Carbohydrate Metabolism (3) PDF

Carbohy drate M etabolism(3) Dr. Walaa AL-Jedda (2024-2025) Pyruvate Metabolism (1) 1 Formation of pyruvic acid (P.A.) in the body: 1- From oxidation of glucose (glycolysis). 2- From lactic acid by oxidation. 3- Deamination of alanin...

Carbohy drate M etabolism(3) Dr. Walaa AL-Jedda (2024-2025) Pyruvate Metabolism (1) 1 Formation of pyruvic acid (P.A.) in the body: 1- From oxidation of glucose (glycolysis). 2- From lactic acid by oxidation. 3- Deamination of alanine. 4- Glucogenic amino acids-pyruvate forming. 5- Decarboxylation of oxaloacetic acid (OAA) Fate of pyruvic acid (P.A.): 1- Form acetyl CoA by oxidative decarboxylation ( in presence of O 2 ) 2- Forms lactic acid by reduction (in absence of O 2 ). 3- Forms alanine by amination. 4- Forms glucose (gluconeogenesis). 5- Forms malic acid → to O.A.A (oxaloacetic acid). 6- Forms oxaloacetic acid (O.A.A) by CO 2 -fixation reaction (carboxylation). 2 (2) 3  Before pyruvate can enter the TCA cycle, it must be transported into the mitochondria via a special pyruvate transporter that aids its passage across the inner mitochondrial membrane. Within the mitochondria, pyruvate is oxidatively decarboxylated to acetyl-CoA; this reaction is catalyzed by sequentially multienzyme complex (pyruvate dehydrogenase complex). The citric acid cycle (TCA) cycle 1- TCA cycle (tricarboxylic acid cycle), also known as the citric acid cycle or the Krebs’ cycle, is the major energy production pathways in the body. *The cycle occurs in the mitochondria. 2- It is a cyclic process. 3-The cycle involves a sequence of compounds inter-related by oxidation- reduction and other reactions which finally produces [CO 2 and H 2 O]. 4- It is the final common pathway of breakdown or catabolism of carbohydrates, fats and proteins. 5-Acetyl CoA derived mainly from oxidation of either glucose or β-oxidation of FA and partly from certain amino acids combines with oxaloacetic acid (OAA) to form “citrate” the first reaction of TCA cycle. 4  In this reaction acetyl CoA transfers its' acetyl-group' (2 C) to OAA. 6- By stepwise dehydrogenations and loss of two molecules of CO 2 , accompanied by internal re-arrangements, the citric acid is reconverted to OAA, which again starts the cycle by taking up another acetyl group from acetyl-CoA. 7-All the enzymes of the TCA cycle are in the mitochondrial matrix, except succinate dehydrogenase which is in the inner mitochondrial membrane. 8-Electrons are transferred by the cycle to NAD+ (Nicotinamide Adenine Dinucleotide) and FAD (Flavin Adenine Dinucleotide). 9-As the electrons subsequently are passed to O 2 by the electron transport chain, ATP is generated by the process of oxidative phosphorylation. 10-ATP is also generated from GTP (Guanosine Triphosphate), produced in one reaction of the cycle by substrate level phosphorylation. 11-The whole process is aerobic, requiring O 2 as the final oxidant of the reducing equivalents. Absence of O 2 (anoxia) or partial deficiency of O 2 (hypoxia) causes total or partial inhibition of the cycle. 12-The H atoms removed in the successive dehydrogenations are accepted by corresponding coenzymes. Reduced coenzymes transfer the reducing equivalents to electron-transport system, where oxidative phosphorylation product ATP molecules. 5  There are three key enzymes in TCA cycle: [Fig.(4)] 1-Citrate synthase (1) 2- Isocitrate dehydrogenase (I.C.D) (3) 3- α-ketoglutarate dehydrogenase (4) or named α-oxoglutarate dehydrogenase 6 (4) 7 8 9 Biomedical importance of TCA cycle: Final common pathway for carbohydrates, proteins and fats, through formation of 2 – carbon unit acetyl-CoA. Acetyl-CoA is oxidized to CO 2 and H2 O giving out energy (Catabolic role). Intermediates of TCA cycle play a major role in synthesis also like heme formation, formation of non essential amino acids, FA synthesis, cholesterol and steroid synthesis (anabolic role). - TCA cycle is called Amphibolic in nature because TCA cycle has dual role catabolic and anabolic. Energy produced by the TCA cycle: The net reaction for the oxidation of one acetyl unit is: Acetyl - CoA + 3NAD+ + FAD + GDP + Pi → 2CO 2 + 3NADH + 3H+ + FADH 2 + GTP + CoA Four pairs of electrons are transferred during one turn of the cycle, three pairs of electrons reducing NAD+ → NADH and, one pair reducing FAD → FADH 2. 10 So the number of ATP molecules produced from the oxidation of one molecule of acetyl CoA (using both substrate – level and oxidative phosphorylation). Energy – producing reaction Number of ATP produced 3NADH → 3NAD+ 3x3=9 FADH 2 → FAD 2x1=2 GDP + P i → GTP 1x1=1 Net gain : 12 ATP The overall energy production in glycolysis and TCA cycle of O 2 is summarized in this table. 