Carbohydrates 3 VP 2024 PDF

Electron Transport Chain (Respiratory Chain) The ETC passes electrons from NADH and FADH2 to protein complexes and mobile electron carriers (CoQ and cytochrome C)  Compounds known to inhibit these proteins complexes are known to be lethal Electrons ultimately combine with O2 and H+ to form H2O (met...

Electron Transport Chain (Respiratory Chain) The ETC passes electrons from NADH and FADH2 to protein complexes and mobile electron carriers (CoQ and cytochrome C)  Compounds known to inhibit these proteins complexes are known to be lethal Electrons ultimately combine with O2 and H+ to form H2O (metabolic water) This requirement for O2 makes the ETC the major consumer of oxygen in mammalian cells!! From: Alberts. Molecular Biology of the Cell Electron Transport Chain (Respiratory Chain) 4 transmembrane enzymatic complexes + 2 mobile electron carriers (CoQ, cytochrome C) ETC is the mitochondria proton pump Electron-transporting groups contain iron, sulfur, copper All are proteins except for CoQ The free energy released by the electrons is used to pump H+ Electrons are transferred along the ETC from electron donor t o electron receptor Oxidation → electrons are removed Reduction → electrons are gained PHOSPHORYLATION OF ADP TO ATP 1. CARBO I NHTYRDORDAUTCETSI O N ETC → pumps H+ H+ are pumped from the matrix across the inner mitochondrial membrane at complexes I, III and IV This creates an electrochemical gradient The energy created from these gradients moves ATP synthase 2. ATP synthase: ATP synthase is a multi-subunit enzyme H+ flow through the proton channel, rotating the enzyme This rotation allows the synthesis of ATP from ADP and Pi ATP-Synthase OX PHOSPHORYLATION INHIBITORS and UNCOUPLERS IINHIBITORS that arrest cellular respiration may block the ETC at any of 4 sites: Complex I → barbiturate, insecticide (rotenone) Complex II → malonate, carboxin and TTFA (an Fe-chelating agent) Complex III → dimercaprol, antimycin FYI Complex IV → hydrogen sulfide (H2S), carbon monoxide (CO), and cyanide The action of UNCOUPLERS is to dissociate oxidation from phosphorylation.  NADH and FADH2 are oxidized, heat is produced, but none of the energy from oxidation generates ATP  this can be metabolically useful: generating heat during hibernation, in the immediate postnatal period, and in animals adapted to the cold. Regulation of TCA cycle and OXPHOS (simplified) Inhibition Stimulation ATP Glucose NADH Acetyl CoA Citrate ADP NAD⁺ C A R B O HY DR A T E S OXPHOS Is regulated primarily by the energy needs of the cell (ATP/ADP ratio) No major hormonal/allosteric regulation GLUCONEOGENESIS Gluconeogenesis is the production of glucose from non-sugar molecules  Supplies the needs for plasma glucose between meals  During a prolonged fast, when hepatic (liver) glycogen stores are depleted (~24h)  It is a continual process in carnivores and ruminants  Hormone controlled (stimulated by glucagon and epinephrine, inhibited by insulin) Substrates:  Lactate  Pyruvate  Glycerol from TAG (triacylglycerol = glycerol + 3 fatty acids)  Glucogenic amino acids GLUCONEOGENESIS o Lactate  pyruvate o Glycerol  glycerol phosphate/3-phosphoglycerate o Glucogenic Amino acids  TCA cycle  Oxaloacetate (OAA)  Alanine, Arginine, Asparagine, Aspartate, Cysteine, Glutamate, Glutamine, Glycine, Proline, Serine, Histidine, Methionine, Threonine, Valine Substrates for gluconeogenesis GLUCONEOGENESIS Gluconeogenesis is not reverse glycolysis!! Gluconeogenesis primarily takes place in the LIVER.  To a lesser extent it can also occur in the kidneys (~ 10%) CORI CYCLE and GLUCONEOGENESIS CORI CYCLE (aka lactic acid cycle) Lactate produced by anaerobic glycolysis (from exercising muscle and cells without mitochondria i.e.,RBCs) is transported to the liver and converted to glucose (gluconeogenesis pathway)  Prevents lactic acidosis during anaerobic conditions in the muscle  Important source of substrate for gluconeogenesis The Cori Cycle https://www.youtube.com/watch?v=YOaAW51IKMQ GLYCOGEN METABOLISM Glycogenesis is a mechanism to store glucose as glycogen  Main stores in the body:  Liver (up to 10% of liver weight)  Skeletal Muscle (up to 1% of muscle weight) Glycogenolysis: glycogen mobilization from glycogen stores  When blood glucose levels are low (i.e., fasting) GLYCOGENESIS Glycogen is a polysaccharide made exclusively of α-D-glucose Glycogen synthesis occurs in the cell cytosol, each molecule contain around 60,000 glucose residues and it is highly hydrophilic GLYCOGENESIS Important enzymes for synthesis:  Glycogenin (primer, start the glycogen chain)  Glycogen synthase (elongate the chain)  Branching enzyme Glycogen storage diseases are associated with enzymes deficiency Prolonged use of steroids can also cause glycogen storage abnormalities GLYCOGEN METABOLISM REGULATION SIMPLIFIED: Insulin  anabolic  stimulates glycogenesis  inhibits glycogenolysis Glucagon (and epinephrine) catabolic  stimulates glycogenolysis  inhibits glycogenesis THE PENTOSE PHOSPHATE PATHWAY (PPP) Synonym: hexose pathway, hexose monophosphate shunt  It is an alternate cytoplasmic route for the metabolism of Glucose 6phosphate (first step of glycolysis) This alternative pathway has 2 main functions: 1. Generation of NADPH for reductive biosynthesis NADPH of lipids (fatty acids, cholesterol and other steroids) 2. Provision of ribose residues for nucleotide and nucleic acid biosynthesis (ATP, NAD+, FAD, RNA, and DNA) RIBOSE THE PENTOSE PHOSPHATE PATHWAY (PPP) Occurs in the cell cytosol, no ATP is consumed or generated PPP has high activity in: Liver and adipose tissue: biosynthesis of fatty acids from acetyl-CoA Endocrine tissues: synthesis of cholesterol and steroid hormones Lactating mammary gland: production of milk fats and proteins Mature erythrocyte, lens and cornea: glutathione production (oxidative damage protection) NADP+/NADPH (it is a coenzyme) Importance of NADP+/NADPH in physiological processes An important source of electrons (reducing/oxidizing agent)  Contributing to the maintenance of cellular redox homeostasis Reducing cytochrome P450 (drug metabolism in liver) Synthesis of Nitric Oxide (NO)  relaxes smooth muscle, neurotransmitter, bactericidal activity Lipogenesis: Synthesis of steroids and fatty acids Respiratory burst in phagocytic cells (NADPH-oxidase) THE RESPIRATORY BURST Phagocytosis: receptor-mediated ingestion (via endocytosis) of microorganisms, foreign particles and cell debris (i.e., WBC neutrophils)  Important cell defense mechanism NADPH is involved in production of Oxygen-containing reactive species (ROS) such as H2O2 RESPIRATORY BURST occurs inside special lysosomes (phagolysosome) → NADPH activates enzymes that produce ROS → destroy microorganisms