Biochem Exam 3 Study Guide PDF

Signal Transduction Study Guide Signal Transduction Overview Definition: The process of converting information into a chemical change. ○ Signal: Detected by specific receptors. ○ Conversion: Involves a chemical process to generate a cellular response. General Features of...

Signal Transduction Study Guide Signal Transduction Overview Definition: The process of converting information into a chemical change. ○ Signal: Detected by specific receptors. ○ Conversion: Involves a chemical process to generate a cellular response. General Features of Signal Transduction 1. Specificity: Achieved by molecular complementarity between signal and receptor molecules (non-covalent interactions). 2. Sensitivity: High receptor affinity for ligands (dissociation constant Kd < 10⁻⁷ M). 3. Amplification: Enzyme cascades amplify the signal. 4. Integration: System integrates multiple signals to produce a unified response. 5. Localization: Signaling components are confined to specific cellular structures for localized responses. Common Features of Signal Transduction Modularity: ○ Proteins have multiple domains for recognizing features. ○ Scaffold Proteins: Non-enzymatic proteins that assemble interacting enzymes. Desensitization: ○ Receptors can become unresponsive to persistent signals. Divergence: ○ Signals often branch out for diverse responses. Types of Cellular Signals Cells respond to: Hormones, neurotransmitters, growth factors, nutrients, odorants, light, tastants, extracellular matrix components, and more. Basic Components of Signal Transduction  Plasma membrane receptors (e.g., GPCRs). G proteins (bind GTP or GDP). Effector enzymes (e.g., adenylyl cyclase). Protein kinases and phosphatases. Steps in Signal Transduction 1. Signal (ligand) binds receptor. 2. Activated receptor produces second messengers or protein activity changes. 3. Cellular response occurs. 4. Signal transduction ends. G Protein-Coupled Receptors (GPCRs) 1. Definition: Largest family of plasma membrane receptors. 2. Components: ○ Receptor with 7 transmembrane helices. ○ G protein (active: GTP-bound, inactive: GDP-bound). ○ Effector enzyme or ion channel. 3. Mechanism: ○ First messenger binds receptor → activates G protein → G protein activates effector enzyme → produces second messengers (e.g., cAMP). 4. Second Messengers: ○ Examples: cAMP, Ca²⁺, IP₃, diacylglycerol. ○ Regulate downstream signaling targets. β-Adrenergic Receptor System Ligand: Epinephrine binds to β-adrenergic receptors. Pathway: ○ GPCR activates G protein (Gs). ○ Gs activates adenylyl cyclase → produces cAMP. ○ cAMP activates PKA (protein kinase A) → phosphorylates target proteins. Termination: ○ Decrease in epinephrine concentration. ○ GTP hydrolysis by G protein. ○ cAMP hydrolyzed to 5'-AMP by phosphodiesterase. Key Terms Agonist: Mimics natural ligand effects. Antagonist: Blocks receptor activity. GTPase Switch: G proteins deactivate by hydrolyzing GTP → GDP. CREB: Transcription factor phosphorylated by PKA to regulate gene expression. Phospholipase C, IP₃, and Ca²⁺ Signaling 1. Phospholipase C (PLC): Cleaves PIP₂ into: ○ Diacylglycerol (DAG): Activates protein kinase C (PKC). ○ IP₃: Releases Ca²⁺ from intracellular stores. 