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Lecture

BIOL 201 - Lectures 7 to 9

14 Pages
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Department
Biology (Sci)
Course Code
BIOL 201
Professor
Greg Brown

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Lecture 7 The tricarboxylic acid (TCA) cycle (Krebs cycle) Common pathway for fuel molecule (carb’s, fats, aa’s) oxidation ∗ Carb’s →pyruvate →acetyl CoA ∗ Allows recovery of much greater portion of free energy than glycolysis ∗ Occurs in mitochondria • Outer membrane is pretty permeable, Inner membrane controls transport. ∗ Mitochondria is the site where ATP is generated through oxidative phosphorylation. TCA cycle overview ∗ Acetyl group of acetyl CoA completely oxidized to CO2 ∗ Electrons removed from acetyl and transferred to NAD and FAD, forming NADH and FADH 2 ∗ 1 GTP formed (substrate level phosphorylation) NADH and FADH 2 formed during cycle reoxidized to NAD and FAD through the action of respiratory or electron transport chain. Eventually these are transferred to oxygen, the terminal electron acceptor! Respiratory chain transfers electrons to O 2o form H O.2Coupled to formation of H+ gradient across inner membrane Discharge of gradient coupled to ATP synthesis Pyruvate + CoA + NAD+→acetyl CoA + CO2+NADH Irreversible, catalyzed by the pyruvate dehydrogenase complex. An oxidative decarboxylation. Carbon dioxide is released (loss of a carbon). At the same time, electrons are releasedand transferred to NAD +to form NADH. The pyruvate dehydrogenase complex Located in mitochondria Three distinct enzymes associated in a huge protein/coenzyme complex (60 polypeptide chains): E1 (thiamine pyrophosphate) {involved in decarboxylations}, E2 (lipoic acid), E3 (FAD) The pyruvate dehydrogenase reaction is irreversibleand highly regulated ∗ Not possible to synthesize carb’s from acetyl CoA ∗ Inhibited by end products NADH and acetyl CoA ∗ Switched off by phosphorylation ∗ Increased NADH/NAD+, acetyl CoA/CoA or ATP/ADP promotes phosphorylation ∗ Pyruvate, ADP inhibit phosphorylation The TCA cycle Lecture 8 TCA cycle summary The equilibrium moves away from oxaloacetate. Hence, the concentration of oxaloacetate is normally very low in the mitochondria. It is likely the limiting factor here, determining the rate of the cycle. Acetyl CoA + 3 NAD + FAD + GDP + P→CoA + 2 CO + 3 NADH + FADH + GTP i 2 2 TCA cycle regulation: Allosteric inhibition. When ATP is low this cycle will be acting in a manner that will help generate ATP. Succinil CoA: End product inhibition. The cycle is inhibited when NADH and ATP are High. TCA cycle as a source of biosynthetic precursor molecules Citrate serves as a vehicle for carrying acetyl groups from the mitochondrion to the cytosol where it can be used to form fatty acids. Transamination: Oxaloacetate to aspartate and α-Ketolutamate to glutamate. Very key for aa snthesis. Succinyl CoA: Porphyrins, inportant for hemes. Oxidation of fatty acids ∗ Lipids →glycerol, fatty acids CoA is a carrier of activated acyl groups ∗ Glycerol →glycolysis ∗ Fatty acids → fatty acyl CoA →acetyl CoA →TCA cycle ∗ Fatty Acyl CoA is thioester bond with fatty acid. Fatty acid oxidation can occur in mitochondria or peroxis omes ∗ Fatty acid →Fa▯y acyl CoA ∗ Pathways similar in both compartments ∗ Products are Fatty acyl CoA that is 2 carbon units shorter and acetyl CoA ∗ In mitochondria, FADH 2 NADH oxidized by respirat ory chain: ADP + Pi →ATP. Acetyl CoA enters: TCA →CO 2 ∗ In peroxisome FADH r2duces O 2 to H2O 2 NADH, acetyl CoA exported ∗ Formation of a double bond ∗ Formation of a β-hydroxy fatty-acyl CoA ∗ Adding a carbonyl group ∗ Forming a shorter acyl CoA. Keep shortening it until we only get Acetyl CoA. Formation of Ketone Bodies When gluconeogeneis and fatty oxidation occur simultaneously, insufficient OAA to react with acetyl CoA produced. Formation of acetoacetate and β-Hydroxy butyrate The blood-brain barrier becomes permeable to Ketone bodies to provide essential energy to the brain. Fatty acid biosynthesis (liver, adipose tissue) Fatty acids are formed from acetyl CoA First step in biosynthesis is the carboxylation ofacetyl CoA to form malonyl CoA, catalyzed bytyl CoA carboxylase Acetyl CoA + HCO3- + ATP → Malonyl CoA + ADP + Pi This cytosolic enzyme has biotin as a cofactor andis inhibited by phosphorylation mediated by AMP-dependent protein kinase: switched off when AMP levels are high. ∗ Switched back on when ATP levels rise ∗ Acyl groups of cytoplasmic malonyl CoA and acetyl CoA get transferred to Acyl carrier protein ∗ Acetyl ACP (2C) and Malonyl ACP (3C) react to form acetoacetyl ACP (4C)and CO2 ∗ Acetoacetyl ACP then undergoes sucessive reduction, dehydration, and reduction to form butyryl ACP ∗ Butyryl ACP will react with malonyl ACP to start asecond series of reactions, leading to the formation of a6 carbon
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