Citric Acid Cycle PDF

Objectives By the end of this lecture, you will be able to explain the primary role of the Citric Acid Cycle in cellular metabolism. This lecture will introduce you to how the Citric Acid Cycle functions as a key step in extracting energy from food molecules. You will gain a comprehen...

Objectives By the end of this lecture, you will be able to explain the primary role of the Citric Acid Cycle in cellular metabolism. This lecture will introduce you to how the Citric Acid Cycle functions as a key step in extracting energy from food molecules. You will gain a comprehensive understanding of the major steps involved in the Citric Acid Cycle, including the participating molecules and enzymes. This lecture will explore the reactions within the Citric Acid Cycle, identifying how it regenerates a crucial intermediate for further fuel breakdown. You will be able to explain how the Citric Acid Cycle generates energy carriers (NADH and FADH2) that fuel ATP production. This lecture will explore the connection between the Citric Acid Cycle and the Electron Transport Chain, highlighting their roles in cellular respiration.  CITRIC ACID CYCLE The primary function of the citric acid cycle is oxidation of acetyl-CoA to The citric acid cycle, also called carbon dioxide. The energy released the Krebs cycle or the from this oxidation is saved as NADH, tricarboxylic acid (TCA) cycle, is FADH2, and guanosine triphosphate in the mitochondria. Although (GTP). The overall result of the cycle is oxygen is not directly required in represented by the following reaction: the cycle, the pathway will not occur anaerobically because NADH and FADH2 will accumulate if oxygen is not available for the electron transport chain. During catabolism, only about 40% of the energy available from oxidizing glucose is used to synthesize ATP. Remaining 60% is lost as heat. The cycle is central to the Key points of TCA cycle oxidation of any fuel that 1. Isocitrate dehydrogenase, the yields acetyl-CoA, including major control enzyme, is inhibited glucose, fatty acids, ketone by NADH and ATP and activated by bodies, ketogenic amino ADP. acids, and alcohol. There is 2. α-Ketoglutarate dehydrogenase no hormonal control of the is similar to the pyruvate cycle, as activity is dehydrogenase complex. It necessary irrespective of requires thiamine, lipoic acid, CoA, the fed or fasting state. FAD, and NAD. Lack of thiamine Control is exerted by the slows oxidation of acetyl-CoA in the energy status of the cell. citric acid cycle. 3-Succinyl-CoA synthetase (succinate thiokinase) catalyzes a The mitochondrial electron substrate-level phosphorylation of transport chain (ETC) carries GDP to GTP. out the following two Reactions 4-Succinate dehydrogenase is on the inner mitochondrial membrane, where it also functions as complex II of the NADH + O2 -► NAD + H20 electron transport chain. ΔG = -56 kcal/mol 5-Citrate synthase condenses the incoming acetyl group with FADH2 + O2 -► FAD + H20 oxaloacetate to form citrate. ΔG = -42 kcal/mol Sources of NADH, FADH2, and O2 The majority of oxygen ========================== required in a tissue is Many enzymes in the consumed in the electron mitochondria, including transport chain ETC. Its those of the citric acid cycle and pyruvate function is to accept dehydrogenase, produce electrons at the end of NADH which can be oxidized the chain, and the water in the electron transport formed is added to the chain. O2 is delivered to cellular water. tissues by hemoglobin.  Electron Transport  NADH dehydrogenase ( complex I) Chain accepts electrons from NADH NADH is oxidized by NADH  Coenzyme Q (a lipid) dehydrogenase (complex I),  Cytochrome b/c1 (an Fe/heme delivering its electrons into the protein; complex III) chain and returning as NAD to  Cytochrome c (an Fe/heme protein) enzymes that require it. The  Cytochrome a/a3 (a Cu/heme electrons are passed along a protein; cytochrome C oxidase, series of protein and lipid carriers complex IV) transfers electrons to oxygen that serve as the wire. These include, in order:  Proton Gradient The three major complexes I, III, The electricity generated by and IV (NADH dehydrogenase, the ETC is used to run proton cytochrome b/c1 and cytochrome pumps (translocators), which a/ a3) each translocate protons in drive protons from the matrix this way as the electricity passes through them. The end result is space across the inner that a proton gradient is normally membrane into the inter maintained across the membrane space, creating a mitochondrial inner membrane. If small proton (or pH) gradient. proton channels open, the This is similar to pumping any protons run back into the matrix. ion, such as Na+, across a Such proton channels are part of membrane to create a the oxidative phosphorylation complex. gradient.  