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29 Gluconeogenesis.Pdf BI/CH 422/622 ANABOLISM OUTLINE: Overview of Photosynthesis Key experiments: Carbohydrate Biosynthesis in Animals Light causes oxygen, which is from water splitting (Hill) precursors NADPH made (Ochoa) Cori cycle Separate from carbohydrate biosynthesis (Rubin & Kamen) Gluconeogenesis Light Reactions energy in a photon reversible steps pigments irreversible steps – four HOW energetics Light absorbing complexes 2-steps to PEP Reaction center Photosystems (PS) mitochondria PSI – oxygen from water splitting Pyr carboxylase-biotin PSII – NADPH PEPCK Proton Motive Force – ATP FBPase Overview of light reactions G6Pase Carbon Assimilation – Calvin Cycle Stage One – Rubisco Glycogen Synthesis Carboxylase UDP-Glc Oxygenase Glycolate cycle Glycogen synthase Stage Two – making sugar branching Stage Three - remaking Ru 1,5P2 Overview and regulation Pentose-Phosphate Pathway Calvin cycle connections to biosyn. C4 versus C3 plants Regulation of Carbohydrate Metabolism Kornberg cycle - glyoxylate Anaplerotic reactions Photosynthesis Assimilation of CO2 into Biomass chloroplast cytosol cytosol • Plant cells: use 3-C intermediates for further synthesis – Glyceraldehyde 3-phosphate (G3P) is the most important one. – made from CO2, H2O, plus ATP and NADPH from photosynthesis 1 Photosynthesis The C4 Pathway C4 versus C3 Plants; Benefits of C4 Plants: Heat and Drought Resistance • C4 plants (tropical, hot climates) have an earlier step, in different cells, that isolate Rubisco from the air. –C4 plants spatially separate CO2 fixation from rubisco activity, resulting in less reaction of rubisco with oxygen and avoidance of the costly glycolate pathway. • Physical separation of reactions: – CO2 is captured into oxaloacetate in mesophyll cells of the leaf. – Oxaloacetate then passes into bundle-sheath cells where CO2 is released for Rubisco • The C4 pathway has the same energy cost as the glycolate cycle, but also has increased efficiency in heat, which favors the oxidase. • Another pathway to avoid photorespiration was first discovered in Crassulacae (Crassulacean Acid Metabolism (CAM)) in high, dry conditions – Stomata open/close; the CO2 from C4 fixation is stored as malate in vacuoles. Photosynthesis Recall in GlyOXylate Cycle animals: Kornberg Cycle Plants Use Fats and Proteins for Carbohydrate Synthesis: • Instead of burning isocitrate, it short circuits TCA, taking isocitrate directly to succinate • The result is the glyoxylate bi-product • Re-cycle this glyoxylate by making malate from more acetyl CoA in a similar reaction as citrate synthase We’ll come back to this later…………. 2 Photosynthesis: Carbon Fixation Summary We learned that: • ATP and NADPH from photosynthesis are needed in order to assimilate CO2 into carbohydrates by Rubisco • This key enzyme of the Calvin cycle fixes carbon dioxide as well as oxygen. • assimilations of six CO2 molecules via the Calvin cycle lead to the formation of one molecule of glucose for use in anabolic reactions • enzymes of Calvin Cycle have common regulation mechanisms via 2+ pH, Mg , and/or NADPH (Fd) • low selectivity of rubisco causes a wasteful incorporation of molecular oxygen in C3 plants. C4 and CAM plants have evolved separate methods for reducing this waste. • plants can convert acetyl-CoA into carbohydrates via the Kornberg Cycle (glyoxylate cycle) ANABOLISM I Carbohydrates Carbohydrate Synthesis in Animals 3 Gluconeogenesis Gluconeogenesis: Making “New” Glucose Precursors: From what compounds can glucose be made? • Animals can produce glucose from sugars or proteins. –sugars: pyruvate, lactate, or oxaloacetate –protein: from amino acids that can be converted to citric acid cycle intermediates (or glucogenic amino acids) • Animals cannot produce glucose from fatty acids. –product of fatty acid degradation is acetyl- CoA –There is no net conversion of acetyl-CoA to oxaloacetate in Kreb’s Cycle Plants, yeast, and many bacteria use the Kornberg Cycle to convert acetyl-CoA to oxaloacetate, thus producing glucose from fatty acids. Gluconeogenesis •Blood glucose is largely The Cori Cycle made in the liver, although other organs can reverse glycolysis, but not deliver free glucose into the blood •Synthesis of glucose from simpler compounds: called gluconeogenesis •Operates only if ATP and NADH are plentiful •Other tissues deliver carbon to liver from “waste” As you can see the two pathways operate in different tissues, but how products. is this