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TAMU NUTR 470 - Nutrient Metabolism: the Oxidation of Pyruvate

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NUTR 470 1st Edition Lecture 6• Nutrient Metabolism: The Oxidation of Pyruvate• know 2 of 5 examples of something— phosphorylation or something.. listen again• Know two examples of phosphorylation and dephosphorylation• Oxidation of Glucose• HK/GK catalyzes the phosphorylation of glucose as the first step of glycolysis• 6PFK1 catalyzes a rate-determining step of glycolysis• ATP is generated at two steps of glycolysis• The reducing equivalents (2H) are collected by the respiratory chain for oxidation and coupled the generation of ATP.• HK/GK: hexokinase/glucokinase• 6PFK1: 6-phosphofructo-1-kinase• Oxidation of Glucose• The production of ATP upon oxidation of 1 mole glucose• Anaerobic conditions• Glycolysis yields only 2 moles of ATP.• Aerobic conditions• Complete oxidation yields up to 38 moles of ATP.• Structure of Mitochondria— the main location of fatty acid oxidation (different lecture)• Enzymes of matrix (outer membrane)• PDH— the enzyme that controls pyruvate oxidation• Enzymes for TCA cycle• β-oxidation enzymes • Enzymes of inner membrane• ATP synthase— to generate ATP/energy• during oxidation— use oxygen and generate CO2 and this shows why we use RQ • Sources of Pyruvate• Glycolysis— • physiological condition: feeding; signals (glucose, insulin) associated with feeding is why we see increase of glycolysis leading to sources of pyruvate• Pyruvate generated from glycolysis is transferred to mitochondria for complete oxidation.• In fact, glycolysis is viewed as the first stage of aerobic oxidation of glucose.• Sources of Pyruvate• Other sources: • Alanine— through transamination• ALT stands for alanine transaminase, whose old name is glutamate pyruvate transaminase (GPT).• ALT is a marker of liver damage.• under fasting condition we see degradation of the amino acid— this is an important condition• Oxidation of Pyruvate• Generation of acetyl-CoA• Pyruvate + NAD+ + CoA → Acetyl-CoA + NADH + H+ + CO2• The reaction is catalyzed by pyruvate dehydrogenase (PDH) complex.• Must give full name • Symport reaction• Pyruvate generates acetylCoA through pyruvate oxidation• why do we see increases or decrease? regulation, physiological conditions• Pyruvate dehydrogenase complex • is huge (2-4 million Da), and is composed of multiple copies of several different subunits.• mammalian cells— 60 copies of E2 subunit in a pentagonal dodecamer• Pyruvate Dehydrogenase Complex— PDH complex (E1-E2-E3)• Know slide 11, it'll be worth 4 points• PDH generates Acetyl-CoA• start with fasting conditions— decrease glucose, decrease insulin, increase in glucagon and the signaling of the cascade. Kinase will transfer phosphate from ATP to PDH, so now PDH+P (inactive)— fasting conditions• Will see less reaction in fasting conditions• Second example of phosphorylation/regulation• 1st= 6PF-2-K• 2nd = PDH phosphorylation/ PDH kinase• Function of PP— removal of phosphate and makes PDH+H —> PDH and now activeagain• Role of PDH• PDH complex links glycolysis, TCA cycle, and lipid synthesis.• PDH complex also controls the switch between glucose and fatty acids as the fuel source.• Need to be able to explain:• How it become phosphorylated and dephosphorylated— “i have pdk-p dephosphorylating”• PDH controls the state between glucose and fatty acid oxidation.• Muscle oxidation is controlled my PDH-kinase to increase fatty acid oxidation in muscle— exercise increases this ability• Basic Concepts of PDKs• PDK isoforms: PDK 1 – 4• PDKs exhibit tissue-specific expression• PDK1: heart, pancreatic islet, skeletal muscle• PDK2: heart, liver, and kidney• PDK3: testis, kidney, and brain• PDK4: heart, skeletal muscle, and liver, kidney, and the pancreatic islet• PDK4 is crucial for the regulation of fatty acid oxidation in muscle.• Regulation of PDK4• Starvation— long term fasting• decrease: insulin• Increase: Fatty acids, glucocorticoids (stress conditions)• these all increase: PDK4 gene expression• Up-regulating PDK4 in muscle to facilitate fatty acid oxidation and to spare glucose• Insulin• Deficiency of insulin causes an increase in the expression of PDK4• Insulin suppresses the expression of PDK4• The suppression of PDK4 by insulin is impaired in acute insulin resistant states.• dont have enough insulin, don't have enough glucose, but you have glucagon and you see more PDK and less glycolysis and pyruvate oxidation.• Basic Concepts of PDH Phosphatase• PDP isoforms— PDP1 and PDP2• Distribution of PDPs• PDP1 : Abundant in heart, brain, and testis— Less abundant in liver, kidney, muscle, spleen• PDP2— Abundant in heart, brain, liver, and kidney• Regulation of PDP• Starvation• Starvation suppresses the expression of PDP2 in rat heart and kidney.• Insulin reverses the effect of starvation on suppressing PDP2.• decreased insulin, decreased PDP2, but increased PDK4, and decreased PDH• Upon feeding• increased insulin, increased PDP2, but decreased PDK4, and increased PDH(because of oxidation)• Significance of PDH Regulation• Regulation of gluconeogenesis during starvation• Sparing pyruvate for GNG• Controls the switch between using glucose and fatty acids as the fuel for energy generation• Promoting fatty acid oxidation by “pulling” acetyl-CoA to TCA cycle during starvation• Summary• Oxidation of pyruvate• Source of pyruvate• Pyruvate dehydrogenase phosphatase• Regulation of pyruvate dehydrogenase• Pyruvate dehydrogenase


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