11 Maximal ATP Production Overall, when 1 mole of glucose is oxidized to CO 2 and H 2 O, approximately (36 moles) of ATP are produced if the glycerol phosphate shuttle is used, or (38 moles) if the malate aspartate shuttle is used. Note : Assuming each high energy bond to be equivalent to 7600 calories. Total energy captured in ATP per mol. of glucose oxidized: =7600× 38= 288,800 calories. 12  Lec. ( 4 ) Electron Transport Chain and Oxidative Phosphorylation Electron Transport Chain: This is the final common pathway in aerobic cells by which electrons derived from various substrates are transferred to oxygen. Electron transport chain (ETC) is a series of highly organized oxidation- reduction enzymes. The ETC is localized in the mitochondria. Energy-rich molecules, such as glucose, are metabolized by a series of oxidation reactions ultimately yielding CO 2 and water. ATP is generated as a result of the energy produced when electrons from NADH and FADH 2 are passed to molecular oxygen by a series of electron carriers, collectively known as the electron transport chain. The components of the chain include: FMN (Flavin mononucleotide), Fe-S centers, coenzyme Q, and a series of cytochromes (b, c 1 , c and aa 3 ). The electron transport chain in the mitochondrial membrane has been separated on four (4) complexes, their components as follows: 1- Complex I : NADH – CoQ reductase. This system has two functions: 1-Electron transfer. 2-Acts as a proton pump. NADH + H+ + FMN → FMN.H 2 + NAD+ 13 2- Complex II: Succinate – CoQ Reductase. Flow of electrons from succinate to CoQ occurs via FAD.H 2. Succinate + CoQ → Fumarate + CoQ.H 2 3- Complex III: CoQ – Cyt.C Reductase. Function as: 1- Proton pump, and 1- Catalyzes transfer of electrons. 2- Fe+3 accepts electron and is oxidized to Fe+2 Co.Q.H 2 + 2 Cyt.C (Fe+3) → Co.Q + 2 Cyt.C (Fe+2) + 2H+ 4- Complex IV: Cyt.C oxidase. The system functions: 1- As proton pump. 2- Catalyzes transfer of electrons from Cyt.C to molecular O 2 to form H 2 O via Cyt.a, Cu+2 ions and Cyt. a 3. 4Cyt.C (Fe+2) + 4H+ + O 2 → 4 Cyt.C (Fe+3) + 2H 2 O The flow of electrons is as follows: Cyt. C → Cyt. a → Cu+2 → Cyt. a 3 → O 2 The energy change permits ATP formation between Cyt. a 3 and molecular O2. * Note: Cyt. C does not form a part of any complexes. It is mobile and acts as a shuttle between complex – III and complex – IV to transfer e- (electron). 14 (6) 15  The energy derived from the transfer of electrons through the electron transport chain is used to pump protons across the inner mitochondrial membrane from the matrix to the cytosolic side. An electrochemical gradient is generated, consisting of a proton gradient and a membrane potential. Protons moves back into the matrix through the ATP synthase complex, causing ATP to be produced from ADP and inorganic phosphate. ATP is transported from the mitochondrial matrix to the cytosol in exchange for ADP (the ATP-ADP antiport system). 16 17 - The oxidation of NADH generates approximately (3 ATP), while the oxidation of one FADH 2 generates approximately (2 ATP). - Because energy generated by transfer of electrons through the electron transport chain to O 2 is used in the production of ATP, the overall process is known as oxidative phosphorylation. - Electron transport and ATP production occur simultaneously and are tightly coupled. - NADH and FADH 2 are oxidized only if ADP is available for conversion to ATP. (9) 18  (10) The energy transformations occurring during oxidative -The energy transformation occurring during oxidative phosphorylation may be summarized as follows: Electron transport → energy → proton gradient → ATP synthesis 19 (11) 20 Clinical correlations: - Cyanide poisoning: Cyanide binds to Fe+3 in cytochrome aa 3. As a result, O 2 cannot receive electrons, respiration is inhibited, energy production is halted, and death occurs rapidly. After cyanide poisoning, the electron transport chain can no longer pump electrons into the intermembrane space. The pH of the intermembrane space would increase, and ATP synthesis would stop. -Acute myocardial infarction: Coronary arteries frequently become narrow because of atherosclerotic plaques. If coronary occlusions occur, regions of heart muscle may be deprived of blood flow and, therefore, of oxygen for prolonged periods of time. Lack of oxygen causes inhibition of the processes of electron transport and oxidative phosphorylation, which results in a decreased production of ATP. Heart muscle, suffering from a lack of energy required for contraction and maintenance of membrane integrity, becomes damaged. Enzymes from the damaged cells (including the MB fraction of creatine kinase) leak into the blood. If the damage is relatively mild, the person may recover. If heart function is severely compromised, death may result. 21 22