Acyl Derivatives of Glyceraldehyde-3-Phosphate Dehydrogenase

Krimsky, I.; Racker, Efraim

doi:10.1126/science.122.3164.319

Cited by 124 publications

(48 citation statements)

References 13 publications

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“…The inhibition of glucose consumption and lactate production by NEM was found to occur only after complete inhibition of GSH. Presumably, at this point NEM is free to react with sulfhydryl-containing glycolytic enzymes such as aldolase and possibly with glucose-6-phosphate dehydrogenase, or with enzymes such as 3-phosphoglyceraldehyde dehydrogenase that may require GSH as a coenzyme (44). It is tempting to postulate that the disruption of cation gradients and spherocytosis produced by NEM is related to such metabolic 7 The concentration of hemoglobin in red cells is about 5 mM.…”

Section: Fig 1 Effects Of Various Quantitiesmentioning

confidence: 99%

Effects of Sulfhydryl Inhibition on Red Blood Cells. I. Mechanism of Hemolysis*

Jacob

Jandl²

1962

J. Clin. Invest.

300

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Section: Fig 1 Effects Of Various Quantitiesmentioning

confidence: 99%

Effects of Sulfhydryl Inhibition on Red Blood Cells. I. Mechanism of Hemolysis*

Jacob

Jandl²

1962

J. Clin. Invest.

300

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“…The radioactive moiety was removed by treatment with neutral hydroxylamine. This suggests that this modification involves thioester formation between the 3-phosphoglyceroyl group and a GAPDH cysteine residue, most likely representing the acylated enzyme intermediate (52,53).…”

Section: Atp Produced By Glycolysis Is Predominantly Utilized For Vesmentioning

confidence: 99%

Glycolysis and Glutamate Accumulation into Synaptic Vesicles

Ikemoto

Bole

Ueda

2003

Journal of Biological Chemistry

173

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Glucose is the major source of brain energy and is essential for maintaining normal brain and neuronal function. Hypoglycemia causes impaired synaptic transmission. This occurs even before significant reduction in global cellular ATP concentration, and relationships among glycolysis, ATP supply, and synaptic transmission are not well understood. We demonstrate that the glycolytic enzymes glyceraldehyde phosphate dehydrogenase (GAPDH) and 3-phosphoglycerate kinase (3-PGK) are enriched in synaptic vesicles, forming a functional complex, and that synaptic vesicles are capable of accumulating the excitatory neurotransmitter glutamate by harnessing ATP produced by vesiclebound GAPDH/3-PGK at the expense of their substrates. The GAPDH inhibitor iodoacetate suppressed GAPDH/ 3-PGK-dependent, but not exogenous ATP-dependent, Glycolysis plays a vital role in maintaining normal brain function. Glucose is known to serve as the major substrate for cerebral energy under normal conditions (1). Recent evidence suggests a direct correlation between glucose utilization and cognitive function (2). Reduction of glucose levels results in pathophysiological states and abnormal electrophysiological activity; however, this occurs long before significant alteration in tissue ATP levels is detected (3-7). Substitution of pyruvate for glucose does not support normal evoked neuronal activity, although tissue ATP level returns to normal (8 -10). Abnormal synaptic transmission caused by hypoglycemia occurs in part if not entirely by a presynaptic mechanism (7,11,12). Fleck et al. (7) have shown that substantial reduction of extracellular glucose results in a decrease in stimulus-evoked Glu release, with no changes in ATP levels. These studies together suggest that glycolysis or glycolytic intermediate(s) are necessary for normal synaptic transmission independent of global cellular ATP levels.In an attempt to reveal the underlying mechanism of hypoglycemia-induced aberrant synaptic transmission, we previously explored the possibility that glycolytic intermediates could modify proteins localized in the nerve ending (13,14). 3-Phosphoglycerate (3-PG) 1 was demonstrated to stimulate phosphorylation of 155-and 72-kDa proteins. The latter was identified as glucose-1,6-bisphosphate synthetase, and 1,3-bisphosphoglycerate (1,3-BPG) was found to serve as the direct substrate for phosphorylation of this enzyme, by donating 1-phosphate. Both of these phosphorylated proteins are enriched in the synaptosomal (nerve ending preparation) as well as cell body soluble fractions, but the significance of these modifications in synaptic transmission remains unclear.In this paper, we show that the glycolytic intermediate 1,3-BPG forms an acyl-enzyme intermediate with vesicle-bound glyceraldehyde phosphate dehydrogenase (GAPDH), that vesicle-bound GAPDH exists in a complex with 3-phosphoglycerate kinase (3-PGK), and that activation of vesicle-associated GAPDH and 3-PGK is sufficient to support vesicular uptake of Glu. Glutamate is now recognized as the major ex...