2. Ca²⁺: Acts as a second messenger. Defects in Signal Transduction Ras Mutations: Disrupt GTPase activity, leading to uncontrolled signaling and cancer. Activating Mutations: Elevated cAMP levels (e.g., in adenomas). Inactivating Mutations: Impaired responses to hormonal signals. Regulation and Adaptation in Signal Transduction 1. Desensitization: ○ Receptors phosphorylated (e.g., by β-adrenergic receptor kinase). ○ Arrestin binding blocks G protein interaction. 2. Adaptor Proteins: ○ Confine signaling molecules to specific regions. ○ Example: AKAPs (A kinase anchoring proteins). Summary of Signal Transducers 1. GPCRs: Coupled with G proteins, act via cAMP or other second messengers. 2. Receptor Tyrosine Kinases: Phosphorylate target proteins on Tyr residues. 3. Ligand-Gated Ion Channels: Direct ion flow. 4. Intracellular Receptors: Bind lipophilic signals (e.g., steroids). Study Tip Focus on understanding the common themes in signal transduction: specificity, amplification, integration, modularity, and termination. Study Guide: Key Concepts in Cell Signaling 1. Mutations in Gα Protein Activating Mutations: ○ Lead to continuously elevated cAMP levels. ○ Found in ~40% of adenomas. Inactivating Mutations: ○ Cause unresponsiveness to hormones that use cAMP as a second messenger. 2. Second Messengers: Diacylglycerol, IP3, and Ca²⁺ Phospholipase C (PLC): ○ Cleaves PIP₂ (phosphatidylinositol 4,5-bisphosphate) into diacylglycerol and inositol 1,4,5-triphosphate (IP₃). Signals Using PLC/IP₃/Ca²⁺ Pathway: ○ Includes acetylcholine, gastrin-releasing peptide, angiotensin II, histamine, vasopressin, and oxytocin. Role of IP₃: ○ Opens IP₃-gated Ca²⁺ channels in the ER, releasing Ca²⁺ into the cytosol. Activation of Protein Kinase C (PKC): ○ Diacylglycerol and elevated Ca²⁺ levels activate PKC. Calcium as a Second Messenger: ○ Cytosolic Ca²⁺ is tightly regulated by pumps and is elevated in response to stimuli. ○ Calmodulin (CaM) binds Ca²⁺, changing conformation to regulate various proteins (e.g., CaM kinases). 3. G Protein-Coupled Receptors (GPCRs) in Vision, Olfaction, and Taste Vision: ○ Rhodopsin: A GPCR in rod cells with 11-cis-retinal as its chromophore. ○ Rhodopsin Kinase and Arrestin: Desensitize activated rhodopsin. Olfaction: ○ Golf Protein: Triggers cAMP-gated ion channels, leading to action potentials. Taste: ○ Gustducin: Stimulates cAMP production and affects K⁺ channel phosphorylation. 4. Common Features of GPCR Signaling Seven-transmembrane helices, intrinsic GTPase activity, cyclic nucleotides, and protein kinases are central to signaling. GPCRs are encoded in many species, including humans (~800 genes). 5. Receptor Tyrosine Kinases (RTKs) Structure: ○ Extracellular ligand-binding domain and cytoplasmic tyrosine kinase domain. Insulin Receptor Activation: ○ Dimer of αβ monomers; autophosphorylation of Tyr residues activates kinase activity. Signal Cascade: ○ IRS1 binds phosphorylated Tyr residues, initiating signaling pathways like the MAPK cascade. ○ PI3K activation leads to PIP₂ to PIP₃ conversion, GLUT4 translocation, and glycogen synthase activation. 