Methylglyoxal in living organisms

Kalapos, Miklös Péter

doi:10.1016/s0378-4274(99)00160-5

Cited by 449 publications

(147 citation statements)

References 186 publications

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“…Instead, we favor the idea that loss of Tpi activity, which interconverts dihydroxyacetone phosphate (DHAP) and glyceraldehyde-3-phosphate (GAP), results in elevated levels of DHAP. DHAP, in turn, spontaneously converts to methylglyoxal, a highly reactive compound that modifies proteins and DNA through the formation of advanced glycation end products (AGEs), which are deleterious to neurons and other cells (22)(23)(24)(25). We contend that enhanced AGE production is responsible for the dysfunction and death of Tpi-deficient neurons (26).…”

mentioning

confidence: 99%

wasted away , a Drosophila mutation in triosephosphate isomerase, causes paralysis, neurodegeneration, and early death

Gnerer

Kreber

Ganetzky

2006

Proc. Natl. Acad. Sci. U.S.A.

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To identify genes required for maintaining neuronal viability, we screened our collection of Drosophila temperature-sensitive paralytic mutants for those exhibiting shortened lifespan and neurodegeneration. Here, we describe the characterization of wasted away (wstd), a recessive, hypomorphic mutation that causes progressive motor impairment, vacuolar neuropathology, and severely reduced lifespan. We demonstrate that the affected gene encodes the glycolytic enzyme, triosephosphate isomerase (Tpi). Mutations causing Tpi deficiency in humans are also characterized by progressive neurological dysfunction, neurodegeneration, and early death. In Tpi-deficient flies and humans, a decrease in ATP levels did not appear to cause the observed phenotypes because ATP levels remained normal. We also found no genetic evidence that the mutant Drosophila Tpi was misfolded or involved in aberrant protein-protein associations. Instead, we favor the hypothesis that mutations in Tpi lead to an accumulation of methylglyoxal and the consequent enhanced production of advanced glycation end products, which are ultimately responsible for the death and dysfunction of Tpi-deficient neurons. Our results highlight an essential protective role of Tpi and support the idea that advanced glycation end products may also contribute to pathogenesis of other neurological disorders.advanced glycation end product

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mentioning

confidence: 99%

wasted away , a Drosophila mutation in triosephosphate isomerase, causes paralysis, neurodegeneration, and early death

Gnerer

Kreber

Ganetzky

2006

Proc. Natl. Acad. Sci. U.S.A.

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“…81 Foram identificadas três principais rotas de formação do metilglioxal in vivo (Esquema 3), quais sejam, a partir da: via glicolítica, pela decomposição espontânea da di-hidroxicetona fosfato ou sua conversão a metilglioxal pela enzima metilglioxal sintase; 82 hidroxilação da acetona, via citocromo P450IIE isoenzimas 83 e, da oxidação aeróbica de aminoacetona, catalisada por íons de metais de transição 84 ou por uma aminoxidase sensível à semicarbazida (SSAO). 85 Aminoacetona, por sua vez, é supostamente formada a partir de treonina e glicina e sua oxidação gera, além de metilglioxal, íons amônio e peróxido de hidrogênio, todos eles tóxicos a culturas de células se administrados em concentrações micro a milimolar.…”

Section: Metilglioxal Reação De Maillard E Agesunclassified

Metilglioxal: uma toxina endógena?

Sartori¹,

Bechara²

2010

Quím. Nova

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IS METHYLGLYOXAL AN ENDOGENOUS TOXIN?Methylglyoxal is a very reactive α-oxoaldehyde putatively produced by glycolysis, cytochrome P 450 -catalyzed acetone oxidation and aminoacetone oxidation. Methylglyoxal has been pointed as a substrate for the glyoxalase system ultimately energy-yielding pyruvate, but methylglyoxal is also a toxicant involved in protein aggregation and DNA modification. Controversial hypothesis on methylglyoxal as an anticancer agent, an energy-yielding glycolysis intermediates, and as a regulator of cell division have also been proposed. Methylglyoxal research focuses now on unveiling its biological properties and on the discovery of drugs capable to inhibit its toxic effects, principally in diabetes.

