15 Could Glycolysis Continue Under Anaerobic Conditions if Lactate Could Not Be Produced Explain

Anaerobic Glycolysis

Anaerobic glycolysis is the main metabolic pathway used in the setting of limited oxygen supply during exercise.

From: Rheumatology (Sixth Edition) , 2015

Metabolic, drug-induced, and other noninflammatory myopathies

George Stojan , Lisa Christopher-Stine , in Rheumatology (Sixth Edition), 2015

Glycogen/glucose metabolism (Fig. 151.1)

Anaerobic glycolysis is the main metabolic pathway used in the setting of limited oxygen supply during exercise. It is used during high-intensity, sustained, isometric muscle activity. ¹ It is inefficient from an energetic standpoint and produces only two ATP molecules per glucose molecule, which is 19 times less than the full energy potential of a glucose molecule. Despite its inefficiency, it is a rapid process, approximately 100 times faster than oxidative phosphorylation. The final step in the pathway is conversion of pyruvate to lactate, which leads to accumulation of lactic acid.

Aerobic glycolysis is more efficient; however, the price needed to maintain this system is high: it requires functional mitochondria, a functioning circulatory system with a constant oxygen supply, and the ability to eliminate carbon dioxide. It is used as the main supply of energy during sustained, dynamic forms of exercise such as walking, but if short bursts of energy are needed, the system is often overwhelmed and anaerobic glycolysis takes over.

The phosphocreatine pathway acts as a "buffer" of ATP stores by limiting changes in ATP and allowing rapid formation of ATP during high-intensity exercise. The amount of phosphocreatine in muscle is small, and it is not able to sustain activity independently.

ATP can also be produced by the adenylate kinase reaction, which catalyzes the conversion of two adenosine diphosphate (ADP) molecules into one ATP and one adenosine monophosphate (AMP); however its clinical significance is limited.

The oxidative phosphorylation system (Fig. 151.2), present in the inner mitochondrial membrane, is the principal source of energy in muscle and other tissues. The flow of electrons from the reduced form of nicotine adenine dinucleotide (NADH) to the last enzyme in the electron transport chain, cytochrome-c oxidase (complex IV), releases energy that is used in the synthesis of ATP.

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The Role of Diet and Nutritional Supplements

Fabio Pigozzi , ... Attilio Parisi , in Clinical Sports Medicine, 2007

Bicarbonate and other buffers

Anaerobic glycolysis allows higher rates of ATP resynthesis than can be achieved by aerobic metabolism, but the capacity of the system is limited and fatigue follows rapidly. The metabolic acidosis that accompanies glycolysis can inhibit key glycolytic enzymes, interfering with Ca ²⁺ transport and binding, and directly with the actin–myosin interaction. Induction of a metabolic alkalosis by ingestion of NAHCO₃ before exercise can increase both the muscle buffering capacity and the rate of efflux of H⁺ from the active muscles, potentially delaying the attainment of a critically low intracellular pH. ⁷⁸

Improvements in performance are typically seen in exercise lasting from about 30 s to a few minutes, but several studies have failed to find positive effects, even when they have used exercise of this duration. Effective doses have been large, typically about 0.3 g/kg body mass. There are, of course, potential problems associated with the use of such large doses of bicarbonate. Vomiting and diarrhea are symptoms that are frequently reported as a result of ingestion of even relatively small doses of bicarbonate. One study ⁷⁹ has investigated the potential of sodium citrate as an exogenous buffer, because sodium citrate might be associated with less gastrointestinal discomfort than sodium bicarbonate.

Sodium citrate does not buffer directly like sodium bicarbonate: the dissociation constant for citrate/citric acid lies well outside the body's pH range, but the consumption of protons during its oxidation effectively generates bicarbonate. McNaughton ⁷⁹ found that ingestion of sodium citrate had a positive effect on work output, without adverse gastrointestinal symptoms but it failed to have a significant effect on performance in other studies. This a good example of a physiological benefit that does not translate into an enhanced sports performance. For this reason, the true effect remains unclear.

Ingestion of other substances could produce an indirect buffering effect similar to that of sodium citrate. One of these substances is sodium lactate, which would also consume protons when it is metabolized. Using lactate as a buffer may seem counter-intuitive to those who believe that lactic acid causes fatigue but it must be remembered that intracellular acidity causes fatigue, not the accumulation of lactate ions.

