Krebs Cycle

11 Key excerpts on "Krebs Cycle"

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  Biochemistry

  • Raymond S. Ochs(Author)
  • 2021(Publication Date)
  • CRC Press

    (Publisher)

  10 The Krebs Cycle

  Thirty years after discovering glycolysis, investigators had identified several intermediates involved in the complete oxidation of pyruvate to CO2 . However, the route itself remained a mystery until Hans Krebs found that pyruvate entered into a reaction with a four-carbon intermediate, producing citric acid, a six-carbon tricarboxylic acid. He also showed that after a series of reactions, the same four-carbon intermediate was regenerated; in other words, the pathway was a cycle. The Krebs Cycle, now considered a landmark study, was published in 1937 as the citric acid cycle (Box 10.1). The result was not well-received, however, for reasons that we explore in this chapter. In fact, many called the route the “Krebs Cycle” not as praise but to suggest that it was just one investigator’s belief. The pathway’s cyclic nature was tentatively accepted, but only the part involving tricarboxylic acid intermediates other than citrate. The pathway was thus referred to as the tricarboxylic acid cycle. Today, the route is well established (Figure 10.1 ), and all three names are used. We choose the Krebs Cycle, as it is pithier, vindicates the findings of a great biochemist, and conforms to the tradition of other named highlights of biochemistry, such as Michaelis–Menten kinetics, the Lineweaver–Burke plot, and the Calvin cycle.

  FIGURE 10.1 Reactions of the Krebs Cycle. The cycle intermediates and their structures are shown as a cycle; acetyl-CoA is the substrate. Cofactors are shown in blue.

  10.1 A Cyclic Pathway

  A series of enzymatic reactions in a cyclic pathway is analogous to the individual steps in an enzymatic reaction. Consider two examples of enzyme reaction mechanisms involved in the formation of ethanol from pyruvate by yeast, drawn in Figure 10.2 as cyclic processes. The first reaction (Figure 10.2a) shows pyruvate decarboxylase (E1) and its other enzyme forms, E1:pyruvate and E1:acetaldehyde, as cycle intermediates. Pyruvate enters the cycle, and the products, CO2 and acetaldehyde, leave. For the second reaction (Figure 10.2b), the cycle intermediates are alcohol dehydrogenase (E2), E2:acetaldehyde and E2:ethanol. Acetaldehyde and NAD+

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  Anatomy and Physiology of Domestic Animals

  • R. Michael Akers, D. Michael Denbow(Authors)
  • 2013(Publication Date)
  • Wiley-Blackwell

    (Publisher)

  There are two critical physiological points to the Krebs Cycle reactions. The first is that some ATP is produced directly via substrate-level phosphorylation of ADP similar to that which occurs in glycolysis. The second and most important is that with each turn of the cycle, reduced forms of the coenzymes NAD and flavin adenine dinucleotide (FAD) are produced. When enzymes of the electron transport chain, also located in the mitochondria, subsequently oxidize these molecules, this yields the energy for synthesis of the vast majority of ATP that can be created from overall catabolism of glucose. We have provided only a skeleton outline showing the names of the intermediates of the Krebs Cycle reactions and locations of specific events. Remember that each molecule of glucose generates two molecules of pyruvate so there are two turns of the cycle for each glucose molecule. Fig. 3.7. Outline of the Krebs Cycle reactions. Since each glucose molecule yields two pyruvate molecules (in the presence of oxygen), this allows two turns of the cycle. With each turn, two carbons are removed from the citric acid (six carbons) by decarboxylation reactions; this leads to the production of the 4-carbon intermediate oxaloacetic acid. Oxaloacetic acid initiates the cycle as it condenses with acetyl-CoA (two carbons) to produce citric acid. Although the pyruvate that entered the mitochondria had three carbons, remember that two carbons were lost as CO 2 to generate acetyl-CoA. Although not “officially” part of the Krebs Cycle, at the time of decarboxylation of the pyruvate, NAD + is simultaneously reduced. Four additional oxidations by the removal of hydrogen atoms occur during the cycle. This yields four molecules of reduced coenzymes (three NADH + H + and one FADH 2). One ATP molecule is made with each turn of the cycle due to the initial creation of GTP, which then provides the phosphate group to make ATP from ADP

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  Biochemistry

  An Integrative Approach with Expanded Topics

  • John T. Tansey(Author)
  • 2022(Publication Date)
  • Wiley

    (Publisher)

