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4.2: Tricarboxylic acid cycle (TCA)

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    37841
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    The TCA cycle is responsible for generating over half of the ATP from the oxidation of fuels. This is primarily because the substrate for the TCA cycle, acetyl-CoA, is generated by the oxidation of fatty acids, glucose, amino acids, and ketone bodies. With each turn of the TCA cycle, there is a net production of three NADH, FADH2, two \(\ce{CO2}\), and one GTP for every acetyl-CoA that enters (figure 4.10).

    Mitochondrial pyruvate carrier arrow pyruvate arrow with enzyme pyruvate dehydrogenase, loss of CO2, NAD+ arrow NADH, and CoA addition to acetyl-CoA arrow into the citric acid cycle (tricarboxylic acid cycle) between oxaloacetate and citrate. Oxaloacetate arrow with enzyme citrate synthase and H2O arrow CoA to citrate arrow with enzyme aconitase and loss of H2O to cis-aconitate arrow with enzyme aconitase and loss of H2O to isocitrate arrow with enzyme isocitrate dehydrogenase, NAD+ arrow NADH, and loss of CO2 to α-ketoglutarate arrow with enzyme α-ketoglutarate dehydrogenase, CoA arrow CO2 and NAD+ arrow NADH to succinyl-CoA arrow with enzyme succinyl-CoA synthetase, Pi addition, CoA loss, GTP bidirectional arrow GDP to succinate arrow with FAD bidirectional arrow FADH2 to succinate dehydrogenase arrow FAD arrow FADH2 to fumarate arrow with enzyme fumarase and loss of H2O to malate arrow with enzyme malate dehydrogenase and NAD+ bidirectional arrow NADH to oxaloacetate. Pyruvate arrow with enzyme pyruvate carboxylase, HCO3- addition, ATP arrow ADP and loss of Pi to oxaloacetate

    Figure 4.10: Overview of the TCA cycle.

    The other major role of the TCA cycle is to provide substrates for other synthetic pathways. Malate is shuttled out of the TCA cycle and used as a substrate for gluconeogenesis and oxaloacetate (OAA) and \(\alpha\)-ketoglutarate are used as substrates for amino acid synthesis. Through transamination reactions, these two keto-acids can be converted into aspartate and glutamate, respectively. \(\alpha\)-ketoglutarate is also a key substrate for the synthesis of neurotransmitters, and succinyl-CoA is the substrate for heme synthesis. Citrate is also a key compound as it is both an intermediate of the TCA cycle and can be shuttled into the cytosol to provide acetyl-CoA for both cholesterol and fatty acid synthesis (figure 4.11).

    Acetyl-CoA enters the TCA cycle arrow citrate arrow α-ketoglutarate arrow succinyl-CoA arrow malate arrow oxaloacetate arrow citrate. Citrate arrow fatty acid synthesis. Α-ketoglutarate arrow amino acid synthesis and neurotransmitter (brain). Succinyl-CoA arrow heme synthesis. Malate arrow gluconeogenesis. Oxaloacetate arrow amino acid synthesis.

    Figure 4.11: Substrates produced by the TCA cycle.

    In order to maintain a pool of TCA cycle intermediates, as substrates are removed from the cycle, there are several key reactions (anaplerotic reactions) that are responsible for the addition of intermediates. These reactions are illustrated in figure 4.12. Notice all of these reactions add carbon back to the cycle from amino acids (reactions 1, 2, 3, 4, 5). These will become very important in the discussion of gluconeogenesis where these substrates will provide the majority of carbon for glucose production. Odd chain fatty acid oxidation can also provide carbon in the from of propionyl-CoA (3) although this is not a primary source of TCA cycle intermediates.

    Carbohydrates, fatty acids, amino acids arrow acetyl-CoA into the TCA cycle as described in figure 4.10. 1: Amino acids arrow pyruvate, CO2, ATP arrow oxaloacetate, ADP, Pi. 2: Α-ketoglutarate bidirectional arrow with TA glutamate. Second bidirectional arrow with GDH add NAD+, lose NADH, NH4+. 3: Valine isoleucine and odd chain fatty acids arrows propionyl-coA arrow succinyl-CoA. 4: Amino acids arrow fumarate.

    Figure 4.12: Anaplerotic reactions of the TCA cycle.