6. Ion Channels and Electrical Signaling Gated Ion Channels: ○ Respond to ligands or voltage changes; regulate Na⁺, K⁺, Cl⁻, and Ca²⁺ flux. Action Potentials: ○ Generated by voltage-gated Na⁺ influx and K⁺ efflux, propagating electrical signals along neurons. Receptor Channels: ○ Ionotropic Receptors: Directly gated ion channels. ○ Metabotropic Receptors: Indirectly trigger second messenger pathways. Key Tables for Review Table 12-4: Signals that activate the PLC/IP₃/Ca²⁺ pathway. Table 12-5: Proteins regulated by Ca²⁺ and calmodulin (e.g., adenylyl cyclase, nitric oxide synthase, myosin light-chain kinase). Key Terms Autophosphorylation: Self-phosphorylation of RTKs to activate downstream signaling. MAPK Cascade: Amplifies growth factor signals (Raf-1 → MEK → ERK). Calmodulin (CaM): Regulates enzymes via Ca²⁺ binding. Second Messengers: Molecules like cAMP, IP₃, and Ca²⁺ that mediate intracellular signaling. This guide highlights the essential information for understanding the signaling pathways and mechanisms described. Study Guide for Biochemistry: Chapter 13 Topics Autotrophs and Heterotrophs Autotrophs: Organisms that use atmospheric CO2 as their sole carbon source (e.g., plants). Heterotrophs: Organisms that must obtain carbon from their environment (e.g., animals, fungi). Metabolites and Intermediary Metabolism Metabolites: Small intermediates in pathways that convert precursors to products. Intermediary Metabolism: The network of pathways involved in metabolite interconversions. Catabolism and Anabolism Catabolism: Breakdown of molecules; releases energy (exergonic). Anabolism: Synthesis of molecules; requires energy (endergonic). Pathway dynamics: ○ Catabolic pathways converge. ○ Anabolic pathways diverge. 13.1 Bioenergetics and Thermodynamics Key Concepts  Bioenergetics: Study of energy transformations in biological systems. Energy Transductions: Conversion of energy forms. Laws of Thermodynamics 1. First Law: Energy is conserved. 2. Second Law: Systems naturally progress toward increased disorder (entropy). Important Thermodynamic Terms Free Energy (G): Energy available for work. ○ ∆G < 0: Exergonic (releases energy, spontaneous). ○ ∆G > 0: Endergonic (requires energy). Enthalpy (H): Heat content. ○ ∆H < 0: Exothermic (releases heat). ○ ∆H > 0: Endothermic (absorbs heat). Entropy (S): Measure of disorder. ○ ∆S > 0: Increased disorder. ○ ∆S < 0: Decreased disorder. Relationships Free energy equation: ΔG=ΔH−TΔSΔG=ΔH−TΔS. K′eq and ∆G′°: ○ ΔG′°=−RTln⁡K′eqΔG′°=−RTlnK′eq ○ K′eq>1.0K′eq>1.0: Reaction proceeds forward (ΔG′°0) can occur when paired with highly favorable reactions (e.g., ATP hydrolysis). Chemical Logic in Metabolic Reactions Common Reaction Types  1. Making/Breaking Carbon–Carbon Bonds: ○ Examples: Aldol condensation, Claisen condensation, decarboxylation. 2. Internal Rearrangements, Isomerizations, and Eliminations: ○ Electron redistribution; examples include cis-trans isomerization. 3. Group Transfer Reactions: ○ Examples: Phosphorylation by kinases. 4. Oxidation-Reduction Reactions: ○ Involve transfer of electrons, often releasing energy. Key Enzyme Types Kinases: Transfer phosphate groups. Oxidases: Use oxygen as an electron acceptor. Dehydrogenases: Catalyze oxidation-reduction reactions. 13.3 Phosphoryl Group Transfers and ATP ATP as Energy Currency Links energy release from catabolism to energy requirements of anabolism. Hydrolysis of ATP: ○ Releases energy (ΔG′°=−30.5 kJ/molΔG′°=−30.5kJ/mol). ○ Reduces electrostatic repulsion in ATP. Other High-Energy Compounds Examples: ○ Phosphoenolpyruvate (ΔG′°=−61.9 kJ/molΔG′°=−61.9kJ/mol). ○ 1,3-Bisphosphoglycerate (ΔG′°=−49.3 kJ/molΔG′°=−49.3kJ/mol). Key Concepts to Focus On 1. Understand the thermodynamic principles governing metabolism. 2. Memorize relationships between K′eqK′eq, ΔG′°ΔG′°, and reaction direction. 3. Recognize the role of ATP in coupling reactions. 