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So I've been doing research on the production of lactic acid, however, I found that lactate will first reform into pyruvate and then go through gluconeogenesis reforming D-glucose. From what I understand, it requires 4 ATP and 2 GTP, so Question: why wouldn't the pyruvate go straight to the citric acid cycle and electron transport chain instead of reforming glucose first?

My research for context:

Carbohydrate Fermentation: The production of Lactic Acid for Anaerobic Glycolysis

Lactic acid, also known as 2-hydroxypropanoic acid, is formed primarily by muscle cells when the body requires Adenosine Triphosphate(ATP) and there isn’t enough O2 for the citric acid cycle and electron transport chain(ETC) to occur.1,2 As a result, the cell will use anaerobic glycolysis as its primary form of energy production. In glycolysis, Nicotinamide adenine dinucleotide (in its oxidized form NAD+) is used when transforming glyceraldehyde 3-phosphate into 1,3-bisphosphoglycerate. However, by the end of the reaction, the NAD+ is left in its reduced form NADH. If O2 were present, the pyruvate would undergo a link reaction on its way to the matrix of the mitochondria, where the citric acid cycle occurs, followed by the ETC in the inner membrane space (IMS). Typically, this NADH would be used as an electron donor in the ETC, where the majority of ATP is generally produced during cellular respiration (34 out of the overall 38 ATP).3 However, in order to be reused for glycolysis, it is oxidized back into NAD+. enter image description here As seen in Figure 1, D-glucose, a six-carbon carbohydrate, undergoes glycolysis in the cytoplasm forming primarily two pyruvate 3-carbon molecules, 2NADH and 2ATP. From there, NADH and H+ react with each pyruvate molecule temporarily forming a lactic acid molecule which is deprotonated in solution forming lactate. Roughly 20 mmol of lactate is formed per kilogram of tissue daily. Although anaerobic glycolysis does produce ATP, it isn’t as efficient as the aerobic ETC, nor can it operate from prolonged periods of time.4,5 The reaction can only occur under these circumstances for between one and three minutes until the lactic acid is exposed to O2. At this point, lactate is transferred to the liver, where it undergoes gluconeogenesis and is reformed into glucose for aerobic respiration. First, lactate catalyzed by lactate dehydrogenase (LDH) reforms pyruvate via C3H6O3+(NAD+) C3H3O3-+NADH, and then the pyruvate is reformed into glucose for aerobic respiration via2 C3H3O3-+6NTPC6H12O6.6,8 Until O2 levels normalize, the lactic acid will build up in the cell, known most commonly as lactic acidosis, reducing the pH in the muscle tissue. This in turn inhibits ATP production as not as much H+ would be available for the anaerobic glycolysis to occur, therefore reducing ATP produced, resulting in fatigue.9 At 15˚C and one atmosphere of pressure, lactic acid is colorless, odorless, and is an alcohol and an acid. Although it can be found in two optically active forms, L(+)-lactic acid, D(-)-lactic acid, L(+)-lactic acid is the most common in human tissue as it is the only isomer formed during muscle contraction. Lactic acid exists as a conjugate base called lactate at pH 7.4, but it does not affect the chirality (L versus D). Normal levels of L-lactic acid in human blood vary slightly between sources but are generally between 0.5 mmol/l and 1 mmol/l.2,5 Cells use anaerobic glycolysis as a short-term solution for energy production. It allows the cell to produce ATP without the need for oxygen; however, after prolonged periods of use, raised lactate levels can reduce the pH of the muscle tissue in less ATP production and, therefore, cause fatigue.4,6

References:

Garlotta, D. A Literature Review of Poly(Lactic Acid). Journal of Polymers and the Environment 9, 63–84 (2001). https://doi.org/10.1023/A:1020200822435 Komesu, A., Oliveira, J. A. R. d., Martins, L. H. d. S., Wolf Maciel, M. R., and Maciel Filho, R. (2017). "Lactic acid production to purification: A review," BioRes. 12(2). 4364-4383. Bettelheim, F. A.; Brown, W. H.; Campbell, M. K.; Farrell, S. O.; Torres, O. J.; Madsen, S. Introduction to general, organic, and biochemistry, 11th ed.; Cengage: Boston, MA, 2020. Lund, J., Aas, V., Tingstad, R.H. et al. Utilization of lactic acid in human myotubes and interplay with glucose and fatty acid metabolism. Sci Rep 8, 9814 (2018). https://doi.org/10.1038/s41598-018-28249-5 Miroslav Pohanka, "D-Lactic Acid as a Metabolite: Toxicology, Diagnosis, and Detection", BioMed Research International, vol. 2020, Article ID 3419034, 9 pages, 2020. https://doi.org/10.1155/2020/3419034 Kraut, J., & Madias, N. (2014). Lactic acidosis. The New England journal of medicine, 371(24), 2309-2319. Report #: 24. http://dx.doi.org/10.1056/nejmra1309483 Retrieved from https://escholarship.org/uc/item/5z25r8s8 Muscle Fatigue: Lactic Acid or Inorganic Phosphate the Major Cause? Håkan Westerblad, David G. Allen, and Jan Lännergren Physiology 2002 17:1, 17-21 Exton, J.; Ui, M.; Lewis, S.; Park, C. Mechanism of Glucagon Activation of Gluconeogenesis. Gluconeogenesis 1972, 21 (10), 945–990 M Nanang et al 2018 IOP Conf. Ser.: Earth Environ. Sci. 197 012049

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