Brooks ⁸⁰ found that lactate can serve as an energy source for exercising muscles. In the study of Fahey and collaborators, ⁸¹ the ingestion of 80% poly-lactate and 20% sodium lactate as a 7% solution in water increased blood pH and bicarbonate compared with ingestion of a glucose polymer drink.

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GLUCOSE | Function and Metabolism

D.A. Bender , in Encyclopedia of Food Sciences and Nutrition (Second Edition), 2003

The Reduction of Pyruvate to Lactate: Anaerobic Glycolysis

In red blood cells, which lack mitochondria, reoxidation of NADH formed in glycolysis cannot be by way of the electron transport chain, as occurs in other tissues. Similarly, under conditions of maximum exertion, for example, in sprinting, the rate at which oxygen can be taken up into the muscle is inadequate to permit reoxidation of all the NADH which is formed in glycolysis. In order to maintain the oxidation of glucose, and the net yield of 2   ×   ATP per mol of glucose oxidized (or 3   mol of ATP if the source is muscle glycogen), NADH is oxidized to NAD⁺ by the reduction of pyruvate to lactate, catalyzed by lactate dehydrogenase (Figure 2).

Figure 2. The Cori cycle – anaerobic glycolysis in muscle and gluconeogenesis in the liver. Lactate dehydrogenase EC 1.1.1.28. ATP, adenosine triphosphate; ADP, adenosine diphosphate.

Lactate is exported from muscle and red blood cells, and taken up by the liver, where it is used for the resynthesis of glucose – the Cori cycle, shown in Figure 2. Synthesis of glucose from lactate is an ATP (and guanosine triphosphate (GTP))-requiring process. The oxygen debt after strenuous physical activity is due to an increased rate of energy-yielding metabolism to provide the ATP and GTP that are required for gluconeogenesis from lactate. While most of the lactate will be used for gluconeogenesis, a proportion will undergo oxidation to CO₂ in order to provide the ATP and GTP required for gluconeogenesis.

The conversion of glucose to lactate is known as anaerobic glycolysis, since it does not require oxygen. However, it is not true to say that human metabolism (apart from red blood cells) is ever wholly anaerobic. The formation of lactate is the fate of much of the pyruvate formed from glucose under conditions of maximum muscle exertion when oxygen is limiting, but as much as possible will continue to undergo complete oxidation.

Many tumors have a low capacity for oxidative metabolism, so that much of the energy-yielding metabolism in the tumor is anaerobic. Lactate produced by anaerobic glycolysis in tumors is exported to the liver for gluconeogenesis; this increased cycling of glucose between anaerobic glycolysis in the tumor and gluconeogenesis in the liver may account for much of the hypermetabolism and consequent weight loss seen in patients with cancer cachexia.

Truly anaerobic glycolysis does occur in microorganisms which are capable of living in the absence of oxygen. Here there are two possible fates for the pyruvate formed from glucose, both of which involve the oxidation of NADH to NAD⁺:

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Reduction to lactate, as occurs in human muscle. This is the pathway in lactic acid bacteria, which are responsible for the fermentation of lactose in milk to form yogurt and cheese;

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Decarboxylation and reduction to ethanol. This is the pathway of fermentation in yeast, which is exploited to produce alcoholic beverages.

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Introduction to Glycolysis (The Embden-Meyerhoff Pathway (EMP))

Larry R. Engelking , in Textbook of Veterinary Physiological Chemistry (Third Edition), 2015

Why is Anaerobic Glycolysis Necessary?

Although anaerobic glycolysis produces only about 5% of the ATP provided during the catabolism of glucose, there are a number of reasons why it is necessary:

1)

There are several instances where animals need quick energy. In moving from rest to full flight, for example, aerobic oxidation would require a rapid increase in the O₂ supply, which could only be achieved by increasing the blood supply (which usually takes a number of seconds). Thus, an animal who initiates a sprint from the resting position relies heavily on anaerobic glycolysis.

2)

A rapid increase in the O₂ supply to tissues requires a well-developed vascular network. In some instances it may prove inefficient to supply a large body mass (i.e., big muscles), with a well-developed blood supply. This is certainly the case for the pectoral muscles of game birds (e.g., pheasants), which are frequently used for escape purposes. In others, the blood supply may be limited because of pathology (e.g., tumors), or physiology (the kidney medulla). In these examples, anaerobic glycolysis may be the major, or only, source of energy.