4. Be familiar with enzyme functions and common reaction mechanisms in metaboli Study Guide: Chapter 13 - Metabolism and Bioenergetics Cellular ATP Levels  ATP Regulation: Cellular [ATP] is maintained above equilibrium to drive metabolic reactions effectively. ○ When [ATP] drops: Available fuel decreases. Fuel's effectiveness reduces. Phosphorylated Compounds and Thioesters High-Energy Compounds: Phosphorylated compounds have negative ∆G′° due to resonance stabilization of Pi. Examples of High-Energy Hydrolysis: ○ Phosphoenolpyruvate: ΔG′°=−61.9 kJ/molΔG′°=−61.9kJ/mol. ○ 1,3-Bisphosphoglycerate: ΔG′°=−49.3 kJ/molΔG′°=−49.3kJ/mol. ○ ATP (to ADP + Pi): ΔG′°=−30.5 kJ/molΔG′°=−30.5kJ/mol. Thioesters: ○ Less resonance stabilization compared to oxygen esters, yielding higher free-energy differences. ATP's Role in Metabolism 1. Energy Provider: ATP activates substrates via group transfers. 2. Muscle Contraction and Biosynthesis: ○ Drives processes like DNA/RNA/protein synthesis and ion transport. 3. Transphosphorylations: ○ ATP transfers phosphates to nucleotides (e.g., GTP, UTP) via nucleoside diphosphate kinase. 13.4 Biological Oxidation-Reduction Reactions Electron Flow in Oxidation-Reduction Purpose: Drives all biological work. Electromotive Force (emf): Proportional to the difference in electron affinity between species. Pathway: Electrons move from substrates to electron carriers, then to final acceptors like O2O2​. Key Concepts  Half-Reactions: Oxidation and reduction are described separately (e.g., Fe2+→Fe3++e−Fe2+→Fe3++e−). Redox Pairs: ○ Reducing Agent: Donates electrons. ○ Oxidizing Agent: Accepts electrons. Biological Redox Examples Dehydrogenation: Catalyzed by dehydrogenases, transferring electrons as: ○ Free electrons. ○ Hydrogen atoms. ○ Hydride ions (:H−:H−). Reduction Potentials (E°) Positive E°E°: High affinity for electrons (oxidizing). Negative E°E°: Donates electrons (reducing). Electron Carriers and Coenzymes 1. NAD and NADP: ○ Reversible reduction of the nicotinamide ring. ○ Example: NAD++2e−+2H+→NADH+H+NAD++2e−+2H+→NADH+H+. 2. FMN and FAD: ○ Derived from riboflavin. ○ Can accept one or two electrons during reduction. Niacin Deficiency Causes: Lack of NAD/NADP synthesis leads to pellagra (dermatitis, diarrhea, dementia). Energetics of Hydrolysis ATP Hydrolysis: Produces PiPi, PPiPPi, or AMP and releases energy. Group Transfers: ○ Coupled to anabolic reactions to overcome unfavorable ∆G′°. ○ Allows synthesis of molecules like DNA and proteins. Flavin Nucleotides in Flavoproteins  Derived from riboflavin (vitamin B2). Mediate oxidation-reduction reactions as tightly bound cofactors. Essential Equations 1. Free Energy: ΔG=ΔH−TΔSΔG=ΔH−TΔS. 2. Reduction Potential (Simplified Nernst):E=E°+0.026nln⁡[acceptor][donor].E=E°+n0.026​ln[donor][acceptor]​. Key Takeaways ATP and related compounds are central to cellular energy transfer. Oxidation-reduction reactions provide the energy for ATP synthesis. Cofactors like NAD, NADP, FAD, and FMN are universal electron carriers facilitating redox processes. Study Guide: Chapter 14 - Glycolysis, Gluconeogenesis, and the Pentose Phosphate Pathway 1. Major Pathways of Glucose Utilization Glycolysis: Converts glucose into pyruvate while producing ATP and NADH. Gluconeogenesis: Synthesizes glucose from non-carbohydrate precursors. Pentose Phosphate Pathway: Produces NADPH and ribose-5-phosphate for biosynthetic reactions. 