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Succination of proteins by fumarate ...

University of South Carolina.

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Succination of proteins by fumarate - A novel mechanism for regulation of metabolism in diabetes and oxidative stress.

Record Type:	Language materials, printed : Monograph/item
Title/Author:	Succination of proteins by fumarate - A novel mechanism for regulation of metabolism in diabetes and oxidative stress./
Author:	Blatnik, Matthew.
Description:	221 p.
Notes:	Adviser: John W. Baynes.
Contained By:	Dissertation Abstracts International69-07B.
Subject:	Chemistry, Analytical. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3321387
ISBN:	9780549710363

Succination of proteins by fumarate - A novel mechanism for regulation of metabolism in diabetes and oxidative stress.
Blatnik, Matthew.

Succination of proteins by fumarate - A novel mechanism for regulation of metabolism in diabetes and oxidative stress. - 221 p.

Adviser: John W. Baynes.

Thesis (Ph.D.)--University of South Carolina, 2008.

Maintenance of normal blood glucose levels in diabetes depends on a complex interplay of glucose stimulated insulin secretion by pancreatic beta cells and insulin responsiveness of skeletal muscle, adipose tissue and liver. Metabolic perturbations, caused by hyperglycemia in type 1 diabetes, lead to oxidative stress and mitochondrial dysfunction. S-(2-succinyl) cysteine (2SC), the product of a Michael addition reaction between the citric acid cycle intermediate, fumarate, and protein thiols at physiological pH, increased in concert with an increase in intracellular fumarate concentration in muscle of diabetic animals.

ISBN: 9780549710363Subjects--Topical Terms:

586156
Chemistry, Analytical.

Succination of proteins by fumarate - A novel mechanism for regulation of metabolism in diabetes and oxidative stress.
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020 $a 9780549710363
035 $a (UMI)AAI3321387
035 $a AAI3321387
040 $a UMI $c UMI
100 1 $a Blatnik, Matthew. $3 1020687
245 1 0 $a Succination of proteins by fumarate - A novel mechanism for regulation of metabolism in diabetes and oxidative stress.
300 $a 221 p.
500 $a Adviser: John W. Baynes.
500 $a Source: Dissertation Abstracts International, Volume: 69-07, Section: B, page: 4150.
502 $a Thesis (Ph.D.)--University of South Carolina, 2008.
520 $a Maintenance of normal blood glucose levels in diabetes depends on a complex interplay of glucose stimulated insulin secretion by pancreatic beta cells and insulin responsiveness of skeletal muscle, adipose tissue and liver. Metabolic perturbations, caused by hyperglycemia in type 1 diabetes, lead to oxidative stress and mitochondrial dysfunction. S-(2-succinyl) cysteine (2SC), the product of a Michael addition reaction between the citric acid cycle intermediate, fumarate, and protein thiols at physiological pH, increased in concert with an increase in intracellular fumarate concentration in muscle of diabetic animals.
520 $a Fumarate, but not succinate, inactivated the glycolytic enzyme, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in vitro, in concert with formation of 2SC. Liquid chromatography/mass spectrometry (LC/MS) analysis of GAPDH tryptic peptides revealed succination of two cysteine-containing peptides (Cys-149 and Cys-244). In extracts of diabetic rat muscle, intracellular fumarate increased &sim;7-fold compared to age-matched control animals, accompanied by a &sim;5-fold increase in intracellular protein levels of 2SC. GAPDH activity also decreased (&sim;30%) in diabetic compared to control animals and correlated with 2SC formation on total intracellular protein. Analysis of GAPDH immunoprecipitates by mass spectrometry indicated that the same peptides were succinated both in vivo and in vitro.
520 $a Fumarate also inactivated bovine superoxide dismutase 1 in vitro with respect to time and fumarate concentration. Unlike GAPDH, LC/MS analysis of bSOD1 tryptic peptides revealed succination of the copper-binding residues His-46 and His-48 and not free cysteine residues. Inactivation of bovine SOD1 correlated with the loss of the unmodified His-46/48 peptide.
520 $a These studies addressed only two enzymes and their response to modification by fumarate. However, numerous enzymes and proteins are potential targets for modification by fumarate. Fumarate may serve as an endogenous electrophile that contributes to metabolic dysfunction during oxidative stress by altering protein structure and function.
590 $a School code: 0202.
650 4 $a Chemistry, Analytical. $3 586156
650 4 $a Chemistry, Biochemistry. $3 1017722
690 $a 0486
690 $a 0487
710 2 $a University of South Carolina. $3 1017477
773 0 $t Dissertation Abstracts International $g 69-07B.
790 $a 0202
790 1 0 $a Baynes, John W., $e advisor
791 $a Ph.D.
792 $a 2008
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3321387