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The Metabolic Fates of NADH and Pyruvate —The Products of Glycolysis

In addition to ATP, the products of glycolysis are NADH and pyruvate. Their processing depends upon other cellular pathways. NADH must be recycled to NAD+, lest NAD+ become limiting in glycolysis. NADH can be recycled by both aerobic and anaerobic paths, either of which results in further metabolism of pyruvate. What a given cell does with the pyruvate produced in glycolysis depends in part on the availability of oxygen.

Under aerobic conditions, pyruvate can be sent into the citric acid cycle, where it is oxidized to CO2 with the production of additional NADH (and FADH2). Under aerobic conditions, the NADH produced in glycolysis and the citric acid cycle is reoxidized to NAD+ in the mitochondrial electron transport chain.

Under anaerobic conditions, the NADH cannot be reoxidized through the respiratory chain to oxygen. Pyruvate is reduced by the NADH to lactate, catalyzed by lactate dehydrogenase (Figure-1).There are different tissue specific isoenzymes lactate dehydrogenases that have clinical significance. The reoxidation of NADH via lactate formation allows glycolysis to proceed in the absence of oxygen by regenerating sufficient NAD+ for another cycle of the reaction catalyzed by glyceraldehyde-3-phosphate dehydrogenase.

 Fate of NADH under anerobic conditions

Figure-1- showing coupling of reactions

Tissues That Function under Hypoxic Conditions Produce Lactate

This is true of skeletal muscle, particularly the white fibers, where the rate of work output, and hence the need for ATP formation, may exceed the rate at which oxygen can be taken up and utilized. Glycolysis in erythrocytes always terminates in lactate, because the subsequent reactions of pyruvate oxidation are mitochondrial, and erythrocytes lack mitochondria. Other tissues that normally derive much of their energy from glycolysis and produce lactate include brain, gastrointestinal tract, renal medulla, retina, and skin. The liver, kidneys, and heart usually take up lactate and oxidize it but will produce it under hypoxic conditions.

Energy yield per molecule of Glucose oxidized through Glycolysis

The net reaction in the transformation of glucose into pyruvate is:

 Summary of glycolysis

Pathway Reaction Catalyzed by Method of ATP Formation ATP per Mol of Glucose
Glycolysis Glyceraldehyde 3-phosphate dehydrogenase Respiratory chain oxidation of 2 NADH 6
Phosphoglycerate kinase Substrate level phosphorylation 2
Pyruvate kinase Substrate level phosphorylation 2
   Total 10
Consumption of ATP for reactions of hexokinase and phosphofructo kinase -1 reactions –2
    Net 8

Under anaerobic conditions electron transport chain does not operate so the ATP is only formed by substrate level phosphorylation. Hence the total energy yield through glycolysis in the absence of oxygen is only 2 ATP per mol of Glucose.

Biological Significance of Glycolysis

Glycolysis is an important pathway for the production of energy especially under anaerobic conditions and in the cells lacking mitochondria, besides that the intermediates of glycolysis can be used for various purposes.

1)      Glucose-6-P is a common intermediate for a number of pathways and is used depending on the need of the cell, like glycogen synthesis, Uronic acid pathway, HMP pathway etc.

2)      Fructose-6-P is used for the synthesis of Glucosamines.

3)      Triose like glyceraldehyde-3-P and other glycolytic intermediates can be used   in the HMP pathway for the production of pentoses.

4)      Dihydroxy Acetone –phosphate can be used for the synthesis of Glycerol -3-P , which is used for the synthesis of Triglycerides or phospholipids.

5)      2,3 BPG is an important compound produced pathway in erythrocytes  in the glycolytic pathway for unloading of O2 to the peripheral tissues.

6)      The sugars like Fructose, Galactose. Mannose and even Glycerol can be oxidized in glycolysis.

7)      Out of the total 10 reactions of Glycolysis, 7 reactions are reversible and are used for the synthesis of Glucose by the process of Gluconeogenesis.

8)      Pyruvate the end product of glycolysis provides precursor for the TCA cycle and for the synthesis of other compounds.

 To See the significance of 2,3 BPG, follow the link as under

Clinical Significance of Glycolysis

Pyruvate kinase deficiency

Pyruvate kinase lies at the end of the glycolytic pathway in RBCs followed only by lactate dehydrogenase. Pyruvate kinase activity is critical for the pathway and therefore critical for energy production. If ATP is not produced in amounts sufficient to meet the energy demand, then those functions are compromised. Energy is required to maintain the Na+/K+ balance within the RBC and to maintain the flexible discoid shape of the cell. In the absence of sufficient pyruvate kinase activity and therefore ATP, the ionic balance fails, and the membrane becomes misshapen. Cells reflecting pyruvate kinase insufficiency rather than a change in membrane composition are removed from the circulation by the macrophages of the spleen. This results in an increased number of circulating reticulocytes and possibly bone marrow hyperplasia, which is a biological response to lowered RBC count as a result of hemolysis of erythrocytes.

Enzyme defects that have been described include decreased substrate affinity, increased product inhibition, decreased response to activator, and thermal instability.

Important intermediates proximal to the PK defect influence erythrocyte function. Two- to 3-fold increases of 2, 3-bisphosphoglycerate levels result in a significant rightward shift in the hemoglobin-oxygen dissociation curve. Physiologically, the hemoglobin of affected individuals has an increased capacity to release oxygen into the tissues, thereby enhancing oxygen delivery. Thus, for a comparative hemoglobin and Haemtocrit level, an individual with PKD has an enhanced exercise capacity and fewer symptoms.

This disorder manifests clinically as a hemolytic anemia, but surprisingly, the symptomatology is less severe than hematological indices indicate. Presumably, this is due to enhanced oxygen delivery as a result of the defect. The clinical severity of this disorder varies widely, ranging from a mildly compensated anemia to severe anemia of childhood. Most affected individuals do not require treatment. Individuals who are most severely affected may die in utero of anemia or may require blood transfusions or Splenectomy, but most of the symptomatology is limited to early life and to times of physiologic stress or infection.

For details of pyruvate kinase deficiency, follow the link as under

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