  The chemical bonds of acetyl-CoA are still energetically rich. The acetyl group of acetyl-CoA is ultimately oxidized in the citric acid cycle into CO 2, and the electrons obtained in these reactions are used to reduce the electron carriers NAD + and FAD to NADH and FADH 2. The electrons are used in subsequent reactions in the electron transport chain to generate a proton gradient, which subsequently drives ATP production in a process known as oxidative phosphorylation. A second and equally important function of the citric acid cycle is to serve as a central metabolic hub. Many molecules, such as the carbon skeletons of amino acids, are also metabolized through the citric acid cycle. FIGURE 7.1 Citric acid cycle. The citric acid cycle (also known as the tricarboxylic acid cycle or the Krebs Cycle) is the central hub of metabolism. While it oxidizes the carbons of acetyl-CoA to CO 2, it captures the electrons as NADH and FADH 2 for use in electron transport. Various pathways feed into and out of the cycle, linking central metabolism with other pathways. (Source: Karp, Cell and Molecular Biology: Concepts and Experiments, 7e, copyright 2013, John Wiley & Sons. This material is reproduced with permission of John Wiley & Sons, Inc.) 7.1.1 There are eight reactions in the citric acid cycle The citric acid cycle begins with a condensation of acetyl-CoA with oxaloacetate, generating the six-carbon tricarboxylic acid citrate. Citrate contains a tertiary alcohol that cannot be oxidized. In the next reaction, citrate is isomerized to the secondary alcohol isocitrate by the enzyme aconitase, and the isocitrate is then oxidized to α-ketoglutarate by isocitrate dehydrogenase. In this process, a molecule of CO 2 is lost, and electrons from isocitrate are captured by NAD +, generating NADH/H +. Recall that in these reactions the equivalent of a hydride ion is transferred to NAD + forming NADH. The proton is released as a second reaction product and maintains charge balance

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  Biochemistry

  An Integrative Approach

  • John T. Tansey(Author)
  • 2019(Publication Date)
  • Wiley

    (Publisher)

  7.1 The Citric Acid Cycle 211 7.1 The Citric Acid Cycle Acetyl-CoA is an important metabolic intermediate in several pathways. Chapter 6 describes how glucose and other monosaccharides are catabolized into pyruvate. Under aerobic conditions, the fate of most pyruvate is decarboxylation into acetyl-CoA. Likewise, Chapter 9 describes how fatty acids are catabolized into acetyl-CoA. Under normal condi- tions most of this acetyl-CoA enters the citric acid cycle (also known as the tricarboxylic acid cycle or the Krebs Cycle) (Figure 7.2). The chemical bonds of acetyl-CoA are still energetically rich. The acetyl group of acetyl-CoA is ultimately oxidized in the citric acid cycle into CO 2, and the electrons obtained in these reactions are used to reduce the elec- tron carriers NAD + and FAD to NADH and FADH 2 . The electrons are used in subsequent reactions in the electron transport chain to generate a proton gradient, which subse- quently drives ATP production in a process known as oxidative phosphorylation. A second FIGURE 7.2 Citric acid cycle. The citric acid cycle (also known as the tricarboxylic acid cycle or the Krebs Cycle) is the central hub of metabolism. While it oxidizes the carbons of acetyl-CoA to CO 2 , it captures the electrons as NADH and FADH 2 for use in electron transport. Various pathways feed into and out of the cycle, linking central metabolism with other pathways. (Karp, Cell and Molecular Biology: Concepts and Experiments, 7e, copyright 2013, John Wiley & Sons. This material is reproduced with permission of John Wiley & Sons, Inc.) Oxaloacetate and acetyl-CoA undergo a Claisen condensation to give citrate. 1 CH 3 C O S CoA Acetyl-CoA Hydroxyl group oxidized to a carbonyl, yielding oxaloacetate and NADH. 8 Double bond is hydrated to an alcohol. 7 Saturated C–C bond is desaturated. The electrons are captured as FADH 2 . 6 Hydrolysis of CoA from succinate is a substrate-level phosphorylation, generating ATP or GTP.