3)

The two major groups of skeletal muscle fibers are red, slow-twitch oxidative fibers (type I), and white, fast-twitch glycolytic fibers (type IIB) (see Chapter 80). The type I fibers have high aerobic capacity, and therefore are reasonably fatigue resistant; whereas the type IIB fibers are largely anaerobic. Many fish possess mainly type IIB fibers, with only a thin section along the lateral line being of type I. The lateral line fibers are used during normal periods of swimming, while the large white muscle mass is used for short bursts of rapid activity. Bluefish, however, contain many type I fibers which provide them with far more aerobic capacity.

When resting skeletal muscle is compared to more highly perfused, oxygen-dependent areas of the body (e.g., liver, kidneys, brain, and heart), a key distinction becomes apparent: The liver, kidneys, brain, and heart normally account for only about 7% of the body mass, yet receive almost 70% of the cardiac output (CO), and consume 58% of the O₂ utilized in the resting state ( Table 24-1 ). Skeletal muscle accounts for nearly 50% of the normal body mass, yet receives only 16% of the CO at rest, and consumes only 20% of the O₂ utilized in the resting state. It is no wonder that anaerobic glycolysis is so important in skeletal muscle, since O₂ is being utilized by more "vital" organs in the resting state, even though these organs occupy a rather small fraction of the total body mass. If exercise were to commence quickly from the resting state, anaerobic glycolysis would be mandatory.

Table 24-1. Regional blood perfusion and oxygen consumption in the resting state.

	Body Mass	Cardiac Output	O2 Consumption
Region	(% Total)	(% Total)	(%Total)
Liver	4.1	27.8	20.4
Kidneys	0.48	23.3	7.2
Brain	2.2	13.9	18.4
Heart M.	0.48	4.7	11.6
Subtotal	7.26	69.7	57.6
Skin	5.7	8.6	4.8
Skeletal M.	49.0	15.6	20.0
Remainder	37.8	6.2	17.6
Whole body	100.0	100.0	100.0

Data from various sources.

4)

Aerobic oxidation of carbohydrates, fats, and amino acids is carried out in mitochondria, rather bulky cell organelles. In some cases it may be desirable to reduce the number of mitochondria (because of their bulk) and, in these instances, the cell would be more dependent on anaerobic glycolysis. For example, the eye (namely the cornea and lens) needs to transmit light signals with high efficiency. Optically dense structures such as mitochondria and capillaries would reduce this efficiency (and, if they were present in large amounts, animals might literally "see" those extra mitochondria, as well as the blood flowing by in capillaries). Therefore, most of the glucose (over 80%) used by the cornea and lens is normally metabolized anaerobically.

Mature red blood cells have no mitochondria, so all of their energy needs are supplied by anaerobic glycolysis (see Chapters 30 and 31). The space is needed for other molecules, in this case hemoglobin, which occupies about 33% of the cell interior. Also, red blood cells are located in a medium (blood plasma), that always has glucose available. On the other hand, heart muscle is an example of a tissue that has retained its aerobic capacity (many mitochondria), but lacks the ability to exhibit powerful contractile forces (like type IIB anaerobic skeletal muscle fibers that have many more actin and myosin filaments (and fewer mitochondria) per unit area).

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Shock: Classification, Pathophysiology, and Approach to Management

Anand Kumar , Joseph E. Parrillo , in Critical Care Medicine (Third Edition), 2008

Gastric Intramucosal pH

Because anaerobic glycolysis with lactate generation is paralleled by the production of hydrogen ions during hypodynamic shock, noninvasive measurement of tissue pH may provide an attractive, metabolism-based assess ment of adequacy of tissue oxygenation and perfusion. Because the stomach is easily accessible and may reflect overall splanchnic perfusion during shock, ³²⁸ and splanchnic perfusion is known to be altered early in shock, ³²⁹ most clinical work has focused on gastric mucosal pH. Studies suggest that gastric intramucosal pH correlates closely with systemic and organ oxygen consumption, organ failure, and outcome in critically ill humans. ^330,331 Normalization of gastric mucosal pH has been suggested as one appropriate target during resuscitation of circulatory shock. ³³² Limited evidence suggests such an approach may be associated with improved survival. ³³³ Further supportive studies are required, however, before this can be accepted as an appropriate therapeutic target.