controlled in a single cell? 4 Gluconeogenesis Glycolysis versus Gluconeogenesis occurs mainly in Gluconeogenesis the liver and Glycolysis occurs 7 PGI kidney cortex. mainly in the •Irreversible reaction of glycolysis must be 6 Aldolase muscle and brain. bypassed in 5 TIM gluconeogenesis. •Opposing pathways that are both – no ATP generated thermodynamically favorable: 4 GAPDH during gluconeogenesis; •Glycolysis: DG°’ = –35 kcal/mol instead 6 ATPs and 2 NADH needed per Glc. •Gluconeogenesis: DG°’=–9 kcal/mol 3 PGK – operate in opposite direction – Some different enzymes results in the different • end product of one is the starting 2 PGM compound of the other pathways •Seven Reversible reactions are 1 Enolase – differentially regulated to prevent a futile cycle used by both pathways. •Three ”glycolysis-specific” steps Lets look at the are reversed with Four energetics of making “gluconeogenesis-specific” steps. glucose….. Gluconeogenesis Changes in Free Energy During G3P Glycolysis and the Citric Acid Cycle Pi PEP 3PGA Pyruvate Favorable Pi energetics for Calvin Cycle Favorable energetics for Gluconeogenesis There are then 3 points that are novel for gluconeogenesis: 1. PyruvateàPEP (complicated) 2. Fru 1,6-P2 à Fru 6-P 3. Glc 6-Pà glucose 5 Gluconeogenesis 3’ The First Gluconeogenic Steps Travel Through Mitochondria 5’ • Best place to assess whether there is ample ATP and NADH is the mitochondria. • The inner mitochondrial membrane is 6 4 selectively permeable: Malate, PEP, and TCA Cycle pyruvate, while oxaloacetate cannot 5 3 escape. • Oxaloacetate can be utilized in the citric citrate acid cycle (Kreb’s cycle) if needed. synthase 2 Acetyl-CoA 2 • There are two ways from pyruvate to PEP. • Oxaloacetate can be converted to PEP or pyruvate dehydrogenase Complex Malate in the mitochondria, then 1 1 transported to cytosol for gluconeogenesis. • Will discuss the decision that pyruvate must make later….. There are two new enzymes here….. Gluconeogenesis Pyruvate to Phosphoenolpyruvate Dr. Kornberg: Lecture 03.22.17 (10:12-11:36) 1.5 min ① ② DG°’ = –0.5 kcal/mol DG°’ = +0.7 kcal/mol • Requires two energy-consuming steps • The first step, pyruvate carboxylase (PC) converts pyruvate to oxaloacetate. – carboxylation using a biotin cofactor – This enzyme is only in the mitochondria; requires transport of pyruvate • The second step, phosphoenolpyruvate carboxykinase (PEPCK) converts oxaloacetate to PEP. – phosphorylation from GTP and decarboxylation – occurs in mitochondria or cytosol depending on the organism Lets look at the PC • During this 2-step conversion, the same carbon from CO is 2 mechanism more added and immediately removed from the structure. closely….. 6 Gluconeogenesis Biotin is a CO2 Carrier Pyruvate Carboxylase Mechanism Gluconeogenesis Biotin is a CO2 Carrier Pyruvate Carboxylase Mechanism 7 Gluconeogenesis Oxaloacetate to Phosphoenolpyruvate Phosphoenolpyruvate Carboxykinase (PEPCK) Phosphoenolpyruvate to Fru 1,6-P2 [2Pyr àà2PEP à2 2-PGA à2 3-PGA à2 1,3BPGA à2 GA3P à DHAP à Fru 1,6P2] Cumulative –3.2 –5.5 +5.5 +1.9 +0.1 –5.6 G°’ (kcal/mol) +0.4 O O Fructose 1,6-bisphosphatase •Fructose 1,6-bisphosphate à fructose 6-phosphate Fru 1,6-P2 to Glucose •Catalyze reverse reaction of [Fru 1,6P2 à Fru6P à Glc6P à Glc] opposing step in glycolysis DG°’ = –4 –0.4 –3.3 kcal/mol – by fructose 1,6-bisphosphatase-1 – coordinately/oppositely regulated with PFK (in liver) Glucose 6-phosphatase – cleaves phosphate with water – DOES NOT generate ATP Gluconeogenesis Why do we need glucose? RECALL: • Physiologically necessary: Brain, nervous system, and red blood cells generate ATP ONLY from glucose. • When can’t get it from pyruvate, amino acids are utilized, which allows generation of glucose when glycogen stores are depleted: – during starvation – during vigorous exercise – can generate glucose from amino acids, but not fatty acids • Costs 4 ATP, 2 GTP, and 2 NADH. Net reaction: + 2 Pyruvate + 4 ATP + 2 GTP + 2 NADH + 2 H + 4 H2O à DG°’ = –9 kcal/mol + Glucose + 4 ADP + 2 GDP + 6 Pi + 2 NAD 8 Glycogen Synthesis Storing a ready-reserve of carbohydrate Glycogen Synthesis • Synthesis of glycogen requires two enzymes, whereas glycogen degradation, only used phosphorylase. Both pathways use a-phosphoglucomutase; the start and end junction is Glc 1-P. • Blood glucose must be: – Phosphorylated: Glc à Glc-6-P – Then converted: Glc 6-P à Glc 1-P – Activated with UDP (UDP-Glc is the precursor) – Added to glycogen 9.
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