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  New and Future Developments in Microbial Biotechnology and Bioengineering

  Microbial Secondary Metabolites Biochemistry and Applications

  • Vijai G. Gupta, Anita Pandey(Authors)
  • 2019(Publication Date)
  • Elsevier

    (Publisher)

  Chapter 13

  Citric Acid Cycle Regulation: Back Bone for Secondary Metabolite Production

  Punit Kumar1 and Kashyap Kumar Dubey2 ,    

  1 Microbial Process Development Laboratory, University Institute of Engineering and Technology, Maharshi Dayanand University, Rohtak, Haryana, India

  ,    

  2 Bioprocess Engineering Laboratory, Department of Biotechnology, Central University of Haryana, Mahendergarh, Haryana, India

  Abstract

  The citric acid cycle (CAC) is recognized as the central hub of a large number of metabolic pathways. It is commonly known as the Krebs Cycle or tricarboxylic acid cycle. It starts from the reaction between oxaloacetate and actyl CoA. It is an enzyme-controlled metabolic cycle involved in metabolizing of biomolecules. The main purpose of the CAC is to furnish the energy demand of all types of cells but its intermediates are used as precursors in the biosynthesis of metabolites, thus different metabolic pathways are joined with the CAC making a network of metabolic pathways. The utilization of CAC flux in energy generation or in the biosynthesis of a metabolite depends on the energy requirements of the cell and physiological conditions. The control and regulation of the CAC reactions have great significance in cell metabolism and the utilization of flux in biomolecule biosynthesis. Researchers are using CAC manipulations (metabolic engineering) to enhance the yield of desired metabolites by altering the flux of specific intermediates or the overexpression of enzymes to catalyze more product formation.

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  Concepts of Biology

  • Samantha Fowler, Rebecca Roush, James Wise(Authors)
  • 2016(Publication Date)
  • Openstax

    (Publisher)

  Acetyl CoA can be used in a variety of ways by the cell, but its major function is to deliver the acetyl group derived from pyruvate to the next pathway in glucose catabolism. 104 Chapter 4 | How Cells Obtain Energy This OpenStax book is available for free at http://cnx.org/content/col11487/1.9 Figure 4.14 Pyruvate is converted into acetyl-CoA before entering the citric acid cycle. Like the conversion of pyruvate to acetyl CoA, the citric acid cycle in eukaryotic cells takes place in the matrix of the mitochondria. Unlike glycolysis, the citric acid cycle is a closed loop: The last part of the pathway regenerates the compound used in the first step. The eight steps of the cycle are a series of chemical reactions that produces two carbon dioxide molecules, one ATP molecule (or an equivalent), and reduced forms (NADH and FADH 2 ) of NAD + and FAD + , important coenzymes in the cell. Part of this is considered an aerobic pathway (oxygen-requiring) because the NADH and FADH 2 produced must transfer their electrons to the next pathway in the system, which will use oxygen. If oxygen is not present, this transfer does not occur. Two carbon atoms come into the citric acid cycle from each acetyl group. Two carbon dioxide molecules are released on each turn of the cycle; however, these do not contain the same carbon atoms contributed by the acetyl group on that turn of the pathway. The two acetyl-carbon atoms will eventually be released on later turns of the cycle; in this way, all six carbon atoms from the original glucose molecule will be eventually released as carbon dioxide. It takes two turns of the cycle to process the equivalent of one glucose molecule. Each turn of the cycle forms three high-energy NADH molecules and one high-energy FADH 2 molecule. These high-energy carriers will connect with the last portion of aerobic respiration to produce ATP molecules. One ATP (or an equivalent) is also made in each cycle.

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  Biology for AP® Courses

  • Julianne Zedalis, John Eggebrecht(Authors)
  • 2018(Publication Date)
  • Openstax

    (Publisher)

