Lactate is oxidized to pyruvate in a reaction catalyzed by Lactate dehydrogenase. The patients with genetic deficiency of lactate dehydrogenase present with muscle cramping and myoglobinuria after intense exercise. The sources of lactate include muscle and red blood cells. Lactate is a waste product in such cells; it is transported to liver and can be converted to glucose through pathway of gluconeogenesis. The energy requirements for conversion of lactate to glucose are:
A. 2 ATP
B. 4 ATP
C. 6 ATP
D. 8 ATP
E. 38 ATP.
The correct answer is C- 6 ATP.
Lactate produced by active skeletal muscle and erythrocytes is a source of energy for other organs. Erythrocytes lack mitochondria and can never oxidize glucose completely. In contracting skeletal muscle during vigorous exercise, the rate at which glycolysis produces pyruvate exceeds the rate at which the citric acid cycle oxidizes it. The rate of formation of NADH by glycolysis is also greater than the rate of its oxidation by aerobic metabolism.
The accumulation of both NADH and pyruvate is reversed by lactate dehydrogenase, which oxidizes NADH to NAD+ as it reduces pyruvate to lactate (Figure-1)
Figure-1- Pyruvate and lactate are inter-convertible, the net amount depends upon the ratio of NADH/NAD+. In conditions of NAD+ excess, (as in the liver) pyruvate is the end product, whereas under anaerobic conditions or in the cells lacking mitochondria, lactate is the important product of this reaction.
This reaction serves two critical functions during anaerobic glycolysis.
1) Regeneration of NAD+– In the direction of lactate formation, the LDH reaction requires NADH and yields NAD+ which is then available for use by the glyceraldehyde-3-phosphate dehydrogenase reaction of glycolysis. These two reactions are, therefore, intimately coupled during anaerobic glycolysis (figure-2).
Figure-2- Coupling of reactions for the continuation of glycolysis. The purpose of the reduction of pyruvate to lactate is to regenerate NAD+ so that glycolysis can proceed in active skeletal muscle and erythrocytes.
2) Gluconeogenesis- The lactate produced by the LDH reaction is at a dead-end in metabolism. It must be converted back, therefore it is released to the blood stream and transported to the liver where it is oxidized to pyruvate, through the same reaction catalyzed by lactate dehydrogenase favored by the low NADH/NAD+ ratio in the cytosol of liver cells. Pyruvate in the liver is converted into glucose by the gluconeogenic pathway. Glucose then enters the blood and is taken up by skeletal muscle. Thus, the liver furnishes glucose to contracting skeletal muscle, which derives ATP from the glycolytic conversion of glucose into lactate. Contracting skeletal muscle supplies lactate to the liver, which uses it to synthesize glucose. These reactions constitute the Cori cycle (figure-3). The formation of lactate buys time and shifts part of the metabolic burden from muscle to other organs.
Figure-3- Cori cycle- Glucose is transported to skeletal muscle, for energy needs. The product of glycolysis, lactate cannot be converted back to pyruvate due to high NADH/NAD+ ratio, lactate is transported back to liver for reconversion to pyruvate and then to glucose through the pathway of gluconeogenesis. Glucose is again transported to muscle for usage and this cycle continues for waste disposal and making the best use of the waste product.
An overview of gluconeogenesis
The three irreversible reactions of glycolysis are substituted by 4 alternative reactions-
1) First barrier- Pyruvate can’t be converted directly to phosphoenol pyruvate due to irreversible reaction catalyzed by pyruvate kinase. To overcome this barrier, alternatively pyruvate is first converted to oxaloacetate and then oxaloacetate is converted to Phospho enol pyruvate by two separate reactions (figure-4).
2) Second barrier- From phosphoenol pyruvate onwards up to fructose 1,6 bisphosphate, the reactions are reversible, the second barrier lies at the level of conversion of fructose 1,6, bisphosphate to fructose 6, phosphate, which is overcome by fructose 1,6 bisphosphatase (figure-4).
3) Third barrier- The conversion of glucose-6-P to free glucose (third barrier) is carried out by glucose-6-phosphatase (figure-4), which is the third and the final barrier of gluconeogenesis.
Figure-4- An overview of gluconeogenesis, highlighting the energy requiring steps.
Energetics of gluconeogenesis
Six nucleotide triphosphate molecules are hydrolyzed to synthesize glucose from pyruvate in gluconeogenesis, (from lactate as well, since lactate enters the pathway through pyruvate and lactate to pyruvate conversion does not require energy) whereas only two molecules of ATP are generated in glycolysis in the conversion of glucose into Lactate. The overall reaction of gluconeogenesis is-
Glucose to lactate generates 2 ATP, whereas Lactate to glucose conversion requires 6 ATP (figure-4). Thus it is not a simple reversal of glycolysis but it is energetically an expensive affair.
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