Metabolic Pathways Revision Lecture, January 2024

METABOLISM Cellular Respiration- OVERVIEW Glyceraldehyde 3 Phosphate GLYCOLYSIS in full…..  Gluconeogenic precursors: lactate, glycerol (which is a part of the triglyceride molecule) alanine and glutamine (TCA cycle). Not completely reversible to Glycolysis Pyruvate carboxylase Phospho...

METABOLISM Cellular Respiration- OVERVIEW Glyceraldehyde 3 Phosphate GLYCOLYSIS in full…..  Gluconeogenic precursors: lactate, glycerol (which is a part of the triglyceride molecule) alanine and glutamine (TCA cycle). Not completely reversible to Glycolysis Pyruvate carboxylase Phosphoenolpyruvate carboxykinase Fructose biphosphatase Glucose 6 phosphatase Cytosol/Mitochondria  TCA cycle Glycerol-3 phosphate: brain, muscle 2NADH +2H+ 1.5 ATP Malate Apartate: liver and heart ETC 2.5  TCA CYCLE Function: Harvest high-energy electrons from carbon fuels. Net energy production 2 GTP 6 NADH 2 2 FADH2 3 TCA Regulation 2. Isocitrate dehydrogenase 3. 𝝰-ketoglutarate dehydrogenase STAGE 1 (step 1 -2): Preparation for decarboxylation STAGE 2 (steps 3-5): Decarboxylation and production of energy molecules STAGE 3 (steps 6-8): Regeneration Summary In eukaryotes TCA cycle occurs in mitochondria. It involves a pyruvate decarboxylation (Link reaction) and a series of 8 enzymatic reactions. Function is to harvest high-energy electrons from carbon fuels. Production of 6 NADH and 2 FADH2. 2 GTP is also produced. GTP is the metabolic equivalent of ATP TCA cycle is regulated by isocitrate dehydrogenase and 𝝰 ketoglutarate dehydrogenase allosteric enzymes  Electron Transport Chain (ETC) H + H H H + ++ H + Cyt C Q e- e- H H H + + + ATP ATP ATP ATP  Final Step F0F1 ATP Synthase-Structure F0: Mitochondria 12 c identical subunits proton gradient F1: Matrix 3x αβ subunits catalytic domain that binds to ADP  F0F1 ATP Synthase-Structure 1a & 14c form the proton channel γ & ε form the central stalk δ holds αβ stable & connects with F0  F0F1 ATP Synthase-Structure https://www.youtube.com/watch?v=3y1dO4nNaKY Rotating a subunit c subunit Stationary  https://www.youtube.com/watch?v=k_DQ1FjFuYM https://www.youtube.com/watch?v=CN2XOe_c0iM Open 𝝰 𝝰 AT Loose P AD 𝝱 𝝱 ADP + Pi P 𝛄 𝛄 Pi + 𝝰 𝝰 𝝰 𝝰 𝝱 ATP Tight Open: The formed ATP is released and new ADP + Pi enter Loose: ADP + Pi become trapped and cannot leave Tight: ADP +Pi come close together and form ATP  Aerobic respiration requires O2 Electron transport chain  generates ATP Occurs in mitochondria Series of redox reactions (transfer of electrons) creates H+ gradient Passage of H+ back across inner membrane allows for oxidative phosphorylation ADP + Pi  ATP (via ATP synthase) Oxygen is the terminal electron acceptor METABOLISM Fate of Lipids Triacylglycerol (TAG) comprises three fatty acids esterified to glycerol 1. FA Mobilisation-Hormone Regulation Epinephrine(adrenaline/caffeine) Not in red blood cells or neurons 1. Mobilisation 2. Activation 3. Mitochondria transport  2. FA Activation-Acyl CoA ATP AMP + PPi FREE FA ACYL COA ACETYL COA SYNTHASE  3. Mitochondria Transport  The remaining reactions of b-oxidation take place in the mitochondrion  Therefore the acyl CoA must be transported into the mitochondrion  The acyl CoA is able to cross the outer mitochondrial membrane but not the inner membrane 3. Mitochondria Transport: Carnitine Shuttle  Location: Inside the matrix of the mitochondrion  Event: carnitine acyl- transferase catalyses the transfer of the acyl group to mitochondrial CoA-SH Inside the mitochondria S-CoA S-CoA Fatty acyl CoA b a S-CoA 3. Oxidative Catabolism inside Mitochondria: beta oxidation O Palmitoyl Coenzyme A (C14H) R C (C16H) R S-CoA 4 enzymes TCA cycle O O 8x Acetyl CoA C C (C14H) R S-CoA CH2 S-CoA (C12H) R  First cycle of beta-oxidation  The products are acetyl CoA and a fatty acyl-CoA that is 2 C atoms shorter than the fatty acyl-CoA that entered the cycle.  This shortened molecule then undergoes another round of the b-oxidation cycle  The net products of each round of b -oxidation are one molecule each of acetyl CoA, NADH, FADH2.  Carbon Fates  The number of molecules of acetyl CoA produced overall is half the number of C atoms in the fatty acid.  The number of NADH and FADH2 is half the number of C atoms – 1.  Example 1: There are 18 C atoms in stearic acid 9 acetyl CoA (move to TCA) 8 NADH +8 FADH2  ATP Production O 1 Acetyl CoA= 10ATP C (C16H) R S-CoA 8x Acetyl CoA TCA 80 ATP 7 cycles of β-oxidation: 7x NADH ETC 17.5 ATP 7x FADH2 ETC 10.5 ATP 108 ATP − 2 ATP Per molecule of palmitoyl CoA 106 ATP  Carbohydrates vs Lipids Example: Examples: triacylglycerides sugars Ready cash Saving account Available for immediate use Released when “ready cash” is used up Used for aerobic & anaerobic Used for aerobic respiration More readily digested Less easily digested Energy released: 4Kcal/g Energy released: 9Kcal/g Water soluble Non-water soluble More oxidised (more O Less oxidised (more C & H atoms) atoms) METABOLISM