  Figure 7.9 Upon entering the mitochondrial matrix, a multi-enzyme complex converts pyruvate into acetyl CoA. In the process, carbon dioxide is released and one molecule of NADH is formed. Note that during the second stage of glucose metabolism, whenever a carbon atom is removed, it is bound to two oxygen atoms, producing carbon dioxide, one of the major end products of cellular respiration. Acetyl CoA to CO 2 In the presence of oxygen, acetyl CoA delivers its acetyl group to a four-carbon molecule, oxaloacetate, to form citrate, a six-carbon molecule with three carboxyl groups; this pathway will harvest the remainder of the extractable energy from what began as a glucose molecule. This single pathway is called by different names: the citric acid cycle (for the first intermediate formed—citric acid, or citrate—when acetate joins to the oxaloacetate), the TCA cycle (since citric acid or citrate and isocitrate are tricarboxylic acids), and the Krebs Cycle, after Hans Krebs, who first identified the steps in the pathway in the 1930s in pigeon flight muscles. Citric Acid Cycle Like the conversion of pyruvate to acetyl CoA, the citric acid cycle takes place in the matrix of mitochondria. Almost all of the enzymes of the citric acid cycle are soluble, with the single exception of the enzyme succinate dehydrogenase, which is embedded in the inner membrane of the mitochondrion. Unlike glycolysis, the citric acid cycle is a closed loop: The last part of the pathway regenerates the compound used in the first step. The eight steps of the cycle are a series of redox, dehydration, hydration, and decarboxylation reactions that produce two carbon dioxide molecules, one GTP/ATP, and reduced forms of NADH and FADH 2 (Figure 7.10). This is considered an aerobic pathway because the NADH and FADH 2 produced must transfer their electrons to the next pathway in the system, which will use oxygen.

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  Essential Biochemistry

  • Charlotte W. Pratt, Kathleen Cornely(Authors)
  • 2017(Publication Date)
  • Wiley

    (Publisher)

  The carbon skeletons of amino acids are broken down to either pyruvate or acetyl-CoA, and fatty acids are broken down to acetyl-CoA. In some tissues, the bulk of acetyl-CoA entering the citric acid cycle comes from fatty acids rather than carbohydrates or amino acids. Whatever their source, the citric acid cycle converts all these two-carbon acetyl groups into CO 2 and LEARNING OBJECTIVE Describe the substrate, product, and type of chemical reaction for each step of the citric acid cycle. 366 CHAPTER 14 The Citric Acid Cycle therefore represents the final stage in fuel oxidation (Fig. 14.5). As the carbons become fully oxidized to CO 2 , their energy is conserved and subsequently used to produce ATP. The eight reactions of the citric acid cycle take place in the cytosol of prokar- yotes and in the mitochondria of eukaryotes. Unlike a linear pathway such as glycolysis (see Fig. 13.2) or gluconeogenesis (see Fig. 13.10), the citric acid cycle always returns to its starting position, essentially behaving as a multistep catalyst. The cycle as a whole is highly exergonic, and free energy is conserved at sev- eral steps in the form of a nucleotide triphosphate (GTP) and reduced cofactors. For each acetyl group that enters the citric acid cycle, two molecules of fully oxidized CO 2 are produced, representing a loss of four pairs of electrons. These electrons are transferred to 3 NAD + and 1 ubiquinone (Q) to produce 3 NADH and 1 QH 2 . The net equation for the citric acid cycle is therefore acetyl-CoA + GDP + P i + 3 NAD + + Q → 2 CO 2 + CoA + GTP + 3 NADH + QH 2 In this section we examine the sequence of eight enzyme-catalyzed reactions of the citric acid cycle, focusing on a few interesting reactions.

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  Landmark Experiments in Protein Science

  • Pascal Leclair(Author)
  • 2023(Publication Date)
  • CRC Press

    (Publisher)

  5 The Energy of Cells Part I Glycolysis and the Krebs Cycle

  DOI: 10.1201/9781003379058-5

  Glycolysis comes from the Greek meaning “splitting of sugar” and it is a process whereby sugars get broken down in a chain of events that leads to the production of energy which cells can use to power cellular processes. As we will see in this chapter, in the absence of oxygen, the metabolism of sugar yields lactic acid in multicellular organisms and ethanol in fermenting yeast, but only a small amount of energy can be produced from this pathway and energy stocks are rapidly depleted. However, in presence of oxygen, pyruvic acid is produced instead, and this molecule is further processed in a second pathway, the Krebs Cycle (also called the tricyclic or citric acid cycle) where most of the energy used by cells is produced, with CO2 and water as by-products. The complexity of these pathways—multi-step processes which include more than two dozen enzymes, most of which acting sequentially on the breakdown of carbohydrates—led to much confusion in the first quarter of the 20th century (and in the writing of this chapter …). As such, to fully understand the metabolism of sugars into usable energy, we must first go back to the process of fermentation.