2. Overview of Glycolysis Definition: A 10-step metabolic pathway that breaks down glucose into two molecules of pyruvate. Phases: 1. Preparatory Phase: Consumes 2 ATP. Converts glucose to glyceraldehyde-3-phosphate (G3P). 2. Payoff Phase: Generates 4 ATP and 2 NADH. Yields 2 pyruvate molecules. 3. Glycolysis Pathway Details Preparatory Phase Steps: 1. Phosphorylation of Glucose: ○ Enzyme: Hexokinase. ○ Produces glucose-6-phosphate (G6P); ATP is consumed. 2. Isomerization of G6P to F6P: ○ Enzyme: Phosphohexose Isomerase. 3. Phosphorylation of F6P to Fructose-1,6-bisphosphate (F1,6BP): ○ Enzyme: Phosphofructokinase-1 (PFK-1). ○ Key regulatory step (irreversible). 4. Cleavage of F1,6BP: ○ Enzyme: Aldolase. ○ Produces glyceraldehyde-3-phosphate (G3P) and dihydroxyacetone phosphate (DHAP). 5. Interconversion of DHAP to G3P: ○ Enzyme: Triose Phosphate Isomerase. Payoff Phase Steps: 6. Oxidation of G3P to 1,3-bisphosphoglycerate (1,3BPG): ○ Enzyme: G3P Dehydrogenase. ○ Produces NADH. 7. Phosphoryl Transfer from 1,3BPG to ADP: ○ Enzyme: Phosphoglycerate Kinase. ○ Produces ATP (substrate-level phosphorylation). 8. Conversion of 3-Phosphoglycerate to 2-Phosphoglycerate: ○ Enzyme: Phosphoglycerate Mutase. 9. Dehydration of 2-Phosphoglycerate to Phosphoenolpyruvate (PEP): ○ Enzyme: Enolase. 10. Transfer of Phosphoryl Group from PEP to ADP: ○ Enzyme: Pyruvate Kinase. ○ Produces ATP and pyruvate. 4. Chemical Transformations in Glycolysis 1. Degradation of Glucose to Pyruvate: ○ Carbon skeleton broken down.  2. ATP Synthesis via Substrate-Level Phosphorylation: ○ High-energy intermediates transfer phosphoryl groups to ADP. 3. NADH Formation: ○ G3P oxidation reduces NAD⁺ to NADH. 5. Energetics of Glycolysis Overall Reaction:Glucose+2 NAD++2 ADP+2 Pi→2 Pyruvate+2 NADH+2 ATP+2 H2OGlucose+2 NAD++2ADP+2Pi​→2Pyruvate+2NADH+2ATP+2H2​O Net ATP Gain: 2 ATP (4 produced − 2 consumed). Free Energy: ○ Overall ΔG′°=−85 kJ/molΔG′°=−85kJ/mol, making glycolysis essentially irreversible. 6. Importance of Phosphorylated Intermediates Functions: ○ Prevents intermediates from diffusing out of the cell. ○ Conserves energy via phosphoryl transfer. ○ Lowers activation energy for enzymatic reactions. 7. Pyruvate Fate Aerobic Conditions: ○ Converted to acetyl-CoA → Citric Acid Cycle. Anaerobic Conditions: ○ Reduced to lactate (in animals) or ethanol (in yeast). 8. Key Regulatory Points 1. Hexokinase: Controls glucose entry into glycolysis. 2. Phosphofructokinase-1 (PFK-1): ○ Activated by: AMP, ADP, fructose-2,6-bisphosphate. ○ Inhibited by: ATP, citrate. 3. Pyruvate Kinase: ○ Activated by: Fructose-1,6-bisphosphate.  ○ Inhibited by: ATP, alanine. 9. Notable Enzymes Hexokinase: Phosphorylates glucose (requires Mg²⁺). Phosphofructokinase-1 (PFK-1): First committed step. Pyruvate Kinase: Converts PEP to pyruvate, producing ATP. 10. Additional Notes Glycolysis is highly conserved across species, emphasizing its central role in energy metabolism. The preparatory and payoff phases are energetically coupled to ensure efficiency. This guide covers glycolysis comprehensively. Let me know if you need details on gluconeogenesis or the pentose phosphate pathway! Study Guide: Chapter 14 - Glycolysis, Gluconeogenesis, and Fermentation 1. Feeder Pathways for Glycolysis Carbohydrate Sources: ○ Dietary glycogen, starch, disaccharides, and hexoses enter glycolysis at different points. Polysaccharides: ○ Glycogen