Covalent attachment of 4-hydroxynonenal to glyceraldehyde-3-phosphate dehydrogenase. A possible involvement of intra- and intermolecular cross-linking reaction.

Uchida, Kôji; Stadtman, Earl R.

doi:10.1016/s0021-9258(18)53264-6

Cited by 495 publications

(76 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In order to demonstrate the significance of GAPDH as a pharmacological target, we searched for low-molecular- weight compounds that exhibit affinity with GAPDH among the published data and found several compounds, including hydroxynonenal (HNE ). HNE is known to be capable of reacting with cysteine and histidine residues in the enzyme molecule, thus inducing its inactivation [ 27 ]. HNE was introduced into the SK-N-SH human neuroblastoma cell culture expressing Q103 linked to the marker gene EGFP .…”

Section: Resultsmentioning

confidence: 99%

Factors Affecting Aggregate Formation in Cell Models of Huntington’s Disease and Amyotrophic Lateral Sclerosis

et al. 2013

View full text Add to dashboard Cite

Most neurodegenerative pathologies stem from the formation of aggregates of mutant proteins, causing dysfunction and ultimately neuronal death. This study was aimed at elucidating the role of the protein factors that promote aggregate formation or prevent the process, respectively, glyceraldehyde-3-dehydrogenase (GAPDH) and tissue transglutaminase (tTG) and Hsp70 molecular chaperone. The siRNA technology was used to show that the inhibition of GAPDH expression leads to a 45–50% reduction in the aggregation of mutant huntingtin, with a repeat of 103 glutamine residues in a model of Huntington’s disease (HD). Similarly, the blockage of GAPDH synthesis was found for the first time to reduce the degree of aggregation of mutant superoxide dismutase 1 (G93A) in a model of amyotrophic lateral sclerosis (ALS). The treatment of cells that imitate HD and ALS with a pharmacological GAPDH inhibitor, hydroxynonenal, was also shown to reduce the amount of the aggregating material in both disease models. Tissue transglutaminase is another factor that promotes the aggregation of mutant proteins; the inhibition of its activity with cystamine was found to prevent aggregate formation of mutant huntingtin and SOD1. In order to explore the protective function of Hsp70 in the control of the aggregation of mutant huntingtin, a cell model with inducible expression of the chaperone was used. The amount and size of polyglutamine aggregates were reduced by increasing the intracellular content of Hsp70. Thus, pharmacological regulation of the function of three proteins, GAPDH, tTG, and Hsp70, can affect the pathogenesis of two significant neurodegenerative diseases.

show abstract

Section: Resultsmentioning

confidence: 99%

Factors Affecting Aggregate Formation in Cell Models of Huntington’s Disease and Amyotrophic Lateral Sclerosis

et al. 2013

View full text Add to dashboard Cite

show abstract

“…As mentioned above, 4-HNE is a highly reactive carbonyl compound that readily interacts with cysteine, histidine, and lysine residues and forms protein adducts via Michael addition or Schiff base reaction (314). Excessive 4-HNE adduct formation in the myocardium during ischemia-reperfusion injury impairs cardiac contractility (1), mitochondrial bioenergetics (116), and redox balance (154) while impairing also protein quality control (31,55) by targeting key metabolic enzymes (313) and the 26S proteasome (FIGURE 3; Ref. 75).…”

Section: Myocardial Infarction Heart Failure and Strokementioning

confidence: 99%

Targeting Aldehyde Dehydrogenase 2: New Therapeutic Opportunities

Chen

Ferreira

Gross

et al. 2014

Physiological Reviews

508

561

View full text Add to dashboard Cite

A family of detoxifying enzymes called aldehyde dehydrogenases (ALDHs) has been a subject of recent interest, as its role in detoxifying aldehydes that accumulate through metabolism and to which we are exposed from the environment has been elucidated. Although the human genome has 19 ALDH genes, one ALDH emerges as a particularly important enzyme in a variety of human pathologies. This ALDH, ALDH2, is located in the mitochondrial matrix with much known about its role in ethanol metabolism. Less known is a new body of research to be discussed in this review, suggesting that ALDH2 dysfunction may contribute to a variety of human diseases including cardiovascular diseases, diabetes, neurodegenerative diseases, stroke, and cancer. Recent studies suggest that ALDH2 dysfunction is also associated with Fanconi anemia, pain, osteoporosis, and the process of aging. Furthermore, an ALDH2 inactivating mutation (termed ALDH2*2) is the most common single point mutation in humans, and epidemiological studies suggest a correlation between this inactivating mutation and increased propensity for common human pathologies. These data together with studies in animal models and the use of new pharmacological tools that activate ALDH2 depict a new picture related to ALDH2 as a critical health-promoting enzyme.

show abstract

“…is associated with increases in lipid hydroperoxides, lipid peroxidation, and production of lipid peroxidation products such as and 4-hydroxy-2-nonenal (HNE) [62][63][64], and modification to mitochondrial protein by oxidized lipids [65,66]. HNE is a major product of lipid peroxidation that readily reacts with and inactivates protein [66][67][68][69][70]. Lipid peroxides and H 2 O 2 have been viewed primarily from the perspective of the damage they may impart.…”

Section: Journal Of Endocrinology and Thyroid Researchmentioning

confidence: 99%

Potential Role of Mitochondrial Dysfunction in Diabetic Hypertriglyceridemia

Parthasarathy¹

2017

JETR

View full text Add to dashboard Cite

Type 2 diabetes patients have increased oxidative stress and hypertriglyceridemia. We tested the hypothesis that these two are related and the latter could be the result of peroxide-mediated mitochondrial dysfunction and increased acetate production. Treatment of isolated liver mitochondria or primary hepatocytes with oxidized linoleic acid (LOOH) or hydrogen peroxide (H 2 O 2 ) resulted in a drastic decrease in activities of pyruvate dehydrogenase (PDHC), aconitase and α-ketoglutarate dehydrogenase (KDHC). In contrast, the incorporation of 14C-acetate into lipids was not affected by peroxides suggesting that fatty acid synthesis was not affected. The livers of Db/db diabetic mice showed reduced enzyme activities as compared to control non-diabetic mice. In vitro reaction of pyruvate in the presence of LOOH or H 2 O 2 showed that pyruvate was non-enzymatically converted to acetate together with the release of carbon dioxide (CO 2 ). These results show that diabetic mice may convert more pyruvate non-enzymatically into acetate in the cytoplasm in the presence of peroxides. In addition, mitochondria in diabetic state may have poor capacity to utilize acetate by TCA cycle to generate energy. Combined with the findings that peroxides did not affect acetate incorporation of acetate into fatty acids, one could expect a net increase in fatty acid triacylglycerol (TG) production.

show abstract

Covalent attachment of 4-hydroxynonenal to glyceraldehyde-3-phosphate dehydrogenase. A possible involvement of intra- and intermolecular cross-linking reaction.

Cited by 495 publications

References 29 publications

Factors Affecting Aggregate Formation in Cell Models of Huntington’s Disease and Amyotrophic Lateral Sclerosis

Factors Affecting Aggregate Formation in Cell Models of Huntington’s Disease and Amyotrophic Lateral Sclerosis

Targeting Aldehyde Dehydrogenase 2: New Therapeutic Opportunities

Potential Role of Mitochondrial Dysfunction in Diabetic Hypertriglyceridemia

Contact Info

Product

Resources

About