Biochemistry, Anaerobic Glycolysis (2023)

introduction

Through the process of glycolysis, one glucose molecule is broken into two pyruvate molecules. Depending on the microcellular environment (specifically, oxygen availability, energy requirements, and the presence or absence of mitochondria), pyruvate has several distinct fates:

In mitochondrial cells, pyruvate can enter and cycle through the citric acid cycle within the mitochondrial matrix.oxidative phosphorylation. Oxidative phosphorylation, aptly named because of its dependence on oxygen as the final electron acceptor, cannot occur in the absence of oxygen. Because citric acid cycle and electron transport chain enzymes reside in mitochondria, cells without mitochondria (such as red blood cells) cannot rely on oxidative phosphorylation for energy production.

In red blood cells and deoxygenated tissues, pyruvate remains in the cytoplasm and is converted to lactate, a process called lactateAnaerobic Glycolysis. This last reaction allows the regeneration of NAD+, a cofactor that must be available in sufficiently high intracellular concentrations for the aforementioned glycolytic reactions to remain favorable. However, compared to oxidative phosphorylation, anaerobic glycolysis is significantly less efficient, producing a net output of only 2 ATP per glucose molecule (vs. 32 ATP per glucose molecule produced during oxidative phosphorylation).[1]

Fundamentals

Glycolysis is the process by which glucose is broken down into pyruvate in the cytoplasm of a cell. Under aerobic conditions, pyruvate can diffuse into the mitochondria, where it enters the citric acid cycle and generates reducing equivalents in the form of NADH and FADH2. These reduction equivalents then enter the electron transport chain, resulting in the production of 32 ATP per glucose molecule. As the electron transport chain requires oxygen as the final electron acceptor, insufficient tissue oxygenation inhibits the process of oxidative phosphorylation.

Under anaerobic conditions, pyruvate has a different fate. Instead of entering the mitochondria, the cytosolic enzyme gets therelactate dehydrogenaseconverts pyruvate to lactate. Although the cell does not use lactate as a direct source of energy, this reaction also allows the regeneration of NAD+ from NADH. NAD+ is an oxidizing cofactor needed to keep glucose flowing through glycolysis. Glycolysis produces 2 ATP per glucose molecule, thus providing a direct means of producing energy in the absence of oxygen. This process of breaking down glucose in the absence of oxygen is aptly calledAnaerobic Glycolysis.[1]

Furthermore, cells that do not contain mitochondria (such as red blood cells) cannot carry out oxidative phosphorylation.[2]The citric acid cycle enzymes are located in the mitochondrial matrix and the electron transport chain enzymes are embedded in the inner mitochondrial membrane. Consequently, these cells depend on anaerobic glycolysis for the production of ATP independent of oxygen concentrations.

questions of interest

Compared to oxidative phosphorylation, which maximizes the energy potential of a single glucose molecule (approximately 32 ATP molecules per 1 glucose molecule), glycolysis is an inefficient means of producing energy. Glycolysis produces only 2 net molecules of ATP for every 1 molecule of glucose. However, in cells that lack mitochondria and/or an adequate supply of oxygen, glycolysis is the only process by which these cells can produce ATP from glucose. In addition, with maximally contracted skeletal muscle, glycolysis is a rapid and relatively efficient means of achieving short-term energy goals.

function

Anaerobic glycolysis serves as a means of energy production in cells that cannot produce adequate energy through oxidative phosphorylation. In oxygen-poor tissues, glycolysis produces 2 ATP by shunting pyruvate from mitochondria and via the lactate dehydrogenase reaction.[1]In skeletal muscle cells, which contract rapidly with energy demands greater than can be generated by oxidative phosphorylation alone, anaerobic glycolysis allows for more rapid production of ATP.[3](Glycolysis is about 100 times faster than oxidative phosphorylation.) In cells that lack mitochondria, pyruvate cannot be oxidatively phosphorylated, regardless of oxygen levels.

Mature erythrocytes do not contain mitochondria and therefore depend only on anaerobic glycolysis for ATP production.[2]Other tissues, such as the cornea and lens of the eye and the inner medulla of the kidney, despite the presence of mitochondria, are poorly vascularized and highly dependent on anaerobic glycolysis.[4][5]

Mechanism

The steps of glycolysis are as follows:

1. Glucose is phosphorylated byHexochinasa, formation of glucose-6-phosphate. This step requires an ATP molecule.

2. Glucose-6-phosphate is thus isomerizedPhosphoglycoseisomeraseto form fructose-6-phosphate.

3. Fructose-6-phosphate is phosphorylated byPhosphofructokinaseto form fructose-1,6-bisphosphate. This step requires an ATP molecule.

4. As a result, fructose 1,6-bisphosphate splits into two separate sugar molecules, dihydroxyacetone phosphate and glyceraldehyde 3-phosphate.aldoliano.

5. The dihydroxyacetone phosphate molecule is thus isomerizedTriosafosfato-Isomerasato form a second glyceraldehyde-3-phosphate.

6. Glyceraldehyde-3-phosphate is phosphorylated byGlyceraldehyde-3-Phosphate Dehydrogenaseto form 1,3-bisphosphoglycerate. This step requires NAD+ as a cofactor.

