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    TCA Cycle Lecture

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    Hadi
    1. The citric acid cycle is the final common pathway where carbohydrates, fatty acids, and amino acids are oxidized to harvest energy in the form of ATP, NADH, and FADH2. 2. The cycle occurs in the mitochondria and produces carbon dioxide and reduced coenzymes that generate most of the cell's ATP through oxidative phosphorylation. 3. In addition to energy production, the citric acid cycle provides precursors for biosynthesis of other molecules.

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    TCA Cycle Lecture

    Uploaded by

    Hadi
    14 views19 pages
    1. The citric acid cycle is the final common pathway where carbohydrates, fatty acids, and amino acids are oxidized to harvest energy in the form of ATP, NADH, and FADH2. 2. The cycle occurs in the mitochondria and produces carbon dioxide and reduced coenzymes that generate most of the cell's ATP through oxidative phosphorylation. 3. In addition to energy production, the citric acid cycle provides precursors for biosynthesis of other molecules.

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    1. The citric acid cycle is the final common pathway where carbohydrates, fatty acids, and amino acids are oxidized to harvest energy in the form of ATP, NADH, and FADH2. 2. The cycle occurs in the mitochondria and produces carbon dioxide and reduced coenzymes that generate most of the cell's ATP through oxidative phosphorylation. 3. In addition to energy production, the citric acid cycle provides precursors for biosynthesis of other molecules.

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    © All Rights Reserved
    Download as PDF, TXT or read online from Scribd
    Download as pdf or txt
    14 views19 pages

    TCA Cycle Lecture

    Uploaded by

    Hadi
    1. The citric acid cycle is the final common pathway where carbohydrates, fatty acids, and amino acids are oxidized to harvest energy in the form of ATP, NADH, and FADH2. 2. The cycle occurs in the mitochondria and produces carbon dioxide and reduced coenzymes that generate most of the cell's ATP through oxidative phosphorylation. 3. In addition to energy production, the citric acid cycle provides precursors for biosynthesis of other molecules.

    Copyright:

    © All Rights Reserved
    Download as PDF, TXT or read online from Scribd
    Download as pdf or txt
    of 19

    Triacylcaboxylic Acid Cycle

    Overview
    • TCA cycle also called the Krebs cycle or the citric acid cycle, plays several roles in
    metabolism.
    • It is final pathway where the oxidative metabolism of carbohydrates, amino acids, &
    fatty acids converge, their carbon skeletons being converted to CO2.
    • This oxidation provides energy for the production of the majority of ATP in most
    animals, including humans.
    • The cycle totally occurs totally in the mitochondria & is, therefore, in close proximity to
    the reactions of electron transport, which oxidize the reduced coenzymes produced by
    the cycle.
    • The TCA cycle is a an aerobic pathway, because O2 is required as the final electron
    acceptor.
    • The TCA cycle also participates in a number of important synthetic reaction e.g
    formation of glucose from the carbon skeletons of some amino acids, and it provides
    building blocks for the synthesis of some amino acid and heme.
    • The cycle should not be viewed as a closed circle, but instead as a traffic circle with
    compounds entering & leaving as required.

    2
    The Citric Acid Cycle
    The citric acid cycle is the final common pathway for the oxidation of fuel molecules:
    amino acids, fatty acids, & carbohydrates.

    • Most fuel molecules enter the cycle as acetyl coenzyme A


    • This cycle is the central metabolic hub of the cell
    • It is the gateway to aerobic metabolism for any molecule that can be transformed
    into an acetyl group or dicarboxylic acid,
    • It is also an important source of precursors for building blocks
    • Also known as, Krebs Cycle, & Tricarboxylic Acid Cycle (TCA)

    ØThe citric acid cycle oxidizes two-carbon units


    ØEntry to the cycle and metabolism through it are controlled
    ØThe cycle is a source of biosynthetic precursors

    3
    Introduction
    1. The function of the cycle is the harvesting of high-energy
    electrons from carbon fuels
    2. The cycle itself neither generates ATP nor includes O2 as a
    reactant
    3. Instead, it removes electrons from acetyl CoA & uses them to
    form NADH & FADH2 (high-energy electron carriers)
    4. In oxidative phosphorylation, electrons from reoxidation of
    NADH & FADH2 flow through a series of membrane proteins
    (electron transport chain) to generate a proton gradient
    5. These protons then flow back through ATP synthase to
    generate ATP from ADP & inorganic phosphate
    6. O2 is the final electron acceptor at the end of the electron
    transport chain
    7. The cytric acid cycle + oxidative phosphorylation provide
    > 95% of energy used in human aerobic cells

    4
    Citric Acid Cycle: Overview
    Input: 2-carbon units
    Output: 2 CO2, 1 GTP,
    & 8 high-energy
    electrons

    5
    Dehydration synthesis or condensation reaction

    Oxaloacetate 4 C molecule:
    Acetyl CoA transfers its acetyl group to
    the #2 carbonyl carbon via
    the methyl end.
    This forms a 6 C citrate molecule.
    First dehydration then hydration. Why?
    Aconitase enzyme catalyzes both reactions

