 2005.

GroEL is a chaperonin that functions in vivo to fold newly synthesized polypeptides as well as to bind and refold denatured proteins during stress. This protein is a suitable model for its eukaryotic, mitochondrial homolog, heat shock protein 60 (Hsp60), due to high conservation in sequence, structure and function. Several studies have suggested that these proteins impart protection during oxidative stress by being "sacrificially" oxidized in this process. To date, none of the chaperonins have had their oxidative susceptibility characterized. Evidence that GroEL is insensitive to endogenous reactive species such as nitric oxide or hydrogen peroxide, but is efficiently modified and inactivated by more reactive species such as peroxynitrite (ONOO-) and hypochlorous acid (HOCl), is provided in this work. HPLC-MS/MS methods detected the products Cys sulfonic acid, as well as Met sulfoxide, Met sulfone, 3-nitrotyrosine, and 3-chlorotyrosine. The use of Met sulfoxide reductase showed that inactivation of GroEL is reversible at low concentrations of HOCl (0.1--0.25 mM) and suggested a mechanism of disassembly and inactivation mediated by oxidation of Met111. Peroxynitrite-mediated inactivation differs from HOCl in product selectivity, and is proposed to occur through the Cys residues. Modification of Cys138 and Cys518 could modulate activity without affecting tetradecameric structure, whereas modification of Cys 458 is proposed to result in disassembly. Met267, Met 307, and Met491 possibly function as endogenous antioxidants. Under physiological conditions, GroEL is bound to ATP and/or GroES. The complete complex (GroEL/ATP/GroES) is more susceptible to inactivation by 0.25 mM HOCl. Tyr199 and Tyr203 are conserved in the chaperonins, have essential function in substrate protein binding, and are targets of oxidation in our studies. Nitration was detected in vitro using GroEL, but not detected for Hsp60 isolated from the liver of young (5-months) or old (30-months) rats. It is possible that Hsp60 nitration occurs in vivo but does not result in accumulation due to accelerated degradation. For more acute forms of oxidative stress such as inflammation of the vasculature, modified Hsp60 could be a factor in atherosclerosis by initiating an auto-immune reaction.

ISBN: 0542267500Subjects--Topical Terms:

1017722
Chemistry, Biochemistry.

Redox modification of the chaperonins.
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500 $a Source: Dissertation Abstracts International, Volume: 66-08, Section: B, page: 4206.
500 $a Chair: Christian Schoneich.
502 $a Thesis (Ph.D.)--The University of Kansas, 2005.
520 $a GroEL is a chaperonin that functions in vivo to fold newly synthesized polypeptides as well as to bind and refold denatured proteins during stress. This protein is a suitable model for its eukaryotic, mitochondrial homolog, heat shock protein 60 (Hsp60), due to high conservation in sequence, structure and function. Several studies have suggested that these proteins impart protection during oxidative stress by being "sacrificially" oxidized in this process. To date, none of the chaperonins have had their oxidative susceptibility characterized. Evidence that GroEL is insensitive to endogenous reactive species such as nitric oxide or hydrogen peroxide, but is efficiently modified and inactivated by more reactive species such as peroxynitrite (ONOO-) and hypochlorous acid (HOCl), is provided in this work. HPLC-MS/MS methods detected the products Cys sulfonic acid, as well as Met sulfoxide, Met sulfone, 3-nitrotyrosine, and 3-chlorotyrosine. The use of Met sulfoxide reductase showed that inactivation of GroEL is reversible at low concentrations of HOCl (0.1--0.25 mM) and suggested a mechanism of disassembly and inactivation mediated by oxidation of Met111. Peroxynitrite-mediated inactivation differs from HOCl in product selectivity, and is proposed to occur through the Cys residues. Modification of Cys138 and Cys518 could modulate activity without affecting tetradecameric structure, whereas modification of Cys 458 is proposed to result in disassembly. Met267, Met 307, and Met491 possibly function as endogenous antioxidants. Under physiological conditions, GroEL is bound to ATP and/or GroES. The complete complex (GroEL/ATP/GroES) is more susceptible to inactivation by 0.25 mM HOCl. Tyr199 and Tyr203 are conserved in the chaperonins, have essential function in substrate protein binding, and are targets of oxidation in our studies. Nitration was detected in vitro using GroEL, but not detected for Hsp60 isolated from the liver of young (5-months) or old (30-months) rats. It is possible that Hsp60 nitration occurs in vivo but does not result in accumulation due to accelerated degradation. For more acute forms of oxidative stress such as inflammation of the vasculature, modified Hsp60 could be a factor in atherosclerosis by initiating an auto-immune reaction.
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