7. 1,3-bisphosphoglycerate is thus converted to 3-phosphoglyceratePhosphoglyceratquinase. This step involves transferring a phosphate molecule to ADP to form 1 ATP molecule.

   (Video) Metabolism | Glycolysis

8. 3-Phosphoglycerate is rearranged by the enzyme to 2-PhosphoglyceratePhosphoglycerato-mutase.

9. 2-Phosphoglycerate is dehydrated by the enzyme to produce phosphoenolpyruvateEnolasa.

10. Phosphoenolpyruvate is converted to pyruvate byPyruvatequinase. This step involves transferring a phosphate molecule to ADP to form 1 ATP molecule.

The cellular microenvironment determines the fate of pyruvate after the first ten steps of glycolysis. When a cell lacks mitochondria, is poorly oxygenated, or has rapidly increasing energy demands to exceed the rate at which oxidative phosphorylation can supply sufficient ATP, the enzyme can convert pyruvate to lactate.Lactate dehydrogenase.[1]This step involves the oxidation of NADH to NAD+, allowing glycolysis to continueGlyceraldehyde-3-Phosphate DehydrogenaseAnswer (Step #6, see above).

Trial

Lactic acid, the end product of anaerobic glycolysis, is usually measured stationary. Because anaerobic glycolysis predominates when tissues are poorly oxygenated or perfused, lactic acid levels are useful in treating severe sepsis, shock, blood loss, anemia, or heart failure. Hyperlactatemia and lactic acidosis indicate inefficient cardiac output and are associated with increased morbidity and mortality.[6][7][8]

clinical importance

1. Serum Lactic Acid:Lactic acid levels increase when oxygen demand exceeds oxygen supply, such as B. in anemia, heart failure, severe infection (sepsis) and shock. Lactic acid measurements are useful for diagnosing and directing management of such conditions.[6][7][8]

2. Anaerobic exercise:During periods of high-intensity exercise, when oxygen demands exceed oxygen supply, muscles rely on anaerobic glycolysis for ATP production. Although oxidative phosphorylation produces about 15 times more ATP than glycolysis, glycolysis occurs about 100 times faster.[3]

3. The Warburg Effect:A hallmark of cancer is the shift from aerobic to anaerobic metabolism observed in tumor cells, known aswarburg effect. As tumors grow, they expand beyond the local blood supply. To combat poor blood flow and tissue oxygenation, cancer cells turn away from oxidative metabolism and instead rely heavily on anaerobic glycolysis.[9]

4. Fibromyalgia:Fibromyalgia is a chronic pain condition characterized by diffuse tender points on the body without abnormal diagnostic tests. Some studies have shown an increase in pyruvate and lactate production in people with fibromyalgia compared to healthy controls, as well as a decrease in ATP production. Individuals with fibromyalgia also commentedlactate dehydrogenaseat lower concentrations.[10][11]

   (Video) Glycolysis Explained (Aerobic vs. Anaerobic, Pyruvate, Gluconeogenesis)

review questions

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references

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Granchi C, Bertini S, Macchia M, Minutolo F. Inhibitors of lactate dehydrogenase isoforms and their therapeutic potential.Curr Med.Chem.2010;17(7):672-97.[PubMed: 20088761]

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Minakami S, Yoshikawa H. Studies on erythrocyte glycolysis. II. Free energy changes and rate-limiting steps in erythrocyte glycolysis.Biochemistry J.February 1966;59(2):139-44.[PubMed: 4223318]

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CB Peek, DC Levine, J Cedernaes, A Taguchi, Y Kobayashi, SJ Tsai, NA Bonar, MR McNulty, KM Ramsey, J Bass.metab. celularJanuary 10, 2017;25(1):86-92.[PMC Free Item: PMC5226863] [PubMed: 27773696]

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Chhabra M, Prausnitz JM, Radke CJ. Modeling of corneal metabolism and oxygen transport during contact lens wear.I want you to knowMayonnaise 2009;86(5):454-66.[PubMed: 19357551]

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Suetrong B, Walley KR. Lactic acidosis in sepsis: not everything is anaerobic: implications for diagnosis and treatment.Breasts.January 2016;149(1):252-61.[PubMed: 26378980]

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Di Mauro FM, Schoeffler GL. Point-of-care lactate measurement.Bester Anim Med Fellow.March 2016;31(1):35-43.[PubMed: 27451047]

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Péronnet F, Aguilaniu B. [Physiological significance and interpretation of plasma lactate concentration and pH in the clinical stress test].Rev Mal Breathe.June 2014;31(6):525-51.[PubMed: 25012038]

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Schwartz L, Supuran CT, Alfarouk KO. The Warburg effect and the properties of cancer.Krebsmittel Med. Chem.2017;17(2): 164-170.[PubMed: 27804847]

10

Is fibromyalgia caused by impaired glycolysis?Nutri Rev.July 1994;52(7):248-50.[PubMed: 8090378]

11

Eisinger J, Plantamura A, Ayavou T. Abnormalities of glycolysis in fibromyalgia.Jelly. Col. NourishApril 1994;13(2): 144-8.[PubMed: 8006296]

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