Lactate dehydrogenase glucose oxidation

Many dehydrogenase enzymes catalyze oxidation/reduction reactions with the aid of nicotinamide cofactors. The electrochemical oxidation of nicotinamide adeniiw dinucleotide, NADH, has been studied in depthThe direct oxidation of NADH has been used to determine concentration of ethanol i s-isv, i62) lactate 157,160,162,163) pyTuvate 1 ), glucose-6-phosphate lactate dehydrogenase 159,161) alanine The direct oxidation often entails such complications as electrode surface pretreatment, interferences due to electrode operation at very positive potentials, and electrode fouling due to adsorption. Subsequent reaction of the NADH with peroxidase allows quantitation via the well established Clark electrode. 

In the 1930s, Peters and co-workers showed that thiamine deficiency in pigeons resulted in the accumulation of lactate in the brainstem [ 15]. Furthermore, they showed that the addition of small quantities of crystalline thiamine to the isolated brainstem tissue from thiamine-deficient birds in vitro resulted in normalization of lactate levels. These findings led to the formulation of the concept of the biochemical lesion in thiamine deficiency. Subsequent studies showed that the enzyme defect responsible for the biochemical lesion was a-KGDH rather than pyruvate dehydrogenase (PHDC), as had previously been presumed. a-KGDH and PHDC are major thiamine diphosphate (TDP)-dependent enzymes involved in brain glucose oxidation (Fig. 34-4). 

Figure 6.1 Pathways involved in glucose oxidation by plant cells (a) glycolysis, (b) Krebs cycle, (c) mitochondrial cytochrome chain. Under anoxic conditions. Reactions 1, 2 and 3 of glycolysis are catalysed by lactate dehydrogenase, pyruvate decarboxylase and alcohol dehydrogenase, respectively. ATP and ADP, adenosine tri- and diphosphate NAD and NADHa, oxidized and reduced forms of nicotinamide adenine dinucleotide PGA, phosphoglyceraldehyde PEP, phosphoenolpyruvate Acetyl-CoA, acetyl coenzyme A FP, flavoprotein cyt, cytochrome e, electron. (Modified from Fitter and Hay, 2002). Reprinted with permission from Elsevier...

When animal tissues cannot be supplied with sufficient oxygen to support aerobic oxidation of the pyruvate and NADH produced in glycolysis, NAD+ is regenerated from NADH by the reduction of pyruvate to lactate. As mentioned earlier, some tissues and cell types (such as erythrocytes, which have no mitochondria and thus cannot oxidize pyruvate to C02) produce lactate from glucose even under aerobic conditions. The reduction of pyruvate is catalyzed by lactate dehydrogenase, which forms the l isomer of lactate at pH 7 ... 

Lactate consumption The direction of the lactate dehydrogenase reaction depends on the relative intracellular concentrations of pyruvate and lactate, and on the ratio of NADH/NAD+ in the cell. For example, in liver and heart, the ratio of NADH/NAD+ is lower than in exercising muscle. These tissues oxidize lactate (obtained from the blood) to pyruvate. In the liver, pyruvate is either converted to glucose by gluconeogenesis or oxidized in the TCA cycle. Heart muscle exclusively oxidizes lactate to CO2 and H20 via the citric acid cycle. 

The ANLSH challenged the classic view [2, 3]. It postulates compartmentaliza-tion of brain lactate metabolism between neurons and astrocytes the activity-induced uptake of glucose takes place predominantly in astrocytes, which metabolize glucose anaerobically. Lactate produced from anaerobic glycolysis in astrocytes is then released from astrocytes and provides the primary metabolic fuel for neurons. The increased lactate in the neurons is converted to pyruvate via lactate dehydrogenase (LDH), which enters the TCA cycle, and increases ATP production in the neurons via oxidative phosphorylation (Fig. 8.1). This view is highly discussed, pro [4, 5]) and contra [1, 6]. 

When complex I is defective, there is an excess of cellular NADH, which pushes the lactate dehydrogenase to form lactate from pyruvate (anaerobic glycolysis). This results in higher than normal utilization of glucose, causing hypoglycemia. Because succinate is oxidized at the complex II level, its oxidation is not affected. 

There is no overall change in the oxidation state when glucose is converted to lactate, because glyceraldehyde-3-phosphate dehydrogenase oxidizes glyceraldehyde 3-phosphate to 1,3-bisphos-phoglycerate, but lactate dehydrogenase reduces pyruvate to lactate. These two reactions also reduce NAD+ to NADH, then reoxidize the NADH to NAD+. 

Many enzymes that have NAD+ or NADH as a substrate exhibit the sequential ordered mechanism. Consider lactate dehydrogenase, an important enzyme in glucose metabolism (Section 16.1.9). This enzyme reduces pyruvate to lactate while oxidizing NADH to NAD+. 

Lactate is oxidized by NAD+ in a reaction catalyzed by lactate dehydrogenase to form pyruvate, which may be converted to glucose (see Figure 5-25). 

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