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PMID: 16321804 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Review

Alpha-ketoglutarate dehydrogenase: a target and generator of oxidative stress.

Philosophical transactions of the Royal Society of London. Series B, Biological sciences ·Vol. 360 ·No. 1464 ·2005-12-29 ·Pages 2335-45

Tretter L, Adam-Vizi V

Abstract

Alpha-ketoglutarate dehydrogenase (alpha-KGDH) is a highly regulated enzyme, which could determine the metabolic flux through the Krebs cycle. It catalyses the conversion of alpha-ketoglutarate to succinyl-CoA and produces NADH directly providing electrons for the respiratory chain. alpha-KGDH is sensitive to reactive oxygen species (ROS) and inhibition of this enzyme could be critical in the metabolic deficiency induced by oxidative stress. Aconitase in the Krebs cycle is more vulnerable than alpha-KGDH to ROS but as long as alpha-KGDH is functional NADH generation in the Krebs cycle is maintained. NADH supply to the respiratory chain is limited only when alpha-KGDH is also inhibited by ROS. In addition being a key target, alpha-KGDH is able to generate ROS during its catalytic function, which is regulated by the NADH/NAD+ ratio. The pathological relevance of these two features of alpha-KGDH is discussed in this review, particularly in relation to neurodegeneration, as an impaired function of this enzyme has been found to be characteristic for several neurodegenerative diseases.

MeSH Terms
Citric Acid Cycle/physiology Humans Ketoglutarate Dehydrogenase Complex/metabolism,physiology Mitochondria/metabolism NAD/metabolism Neurodegenerative Diseases/metabolism Oxidative Stress/physiology Reactive Oxygen Species/metabolism
Chemicals
Reactive Oxygen Species NAD Ketoglutarate Dehydrogenase Complex
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Tretter Laszlo
Semmelweis University and Neurobiochemical Group, Hungarian Academy of Sciences Department of Medical Biochemistry, Szentagothai Janos Knowledge Center PO Box 262, Budapest 1444, Hungary.
Adam-Vizi Vera
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Article Info
Journal
Philosophical transactions of the Royal Society of London. Series B, Biological sciences
Abbr.
Philos Trans R Soc Lond B Biol Sci
ISSN
0962-8436
DOI
10.1098/rstb.2005.1764
Published
2005-12-29
Pages
2335-45
Language
English
Region
England
NLM ID
7503623
PMCID
PMC1569585
Subset
IM
External Links
PubMed source DOI: 10.1098/rstb.2005.1764 PMC Full Text View journal details
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