Oxidative Phosphorylation ATP synthesis by oxidative phosphorylation uses the energy of the proton gradient and is carried out by the F1-F0-ATP synthase complex, which spans the inner membrane as shown previously. As protons flow into the mitochondria through the F0 component, their energy is used by the F1 component (ATPsynthase) to phosphorylate ADP using Pi. On average, when an NADH is oxidized in the ETC, sufficient energy is contributed to the proton gradient for the phosphorylation of 3 ATP by F1F0 ATP synthase. FADH2 oxidation provides enough energy for approximately 2 ATP.  Cyanide Inhibitors Cyanide is a deadly poison because it binds irreversibly to cytochrome a/a3, The ETC is coupled to oxidative preventing electron transfer to oxygen, phosphorylation so that their and producing many of the same changes activities rise and fall together. seen in tissue hypoxia. Inhibitors of any step effectively inhibit the whole coupled process, Carbon monoxide resulting in: Carbon monoxide binds to cytochrome 1- Decreased oxygen consumption a/a3 but less tightly than cyanide. It also 2- Increased intracellular NADH/NAD binds to hemoglobin, displacing oxygen. and FADH2/FAD ratios Symptoms include headache, nausea, 3- Decreased ATP tachycardia, and tachypnea. Lips and Important inhibitors include cheeks turn a cherry-red color. Respiratory depression and coma result cyanide and carbon monoxide. in death if not treated by giving oxygen.  Uncouplers Uncouplers decrease the proton gradient, causing: 1- Decreased ATP synthesis 2- Increased oxygen consumption 3- Increased oxidation of NADH Because the rate of the ETC increases, with no ATP synthesis, energy is released as heat. Important uncouplers include 2,4- dinitrophenol (2,4-DNP) and aspirin (and other salicylates). Brown adipose tissue contains a natural uncoupling protein (UCP, formerly called thermogenin), which allows energy loss as heat to maintain a basal temperature around the kidneys, neck, breastplate, and scapulae in newborns. Note: When adults are cold, our bodies shiver to engage our muscles and produce more body heat. When babies are cold their bodies do not react in the same way. Instead of shivering, babies warm themselves by burning body fat. Babies are born with brown thermogenesis fat, also known as brown fat (because of its color) There are bacterial toxins that can act as indirect uncouplers in the respiratory chain of humans, by increasing membrane permeability to protons (H⁺ ions). This dissipates the proton gradient across the inner mitochondrial membrane, preventing the proton motive force required for ATP synthesis by ATP synthase, effectively uncoupling oxidative phosphorylation.like 1.Pneumolysin by Streptococcus pneumoniae 2. Staphylococcal α-Toxin (Alpha-Hemolysin) by Staphylococcus aureus 3. Listeriolysin O by Listeria monocytogenes These toxins disrupt mitochondrial function by creating pores in membranes, leading to proton leakage and reduced efficiency of ATP production. This is similar to other pore-forming toxins that indirectly lead to uncoupling. These bacterial toxins that have the ability to damage mitochondrial membranes or disrupt cellular ion gradients can lead to uncoupling effects, significantly impairing energy production as ATP in host cells.  The NADH shuttle system, which FATE OF NADH transports the substrate for oxidative metabolism directly from the cytosol to Although most NADH molecules the mitochondrial electron transport are produced by TCA cycle inside chain, has been shown to be essential for glucose-induced activation of of mitochondria, those by mitochondrial metabolism and insulin glycolysis are in cytosol. secretion in adult β-cells. Two pathways Mitochondrial inner membrane that transport reducing equivalents does not have any direct NADH from NADH into mitochondria have transport system. Therefore must been characterized and are known rely on “shuttle” systems for as the glycerol-phosphate shuttle and the malate-aspartate shuttle. It transfers transporting the reducing electrons from the hydrogens of equivalents of cytosolic NADH cytoplasmic NADH to the mitochondrial into mitochondria. electron carriers across the mitochondrial membrane.