    Citrate:
    Note that it is a tertiary alcohol which is not oxidizable.
    Isomer is a 2o alcohol (isocitrate) that can be oxidized
    First of 4 Redox reactions,
    followed by decarboxylation.
    NAD+ is the oxidizing agent.
    Isocitrate dehydrogenase is the catalyst

    Alpha ketoglutarate (a ketone) is formed


    when Isocitrate is oxidized,
    leading to the reduction of NAD+ to NADH,
    & also decarboxylated (first CO2 formed)
    Redox reaction #2:
    Oxidation of a-ketoglutarate
    into 4 C Succinyl CoA (also a ketone)
    again more CO2 and NADH are formed

    Three enzymes used as a group:


    a-ketoglutarate dehydrogenase complex.
    H atom must be removed from
    sulfhydryl group for coenzyme A to form
    a high energy thioester bond.
    Pyurvate dehydrogenase complex
    A large, highly integrated complex of three kinds of enzymes

    Pyruvate + CoA + NAD+ Þ acetyl CoA + CO2 + NADH

    Groups travel from one active site to another, connected by


    tethers to the core of the structure

    11
    Summary of total energy yield of complete
    oxidation of 1 glucose molecule
    Step Coenzyme ATP Source of ATP
    Yield Yield
    Glycolysis –Stage 1 - 2 Phosphorylation of glucose and
    fructose uses 2 ATP
    Glycolysis –Stage 2 4 Substrate level phosphorylation
    2 NADH 6 Oxidative phosphorylation
    Pyruvate metabolism 2 NADH 6 Oxidative phosphorylation
    TCA cycle 2 Substrate level phosphorylation
    6 NADH 18 Oxidative phosphorylation
    2 FADH2 4 Oxidative phosphorylation
    Total Yield 38 ATP
    Inhibitors of TCA Cycle
    • Fluoroacetyl CoA:
    -It inhibits aconitase enzyme
    -It combines with oxaloacetate giving rise to fluorocitrate .
    • Malonic acid:
    -Inhibits succinate dehydrogenase (competitive
    inhibition)
    • Arsenate and Mercury :
    -Inhibit Pyruvate dehydrogenase and α-ketoglutarate
    dehydrogenase complexs.
    - By reacting with sulphydral group of lipoic acid leading
    to accumulation of pyruvic lactic acid and α-
    ketoglutarate.
    Regulation of CAC:
    Rate controlling enzymes:
    Citrate synthatase
    Isocitrate dehydrogenase
    a-keoglutaratedehydrogenase

    Regulation of activity by:


    Substrate availability
    Product inhibition
    Allosteric inhibition or activation by
    other intermediates

    14
    Regulation of pyruvate dehydrogenase

    Inhibited by products,
    NADH & Acetyl CoA

    Also regulated by covalent modification,


    the kinase & phosphatase also regulated

    15
    Biosynthetic roles of the citric acid cycle

    16
    Arsenic Compound poisoning: Inactivation of E-2 of PDC, and other proteins.

    Organic Arsenical were used


    as antibiotics for the treatment
    of syphilis and
    trypanosomiasis.
    Micro-organisms are more
    sensitive to organic arsenicals
    than humans.
    But these compounds had
    severe side effects and As-
    poisoning.
    Fowler’s solution, the famous
    19th century tonic contained
    10mg/ml As. Charles Darwin
    died of As poisoning by taking
    this tonic.
    Napoleon Bonaparte’s death
    was also suspected to be due
    to As poisoning.

    17
    Thiamin (Vitamine B1) deficiency causes Beriberi:
    Thiamine pyrophosphate (TPP) is an important cofactor of pyruvate
    dehydrogenase complex, or PDC a critical enzyme in glucose metabolism.
    Thiamine is neither synthesized nor stored in good amounts by most vertebrates.
    It is required in the diets of most vertebrates. Thiamine deficiency ultimately
    causes a fatal disease called Beriberi characterized by neurological disturbances,
    paralysis, atrophy of limbs and cardiac failure. Note that brain exclusively uses
    aerobic glucose catabolism for energy and PDC is very critical for aerobic
    catabolism. Therefore thiamine deficiency causes severe neurological symptoms.
    Arsenic Poisoning: Arsenic compounds such as arsenite (AsO3---) organic
    arsenicals are poisonous because they covalently bind to sulfhydryl compounds
    (SH- groups of proteins and cofactors). Dihydrolipoamide is a critical cofactor of
    PDC, and it has two-SH groups, which are important for the PDC reaction. These
    –SH groups are covalently inactivated by arsenic compounds as shown below;
    OH HS S
    -O As + -O As + 2H2O
    OH HS S
    R R

    18
    Arsenic compounds in low doses are very toxic to microorganisms,
    therefore these compounds were used for the treatment of syphilis and
    other diseases in earlier days. Arsenicals were first antibiotics, but with a
    terrible side effects as they are eventually very toxic to humans.
    Unfortunately and ignorantly, a common nineteenth century tonic, the
    Fowler’s solution contained 10 mg/ml arsenite. This tonic must have
    been responsible for many deaths, including the death of the famous
    evolution scientist Charlse Darwin.

    19

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