    Regulation of the TCA cycle

    Throughout the cycle, there are two key regulatory and irreversible steps to be aware of. The first is the conversion of isocitrate to \(\alpha\)-ketoglutarate by isocitrate dehydrogenase, and the second is the conversion of \(\alpha\)-ketoglutarate to succinyl-CoA by \(\alpha\)-ketoglutarate dehydrogenase. The two key regulatory points are:

    Isocitrate dehydrogenase, which can be activated by Ca2+ and ADP to increase flux through the cycle, and inhibited by NADH, which would suggest adequate energy in the cell.

    Likewise, \(\alpha\)-ketoglutarate dehydrogenase can be activated by Ca2+ and inhibited by NADH (and succinyl-CoA) (figure 4.13).

    Citrate inhibits citrate synthase. ADP and calcium activate and NADH inhibits isocitrate dehydrogenase. Calcium activates and NADH inhibits α-ketoglutarate dehydrogenase. NADH inhibits malate dehydrogenase.

    Figure 4.13: Regulation of the TCA cycle.

    Malate dehydrogenase can also be inhibited by NADH, however, the reaction is reversible depending on levels of NADH. The oxidation of malate to OAA requires NAD+, and under certain pathological situations the lack of free NAD+ within the mitochondria will reduce the rate of this reaction (this is common in the case of alcohol metabolism).

    Keep in mind that with the addition of each acetyl-CoA (comprised of 2 carbons) to the TCA cycle, two molecules of \(\ce{CO2}\) are released, thus there is no net gain or loss of carbons in the cycle. The process moves forward driven by energetics and substrate availability. The pathway can be active in both the fed and fasted states. In the fed state, acetyl-CoA is generated primarily through glucose oxidation. In contrast, in the fasted state acetyl-CoA is generated primarily from \(\beta\)-oxidation, and the majority of acetyl-CoA is used to synthesize ketones.

    Summary of pathway regulation

    Metabolic pathway Major regulatory enzyme(s) Allosteric effectors Hormonal effects
    TCA cycle Isocitrate dehydrogenase ADP, Ca+ (+) NADH (-)  
    Alpha-ketoglutarate dehydrogenase Ca+ (+) NADH (-)  

    Table 4.2: Summary of pathway regulation.

    References and resources

    Text

    Ferrier, D. R., ed. Lippincott Illustrated Reviews: Biochemistry, 7th ed. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins, 2017, Chapter 6: Bioenergetics and Oxidative Phosphorylation: Section V, VI, Chapter 8: Introduction to Metabolism and Glycolysis, Chapter 9: TCA Cycle and Pyruvate Dehydrogenase Complex: Section IIA, IIB, Chapter 11: Glycogen Metabolism: Section V, VI, Chapter 16: Fatty Acid Ketone Body and TAG Metabolism: Section II, IV, V, Chapter 23: Metabolic Effect of Insulin and Glucagon, Chapter 25: Diabetes Mellitus.

    Le, T., and V. Bhushan. First Aid for the USMLE Step 1, 29th ed. New York: McGraw Hill Education, 2018, 72–78, 85–89.

    Lieberman, M., and A. Peet, eds. Marks' Basic Medical Biochemistry: A Clinical Approach, 5th ed. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins, 2018, Chapter 2: The Fed or Absorptive State, Chapter 19: Basic Concepts of Regulation: Section IV.A.1.2, Chapter 20: Cellular Bioenergetics, Chapter 22: Generation of ATP from Glucose: Section I.A.B.C, III, Chapter 24: Oxidative Phosphorylation and the ETC: Section I.E, II, III, Chapter 31: Synthesis of Fatty Acids: Section I.A.B, IV, V.

    Figures

    Grey, Kindred, Figure 4.10 Overview of the TCA cycle. 2021. https://archive.org/details/4.10-new. CC BY 4.0.

    Grey, Kindred, Figure 4.11 Substrates produced by the TCA cycle. 2021. https://archive.org/details/4.11_20210924. CC BY 4.0.

    Lieberman M, Peet A. Figure 4.12 Anaplerotic reactions of the TCA cycle. Adapted under Fair Use from Marks' Basic Medical Biochemistry. 5th Ed. pp 473. Figure 23.18 Major anaplerotic pathways of the tricarboxylic acid (TCA) cycle. 2017.

    Lieberman M, Peet A. Figure 4.13 Regulation of the TCA cycle. Adapted under Fair Use from Marks' Basic Medical Biochemistry. 5th Ed. pp 468. Figure 23.11 Major regulatory interaction in the tricarboxylic acid (TCA) cycle. 2017. Added ion channel by Léa Lortal from the Noun Project.


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