Metabolism Exam 2Pyruvate MetabolismWe all know there are 4 things that can go through gluconeogensis in order to be converted into energy. Those things consist of amino acids, glycerol, lactate, and pyruvate. We will be discussing pyruvate metabolism.There are 3 forms of potential energy sources for gluconeogensis, pyruvate metabolism. All three are reversible. 1. Amino acid- alanine2. Glucose3. LactateAfter being converted into pyruvate (3C molecule), they can use the enzyme pyruvate dehydrogenase (PDH) to convert into Acetyl-CoA (2 C molecule) + CO2.- This process is an example of a oxidative decarboxylation of an alpha-ketoacid (amino acid without amine group). - The irreversible process occurs in the mitchondria- The PDH enzyme step generate NADH + H+. Also, cofactors TPP, FAD, CoASH are formed (explained later). PDH is insulin favord, as it isrequires a dephosphorylation to be activated.o Inhibited by: Increased NADH + H+ Increased Acetyl-Coa Increased ATP Starvation, uncontrolled diabetes, and endurance exerciseo Favored by: Increased Insulin in the adipose tissue Conditions that favor fat synthesis- Acetyl-CoA is the common intermediate for synthesis of TAG. Tricarboxylic (TCA) Cycle- also known as Citric Acid or Krebs Cycle- This process requires O2 and is in the mitochondria and represents a common metabolic pathway. o Proteins that are converted to amino acids to enter the cycle can either be converted to pyruvate or Acetyl-CoA TCA cycle Pyruvate- amino acid is glucogenic Acetyl-CoA- amino acid is Ketogenic- When Acetyl-Coa is entering the TCA cycle, it binds to Oxaloacetate (OAA) which requires Citrate Synthase to generate Citrate + CoenzymeA (CoASH). This process has an importance to regenerate OAA and 2 CO2 are formedo Citrate (important for fatty acid synthesis) is converted to Isocitrate with the enzyme Aconitase This is a 2 step process1. CitrateCis-asconitate (dehydration)2. Cis-asconitateIsocitrate (hydration)- Isocitrate alpha-Ketoglutarate (glutamate)o Isocitrate dehydrogenase is the enzyme usedo NADH + H+ is generatedo CO2 is released- Alpha-ketoglutarate Succinyl-CoA (Heme)o Alpha-ketoglutarate Dehydrogenase (TPP, FAD) o CoASH enters to make the CoA on Succinylo NADH + H+ is generatedo 2nd CO2 releasedo This is an oxidative decarboxylation of an alpha-ketoacid- Succinyl-CoASuccinateo Succinic Thiokinase is the enzymeo GTP (ATP) produced substrate level phosphorylationo CoASH released- Succinate Fumarateo Succinate Dehydrogenaseo FADH2- only step where FAD is used- FumarateMalateo Fumeraseo H20 enters (hydration)- MalateOAA (pyrimidines or glucose)o Malate Dehydrogenaseo NADH + H+o This is where the cycle can continue to repeat itself- Energeticso 12 ATP produced from TCA cycle and all starts from molecule Acetyl-CoA. 9 from NADH + H+ 1 from GTP 2 from FADH2o 15 ATP if you begin with Pyruvate 12 from NADH + H+ 1 from GTP 2 from FADH2o If you are using one molecule of glucose you end with 38 ATP and4 CO2. 2 ATP from glycolosis 4 NADH from glycolosis and 6 from Krebb cycle 2 FADH from krebb cycle 2 GTP from Krebb cycle- When you create energy from NADH + H+ and FADH2, you are using theH’s and transporting them to ETC shuttle systems in the mitochondriao Malate shuttle- For H’s to end up in the mitochondria the H’s from NADH + H+ attach to OAA. OAA goes to malate so that it can go through the membrane. Then, malate goes back to OAA and gives H’s to NAD in the mitochondria. There is no energy being used. H’s end up on NAD+ to form NADH + H+ 3 ATP can be formed Active in the liver, kidney, and hearto Glycerol-3-PO4- NAD as cofactor in cytoplasm and FAD in the mitochondria. So, H’s are taken from NAD and given to FAD. There is an energy change, so lose 2 ATP. 38 ATP- 2ATP= 36 net ATP. 37 if from muscle and hexokinase is not needed. H’s end up attached to FAD to form FADH2 2 ATP formed Active in muscle and brain- The rate limiting enzymes are:o Citrate Synthaseo Isocitrate dehydrogenaseo Alpha-ketoglutarate dehydrogenase- Inhibition by accumulation productso NADH + H+ - Inhibits dehydrogenaseo Citrate- Blocks citrate synthesiso ATP- inhibits citrate cynthase and isocitrateo Succinyl-CoA- inhibts alphaketoglutarate dehydrogenase and citrate synthaseElectron Transport Chain- accomplished in the mitochondria- The purpose is to capture energy in the form of ATP by coupling the two processes of oxidation and phosphorylationo Oxidation- loss of of H’s. NADH2 NADo Phosphorylation- addition of phosphorus. ADPATPo Uncoupling- This term corresponds to protein producing heat, not energy. An important tissue for this is Brown eyed tissue.- Proton Pumpso There are 4 complexes which remove electrons from coenzymes located in the inner mitochondria space and/or pump protons into the outer membrane space 1- NADH-Q oxidoreductase 2- Succinate Q reductase 3- Cytoochrome C oxidoreductase 4-Cytochrome c oxidase- Electron Transporterso Transports between complexes in the ETC Ubiquinone (Coenzyme Q)- Transports between complex 1 and 3; and 2 and 3 Cytochrome C- Transports electrons between 3 and 4- ATP synthase- Transports protons across the inner mitochondrial membrane for phosphorylation of ADPATP- During H+ pumpo During the transfer of electrons (oxidation) energy is releasedo This energy can be used to pump protons into the inner membrane space, creating a gradiento When the gradient is diffused as protons flow back into the matrix,this energy can be used to make ATP (if the protons are diffused back through ATP synthase)o Looking at the last chart on this slide set, the 4,4,2 H’s that are pumped from complexes 1,3, and 4 are pumped into the innermembrane space. They enter ATP synthase complex. The ATP synthase has 2 subunits (F0 and F1). F0 allows for the H’s to move in and F1 to allow for phosphorylation. The 4th complex only allows 2 H’s instead of 4 because 2 H’s are used with ½ O2 to generate H20 The electrons from 1-3 and 2-3 are accepted by Coenzyme Q and are accepted at complex 4 by Cyt C. Fructose and Galactose Metabolism- Fructose and Galactose can both be converted to glucose and phosphorylated in the liver and then can be used to produce energyo After becoming glucose, it can attach to GLUT 2 in the blood- The main reason that they need to be converted to glucose is because the Km is much lower for
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