  We saw in Chapter 3 that the Buchner brothers had put to rest the vitalistic versus enzyme theory of fermentation in the late 1800s, which resulted in the realization that cellular processes were performed not by an intrinsic force but rather by a complement of enzymes that catalyze chemical reactions. Specifically, they had ascribed the process of fermentation to one enzyme, zymase, which was found to be essential for fermentation, but could not bring it about on its own. They subsequently found that zymase was dependent on a second enzyme, which was named, aptly enough, co-enzyme.1

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  Biochemistry

  • Donald Voet, Judith G. Voet(Authors)
  • 2021(Publication Date)
  • Wiley

    (Publisher)

  19 Citric Acid Cycle

  1 Cycle Overview

  A. Reactions of the Cycle

  B. Historical Perspective

  2 Metabolic Sources of Acetyl-Coenzyme A

  A. Pyruvate Dehydrogenase Multienzyme Complex (PDC)

  B. The Mechanism of Dihydrolipoyl Dehydrogenase

  C. Control of Pyruvate Dehydrogenase

  3 Enzymes of The Citric Acid Cycle

  A. Citrate Synthase

  B. Aconitase

  C. NAD+ -Dependent Isocitrate Dehydrogenase

  D. α-Ketoglutarate Dehydrogenase

  E. Succinyl-CoA Synthetase

  F. Succinate Dehydrogenase

  G. Fumarase

  H. Malate Dehydrogenase

  I. Integration of the Citric Acid Cycle

  4 Regulation of The Citric Acid Cycle

  5 The Amphibolic Nature of The Citric Acid Cycle

  6 The Glyoxylate Cycle

  In this chapter we continue our metabolic explorations by examining the citric acid cycle, the common mode of oxidative degradation in eukaryotes and prokaryotes. This cycle, which is alternatively known as the tricarboxylic acid (TCA) cycle and the Krebs Cycle, marks the “hub” of the metabolic system: It accounts for the major portion of carbohydrate, fatty acid, and amino acid oxidation and generates numerous biosynthetic precursors. The citric acid cycle is therefore amphibolic, that is, it operates both catabolically and anabolically.

  We begin our study of the citric acid cycle with an overview of its component reactions and a historical synopsis of its elucidation. Next, we explore the origin of the cycle's starting compound, acetyl-coenzyme A (acetyl-CoA), the common intermediate formed by the breakdown of most metabolic fuels. Then, after discussing the reaction mechanisms of the enzymes that catalyze the cycle, we consider the various means by which it is regulated. Finally, we deal with the citric acid cycle's amphibolic nature by examining its interrelationships with other metabolic pathways.

  1 Cycle Overview

  See Guided Exploration 18: Citric acid cycle overview The citric acid cycle (Fig. 19-1

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  Pratt's Essential Biochemistry

  • Charlotte W. Pratt, Kathleen Cornely(Authors)
  • 2020(Publication Date)
  • Wiley

    (Publisher)

  4. Identify the steps that generate ATP, CO 2 , and reduced cofactors. Because the eighth reaction of the citric acid cycle returns the system to its original state, the entire pathway acts in a catalytic fashion to dispose of carbon atoms derived from amino acids, carbohydrates, and fatty acids. Albert Szent-Györgyi discovered the catalytic nature of the pathway by observing that small additions of organic compounds such as suc- cinate, fumarate, and malate stimulated O 2 uptake in a tissue preparation. Because the O 2 consumption was much greater than would be required for the direct oxidation of the added substances, he inferred that the compounds acted catalytically. THE CITRIC ACID CYCLE IS AN ENERGY-GENERATING CATALYTIC CYCLE We now know that oxygen is consumed during oxidative phosphorylation, the process that reoxidizes the reduced cofactors (NADH and QH 2 ) that are produced by the citric acid cycle. Although the citric acid cycle generates one molecule of GTP (or ATP), considerably more ATP is generated when the reduced cofactors are reoxidized by O 2 . Each NADH yields approximately 2.5 ATP, and each QH 2 yields approxim- ately 1.5 ATP (we will see in Section 15.4 why these values are not whole numbers). Every acetyl unit that enters the citric acid cycle can therefore generate a total of 10 ATP equivalents. The energy yield of a molecule of glucose, which generates two acetyl units, can be calculated (Fig. 14.13). A muscle operating anaerobically produces only 2 ATP per glucose, but under aerobic conditions when the citric acid cycle is fully func- tional, each glucose molecule generates about 32 ATP equivalents. This general phenomenon is called the Pasteur effect, after Louis Pasteur, who first observed that the rate of glucose consumption by yeast cells decreased dramatically when the cells were shifted from anaerobic to aerobic growth conditions.

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