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“…To induce oxidative stress, the cells were treated with 4-HNE, the major toxic product of lipid peroxidation (32,33), and MGO, an ␣-oxoaldehyde produced by conversion of acetone or dihydroxyacetone phosphate (49). Expression of FALDH protected cells from oxidative stress induced by 4-HNE but not from oxidative stress induced by MGO.…”

Section: Fig 6 Faldh Gene Expression In White Adipose Tissue Of Insmentioning

confidence: 99%

Fatty Aldehyde Dehydrogenase

Demozay¹,

Rocchi²,

Más

et al. 2004

Journal of Biological Chemistry

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Phosphatidylinositol 3-kinase signaling regulates the expression of several genes involved in lipid and glucose homeostasis; deregulation of these genes may contribute to insulin resistance and progression toward type 2 diabetes. By employing RNA arbitrarily primed-PCR to search for novel phosphatidylinositol 3-kinase-regulated genes in response to insulin in isolated rat adipocytes, we identified fatty aldehyde dehydrogenase (FALDH), a key component of the detoxification pathway of aldehydes arising from lipid peroxidation events. Among these latter events are oxidative stresses associated with insulin resistance and diabetes. Upon insulin injection, FALDH mRNA expression increased in rat liver and white adipose tissue and was impaired in two models of insulin-resistant mice, db/db and high fat diet mice. FALDH mRNA levels were 4-fold decreased in streptozotocin-treated rats, suggesting that FALDH deregulation occurs both in hyperinsulinemic insulin-resistant state and hypoinsulinemic type 1 diabetes models. Moreover, insulin treatment increases FALDH activity in hepatocytes, and expression of FALDH was augmented during adipocyte differentiation. Considering the detoxifying role of FALDH, its deregulation in insulin-resistant and type 1 diabetic models may contribute to the lipid-derived oxidative stress. To assess the role of FALDH in the detoxification of oxidized lipid species, we evaluated the production of reactive oxygen species in normal versus FALDH-overexpressing adipocytes. Ectopic expression of FALDH significantly decreased reactive oxygen species production in cells treated by 4-hydroxynonenal, the major lipid peroxidation product, suggesting that FALDH protects against oxidative stress associated with lipid peroxidation. Taken together, our observations illustrate the importance of FALDH in insulin action and its deregulation in states associated with altered insulin signaling.Phosphatidylinositol 3-kinase (PI3K) 1 is a key component of the intracellular insulin signaling machinery. PI3K activation occurs after binding of the Src homology 2 domains of its p85 regulatory subunit to specific tyrosine-phosphorylated sites of the insulin receptor substrates (1, 2). By phosphorylating the D3 position of the inositol ring of phosphoinositides, PI3K generates the second messenger phosphatidylinositol 3,4,5-triphosphate (3-5) that participates in the recruitment and/or activation of downstream kinases such as 3-phosphoinositidedependent protein kinase-1, protein kinase B (PKB), and atypical protein kinases C and (3, 4). By activating these kinases, PI3K generates several insulin-dependent actions on metabolism such as glucose transport, glycogen synthesis, glycolysis, and lipogenesis. Moreover, PI3K acts by modulating the expression of a number of genes involved in lipid and glucose homeostasis, including phosphoenolpyruvate carboxykinase (5-7) and glucose-6-phosphatase (8), two enzymes that control key steps of gluconeogenesis in liver and the expression of which is repressed by insulin via activation of ...

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Methylglyoxal in living organisms

Cited by 449 publications

References 186 publications

wasted away , a Drosophila mutation in triosephosphate isomerase, causes paralysis, neurodegeneration, and early death

wasted away , a Drosophila mutation in triosephosphate isomerase, causes paralysis, neurodegeneration, and early death

Metilglioxal: uma toxina endógena?

Fatty Aldehyde Dehydrogenase

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