Glutamate Dehydrogenase in Human Brain: Regional Distribution and Properties

Filla, A.; Michele, G. De; Morra, Vincenzo Brescia; Palma, V.; Lauro, Andrea Di; Geronimo, G.; Campanella, G

doi:10.1111/j.1471-4159.1986.tb12985.x

Cited by 22 publications

(14 citation statements)

References 13 publications

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“…Enzyme activity in occipital cortex (n = 3) was also determined in both the presence and absence of 1 mM L-lactic acid, pH 8.0. Activity of two "control" mitochondria1 enzymes, glutamate dehydrogenase (GDH) and citrate synthase (CS), was determined by the spectrophotometric procedures of Filla et al (1986) and Coore et al ( 1 97 I), respectively, in frontal cortex of the control and AD groups. Brain pH and lactic acid levels were determined according to the procedures of Yates et al ( 1990) and Hohorst ( 1 965), respectively.…”

Section: Methodsmentioning

confidence: 99%

Brain α‐Ketoglutarate Dehydrotenase Complex Activity in Alzheimer's Disease

Mastrogiacomo

Bergeron

Kish

1993

Journal of Neurochemistry

172

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We measured the activity of the alpha-ketoglutarate dehydrogenase complex (alpha-KGDHC), a rate-limiting Krebs cycle enzyme, in postmortem brain samples from 38 controls and 30 neuropathologically confirmed Alzheimer's disease (AD) cases, in both the presence and absence of thiamine pyrophosphate (TPP), the enzyme's cofactor. Statistically significant correlations between brain pH and lactate levels and alpha-KGDHC activity in the controls were observed, suggesting an influence of agonal status on the activity of alpha-KGDHC. As compared with the controls, mean alpha-KGDHC activity, with added TPP, was significantly (p < 0.005) reduced in AD brain in frontal (-56%), temporal (-60%), and parietal (-68%) cortices, with the reductions (-25 to -53%) in the occipital cortex, hippocampus, amygdala, and caudate failing to reach statistical significance. In the absence of exogenously administered TPP, mean alpha-KGDHC activity was reduced to a slightly greater extent in all seven AD brain areas (-39 to -83%), with the reductions now reaching statistical significance in the four cerebral cortical areas and hippocampus. A statistically significant negative correlation was observed between alpha-KGDHC activity and neurofibrillary tangle count in AD parietal cortex, the brain area exhibiting the most marked reduction in enzyme activity; this suggests that the enzyme activity reduction in AD brain may be related to the disease process and severity. In each brain area examined, TPP produced a greater stimulatory effect on alpha-KGDHC activity in the AD group (23-280% mean stimulation) as compared with the controls (-4 to +50%); this TPP effect could be explained by reduced endogenous TPP levels in AD brain.(ABSTRACT TRUNCATED AT 250 WORDS)

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Section: Methodsmentioning

confidence: 99%

Brain α‐Ketoglutarate Dehydrotenase Complex Activity in Alzheimer's Disease

Mastrogiacomo

Bergeron

Kish

1993

Journal of Neurochemistry

172

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“…Our study showed that it is, however, not inhibited by hydrogen peroxide from 10 -220 M concentration. 2 GDH has been found to be widely distributed in numerous areas of the human brain (53), and it is tempting to conclude that its inhibition by sulfite is responsible for the widespread abnormal ischemic patterns in MR imaging of a patient with SO deficiency (54). We propose that the energy deficiency is the result of an inhibition of GDH with decrease in ␣-ketoglutarate and other tricarboxylic acid cycle intermediates, an overall decrease in NADH flux through the mitochondrial electron transport chain, a compromised MMP, and a decrease in ATP biosynthesis.…”

Section: Nadmentioning

confidence: 99%

A Mechanism of Sulfite Neurotoxicity

Zhang

Vincent

Halliwell

et al. 2004

Journal of Biological Chemistry

123

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Exposure of Neuro-2a and PC12 cells to micromolar concentrations of sulfite caused an increase in reactive oxygen species and a decrease in ATP. Likewise, the biosynthesis of ATP in intact rat brain mitochondria from the oxidation of glutamate was inhibited by micromolar sulfite. Glutamate-driven respiration increased the mitochondrial membrane potential (MMP), and this was abolished by sulfite but the MMP generated by oxidation of malate and succinate was not affected. The increased rate of production of NADH from exogenous NAD ؉ and glutamate added to rat brain mitochondrial extracts was inhibited by sulfite, and mitochondria preincubated with sulfite failed to reduce NAD ؉ . Glutamate dehydrogenase (GDH) in rat brain mitochondrial extract was inhibited dose-dependently by sulfite as was the activity of a purified enzyme. An increase in the K m (glutamate) and a decrease in V max resulting in an attenuation in V max /K m (glutamate) at 100 M sulfite suggest a mixed type of inhibition. However, uncompetitive inhibition was noted with decreases in both K m (NAD ؉ ) and V max , whereas V max /K m (NAD ؉ ) remained relatively constant. We propose that GDH is one target of action of sulfite, leading to a decrease in ␣-ketoglutarate and a diminished flux through the tricarboxylic acid cycle accompanied by a decrease in NADH through the mitochondrial electron transport chain, a decreased MMP, and a decrease in ATP synthesis. Because glutamate is a major metabolite in the brain, inhibition of GDH by sulfite could contribute to the severe phenotype of sulfite oxidase deficiency in human infants.

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“…Glutamate dehydrogenase (GDH) is relatively active in brain [33,34], especially in synaptic mitochondria [34] or in regions near to glutamatergic neurons [36,37], The Km of the brain enzyme for ammonia is extremely high (10-28 mA/) [38][39][40][41], but the equilibrium of the enzyme should favor the synthesis of glutamate [42].…”

Section: Glutam Ate D E Hydro Genase Reaction and Glutam Ate S Yn Th mentioning

confidence: 99%

Brain Glutamate Metabolism: Neuronal-Astroglial Relationships

Yudkoff¹,

Nissim²,

Daikhin³

et al. 1993

Dev Neurosci

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The concentration of glutamate in the brain extracellular fluid must be kept low (∼3 µM)in order to maximize the signal-to-noise ratio upon the release of glutamate from neurons. In addition, the nerve endings require a supply of glutamate precursors that will not cause depolarization. The major precursor to neuronal glutamate is glutamine, which is synthesized in astrocytes and converted to glutamate in neurons. However, glutamine is not the sole source. Alanine also might serve as a precursor to glutamate via transamination, although this reaction is relatively inactive in synaptosomes. Finally, the branched-chain amino acids, and in particular leucine, appear to be very important precursors to glutamate and glutamine in astrocytes. By providing α-NH₂ groups for the synthesis of glutamine, leucine also abets the uptake into brain of neutral amino acids, which are transported in exchange for brain glutamine. In addition, the branched-chain ketoacids are readily reaminated to the cognate amino acids, in the process consuming glutamate. Intraneuronal consumption of glutamate via ketoacid reamination might serve to buffer internal [glutamate] and to modulate the releasable pool.

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Glutamate Dehydrogenase in Human Brain: Regional Distribution and Properties

Cited by 22 publications

References 13 publications

Brain α‐Ketoglutarate Dehydrotenase Complex Activity in Alzheimer's Disease

Brain α‐Ketoglutarate Dehydrotenase Complex Activity in Alzheimer's Disease

A Mechanism of Sulfite Neurotoxicity

Brain Glutamate Metabolism: Neuronal-Astroglial Relationships

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