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Carrier-Mediated Transport

Wilfred D. Stein , Thomas Litman , in Channels, Carriers, and Pumps (Second Edition), 2015

Note first that anaerobic glycolysis is far more costly in energy than is the burning of glucose that is carried out by the mitochondria. Anaerobic glycolysis yields two ATP molecules for each glucose molecule metabolized…oxidation of glucose in the mitochondrion would yield an additional 34 ATP molecules. But the glucose's carbons are lost if the glucose is being burned to CO ₂ and water. A rapidly growing cell has needs other than merely for its ATP. It must produce, every time it divides, its own weight of nucleotides (DNA and RNA), lipids (for its daughter's external and internal membranes), and proteins. It cannot do this if the carbon in the glucose it metabolizes is burnt to CO₂. The nucleotides in particular (and they provide the largest component of the ribosomes that the daughter cell will need for its protein synthesis) are formed by diverting much glucose metabolism away from the pyruvic acid that fuels the mitochondrion. (Most, however, of the material that forms the new proteins arises from the cancer cell's consumption of glutamine, another pathway that is specifically enhanced in cancer cells.) The lactate that the cancer cell produces as the end product of anaerobic glycolysis is exported, producing an acidic environment around the growing front of the tumor. This acidity helps destroy the normal tissues present there, providing a space into which the cancer can grow. Indeed, the glucose transporter (GLUT-1) is greatly up-regulated at the growing front of a tumor (see Figure 6.9B), as is a second transporter, the sodium–hydrogen exchanger (NHE-1), that can pump protons out of the cell and acidify the region into which the cancer is growing.

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Glycolysis Overview

R.A. Harris , in Encyclopedia of Biological Chemistry (Second Edition), 2013

Lactic Acidosis

Regardless of whether anaerobic or aerobic, glycolysis produces acid if lactate is the end product of the pathway. The acid produced by glycolysis lowers the pH both inside cells where lactate is produced as well as outside where protons can diffuse. Since the pH range in which cells can function is quite narrow (pH 7.0–7.6), uncontrolled glycolysis can lead to cell death. This is the Achilles' heel of glycolysis. Indeed, in the final analysis it is overproduction of acid and lowering of the pH by glycolysis that kills most organisms, including humans. Cells incubated under anaerobic conditions produce large amounts of acid by anaerobic glycolysis. Likewise, forcing an area of the heart to obtain all of its energy from glycolysis by occluding a coronary artery causes rapid production of large amounts of acid, which lowers the pH, activates the nerve endings, and registers as pain. That the conversion of glucose to lactate produces acid is apparent when we write the balanced overall equation for glycolysis in the following manner:

$\text{Glucose}\to {2\text{Lactate}}^{-}+2{\text{H}}^{+}$

Since the empirical formula for glucose is C₆H₁₂O₆, and there are six carbons, 12 hydrogens, and six oxygens in the products, this equation is balanced for mass and charge. Thus, two protons are produced for every glucose molecule converted to lactate molecules by glycolysis. Since glycolysis produces two ATPs per glucose, the equation seems incomplete, and in one sense it is incomplete. Expanding the equation to include ADP, Pi, and ATP in their predominant ionization states at physiological pH yields

$\text{Glucose}+2{\text{ADP}}^{3-}+2{\text{Pi}}^{2-}\to 2{\text{Lactate}}^{-}+2{\text{ATP}}^{4-}+2{\text{H}}_2\text{O}$

If this is accepted as the appropriate equation for glycolysis, balanced as it is for mass and charge, the pathway does not produce acid and therefore should have no effect on cellular pH. However, anaerobic glycolysis can clearly be shown to produce acid experimentally, and it does so because the pool size of ATP is small compared to the amount of glucose that is converted to lactate to meet the energy needs of a cell. For every glucose molecule converted to lactate, two ATP molecules have to be hydrolyzed according to the equation

$2{\text{ATP}}^{4-}+2{\text{H}}_2\text{O}\to {2\text{ADP}}^{3-}+2{\text{Pi}}^{2-}+2{\text{H}}^{+}+\text{Work}$

Work refers to many energy-requiring processes that can only occur as a consequence of ATP hydrolysis, such as muscle contraction, Na⁺,K⁺-ATPase activity. Summing up the last two equations brings us back to the overall balanced equation that shows acid production by glycolysis:

$\text{Glucose}\to 2{\text{Lactate}}^{-}+2{\text{H}}^{+}$

Anaerobic glycolysis therefore produces acid. Conditions in humans that greatly increase anaerobic glycolysis because of a shortage of oxygen, for example, failure of the respiratory system or the blood circulatory system, often cause the production of more acid than can be handled by the buffering systems of the body. The consequence is lactic acidosis, a life-threatening condition. Lactic acidosis can be dealt with most effectively by re-establishing the supply of oxygen. Reinstating ATP synthesis by oxidative phosphorylation will inhibit the production of lactic acid by glycolysis and also promote the oxidation of lactate as well as the consumption of the excess acid (H⁺'s) by the sum reaction:

$2{\text{Lactate}}^{-}{+2\text{H}}^{+}+6{\text{O}}_2\to 6{\text{CO}}_2+6{\text{H}}_2\text{O}$

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Carbohydrate Metabolism

Antonio Blanco , Gustavo Blanco , in Medical Biochemistry, 2017

General Considerations About Gluconeogenesis

Lactate formed during anaerobic glycolysis enters the gluconeogenic pathway after oxidation to pyruvate by lactate dehydrogenase. After intense exercise, the lactate produced diffuses from the muscle into the blood and is taken up by the liver to be converted into glucose and glycogen.

Oxaloacetate is a common intermediary in the first reactions of gluconeogenesis and the citric acid cycle. All cycle intermediates and any compound producing it may become a glucose precursor. The carbon chains of some amino acids originate α-ketoglutarate, others produce succinate, fumarate, oxaloacetate, or pyruvate (p. 383) and can contribute to glucose formation.

Acetyl-CoA is not glucogenic. Practically, each acetate moiety entering the citric acid cycle is completely oxidized. Therefore, fatty acids degraded to acetyl-CoA in the organism are nonglucogenic. However, glycerol, another lipid component, is glucogenic. In liver tissue, for example, glycerol can be phosphorylated to glycerol-3-phosphate, which is subsequently oxidized to DHAP, and then oxidized. The triose-phosphate has two metabolic choices: (1) to follow the gluconeogenesis pathway by binding to glyceraldehyde-3-phosphate to yield fructose-1,6-bisphosphate or (2) to enter glycolysis to become glyceraldehyde-3-phosphate and 1,3-bisphosphoglycerate. The final destination is determined by the cell needs.

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Intermediate Reactions in Anaerobic Glycolysis

Larry R. Engelking , in Textbook of Veterinary Physiological Chemistry (Third Edition), 2015

Abstract:

The intermediate reactions in anaerobic glycolysis involve the cleavage of fructose 1,6-bisphosphate into two triose phosphates, which are ultimately converted to pyruvate in some ATP-yielding reactions. NAD+  is required for glycolysis to continue, and is used in the conversion of glyceraldehyde 3-phosphate to 1,3-bisphosphoglycerate. Carbon atoms from glyceraldehyde, derived through the action of aldolase on fructose 1-phosphate, can enter the glycolytic scheme at the level of glyceraldehyde 3-phosphate, or at the level of 3-phosphoglycerate. The first site of ATP production in the EMP is from 1,3-bisphosphoglycerate to 3-phosphoglycerate. Conversion of 2-phosphoglycerate to phosphoenolpyruvate in erythrocytes can be prevented with fluoride, thus keeping the plasma glucose concentration from changing in stored blood. Conversion of phosphoenolpyruvate to pyruvate is "physiologically irreversible". Diphosphoglyceromutase catalyzes formation of an important glycolytic intermediate in erythrocytes. The anaerobic phase of glycolysis does not yield as much ATP as the aerobic phase.

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Oxidative and Nitrosative Stress

J.M. Modak , L.D. McCullough , in Primer on Cerebrovascular Diseases (Second Edition), 2017

Hydrogen Peroxide: A Superoxide Dismutant

Accumulation of lactic acid due to anaerobic glycolysis, is a result of energy depletion, and leads to cellular acidosis. An increase in the H ⁺ ion concentration further enhances the rate of conversion of superoxide anion (O₂ ⁻) to H₂O₂ or a hydroperoxy radical (HO₂). Superoxide dismutase [SOD; the enzyme that alternately catalyzes the dismutation of O₂ ⁻ into either molecular oxygen (O₂) or hydrogen peroxide (H₂O₂)], is also important in limiting the deleterious effects of ROS in ischemic tissue. Of the three forms of SODs, copper–zinc SOD and manganese SOD are abundant in neural tissues. H₂O₂ is chemically more stable than superoxide, and diffuses more easily across the cell membranes. It can act both as a vasodilator or a vasoconstrictor. High concentrations of H₂O₂ can produce vasoconstriction, followed by vasodilatation. H₂O₂ also promotes lipid peroxidation, which is important in the lipid-rich brain. Uncontrolled lipid peroxidation has shown to trigger nonapoptotic cell death pathways via iron-dependent enzymatic degradation.

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