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“…However, it may be of no primary importance in determining red cell destruction. Glyceraldehyde-3-phosphate dehydrogenase, which is rich in sulfhydryl groups (44), and can be inhibited by -SH binding substances, may contain glutathione as a prosthetic group (45). This enzyme occupies a vital position in red cell glycolysis, and its inactivation may lead to an overwhelming of red cell reducing systems by oxidant drugs.…”

mentioning

confidence: 99%

Oxidative Hemolysis and Precipitation of Hemoglobin. Ii. Role of Thiols in Oxidant Drug Action*

Allen¹,

Jandl²

1961

J. Clin. Invest.

203

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In a preceding report (1) it was shown that those redox compounds that cause Heinz body anemias in vivo produce a sequence of changes in vitro in solutions of crystalline hemoglobin culminating in the precipitation of hemoglobin as spherical granules. These granules appear to be identical with Heinz bodies. The sequence of changes produced in hemoglobin by these compounds includes: 1) the formation of methemoglobin, 2) an increase in electrophoretic and chromatographic mobility, 3) the appearance of irreversible hemochromes such as sulfhemoglobin and 4) frank precipitation. It was found that similar changes in hemoglobin were produced rapidly by "simple" oxidants such as ferricyanide and slowly by prolonged incubation of hemoglobin alone under oxygen. Com breakdown by acting as a hydrogen donor in the peroxidative destruction of hydrogen peroxide. The necessity for regenerating GSH in such a mechanism would conceivably explain the hypersusceptibility to the action of oxidant compounds of red cells deficient in glucose or in glucose-6-phosphate dehydrogenase (7), since in the red cell, oxidative glycolysis via the pentose phosphate pathway (8), possibly supplemented by anaerobic glycolysis (9), provides the energy for reducing glutathione. On the other hand, there are certain differences between phenylhydrazine-like compounds and hydrogen peroxide in their action on hemoglobin (1). Phenylhydrazine and related compounds appear to destroy hemoglobin through the formation of a series of oxidant derivatives which may resemble, but are not identical with, hydrogen peroxide.The following studies were conducted in order to explore the participation of thiol groups in the oxidative destruction of hemoglobin. METHODSPreparation of reagents. As described previously (1) buffered solutions of crystalline human hemoglobin were prepared by the method of Drabkin (10), and phenylhydrazine and related compounds were dissolved in isotonic (0.12 M) phosphate buffer, pH 7.4. Unless otherwise stated, glutathione,l an acid, was dissolved immediately before use in physiologic saline [since its reduced form is more stable at a low pH (11)] and was added slowly to buffered solutions of hemoglobin in amounts that did not affect the final pH of the solution. The sulfhydryl-binding compound, sodium p-chloromercuribenzoate2 (PCMB), is a base (probably existing as sodium p-hydroxymercuribenzoate) that is very poorly soluble at a physiologic pH; therefore it too was dissolved in unbuffered saline as a concentrate, which was then added slowly to buffered solutions of hemoglobin.General procedures. Methemoglobin and so-called sulfhemoglobin were measured by the Evelyn-Malloy

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Acyl Derivatives of Glyceraldehyde-3-Phosphate Dehydrogenase

Cited by 124 publications

References 13 publications

Effects of Sulfhydryl Inhibition on Red Blood Cells. I. Mechanism of Hemolysis*

Effects of Sulfhydryl Inhibition on Red Blood Cells. I. Mechanism of Hemolysis*

Glycolysis and Glutamate Accumulation into Synaptic Vesicles

Oxidative Hemolysis and Precipitation of Hemoglobin. Ii. Role of Thiols in Oxidant Drug Action*

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