phosphorylase: Degrades glycogen to glucose-1-phosphate. ○ Starch phosphorylase: Performs the same for starch. Disaccharides: ○ Enzymes like lactase hydrolyze disaccharides into monosaccharides (e.g., lactose → glucose + galactose). Specific Pathways: Galactose: ○ Converted to glucose-1-phosphate via UDP-galactose intermediates. ○ Defects in this pathway cause galactosemia. Fructose: ○ In liver: Fructose is phosphorylated to fructose-1-phosphate, then cleaved into glyceraldehyde and dihydroxyacetone phosphate. ○ In muscle: Hexokinase phosphorylates fructose to fructose-6-phosphate.  Mannose: ○ Phosphorylated to mannose-6-phosphate, which is converted to fructose-6-phosphate. 2. Fates of Pyruvate Three Catabolic Fates: 1. Aerobic Conditions: Pyruvate is oxidized to acetyl-CoA, which enters the citric acid cycle. 2. Anaerobic Conditions: Reduced to lactate (lactic acid fermentation). Converted to ethanol and CO₂ (alcohol fermentation). 3. Biosynthesis: Used for alanine or fatty acid synthesis. Fermentation Processes Definition: Energy production in the absence of oxygen; regenerates NAD⁺ for glycolysis. Lactic Acid Fermentation: ○ Enzyme: Lactate dehydrogenase. ○ Converts pyruvate to lactate, regenerating NAD⁺. ○ Lactate can be recycled to glucose in the liver (Cori cycle). Ethanol Fermentation: ○ Enzymes: Pyruvate decarboxylase, alcohol dehydrogenase. ○ Converts pyruvate to ethanol and CO₂. ○ Example: Beer production by yeast. Industrial and Food Applications of Fermentation Fermented Foods: ○ Yogurt (lactic acid bacteria), Swiss cheese (propionic acid bacteria), pickles, kimchi, kombucha. Industrial Chemicals: ○ Produced by microorganisms (e.g., acetone, butanol, ethanol). 3. Gluconeogenesis  Definition: ○ Synthesis of glucose from non-carbohydrate precursors like pyruvate, lactate, glycerol. Location: ○ Occurs primarily in the liver and kidney. Shared Steps with Glycolysis: ○ Seven glycolytic reactions are reversible and shared between the pathways. Key Differences Between Glycolysis and Gluconeogenesis Bypassed Steps in Gluconeogenesis: ○ Glycolytic steps catalyzed by hexokinase, phosphofructokinase-1, and pyruvate kinase are irreversible and bypassed with exergonic reactions. Bypass Reactions 1. Pyruvate to Phosphoenolpyruvate (PEP): ○ Requires two reactions: 1. Pyruvate carboxylase: Converts pyruvate to oxaloacetate (requires biotin). 2. Phosphoenolpyruvate carboxykinase (PEPCK): Converts oxaloacetate to PEP. 4. Regulation and Integration Glycolysis and Gluconeogenesis are tightly regulated to prevent futile cycling. Key Regulators: ○ ATP inhibits glycolysis and stimulates gluconeogenesis. ○ AMP and fructose-2,6-bisphosphate activate glycolysis and inhibit gluconeogenesis. 5. The Warburg Effect Definition: ○ Tumor cells exhibit high rates of glycolysis with fermentation to lactate, even in the presence of oxygen. Application: ○ Basis for PET scans to detect tumors. This guide captures key details of feeder pathways, pyruvate fates, fermentation, and gluconeogenesis. Let me know if you need further elaboration on any topic! Study Guide: Gluconeogenesis (14.4) Definition and Overview Gluconeogenesis: ○ Synthesis of glucose from simpler precursors like pyruvate and lactate. ○ Primarily occurs in the liver (also in renal and intestinal cells). ○ Essential for maintaining blood glucose levels during fasting or intense exercise. Relation to Glycolysis: ○ Shares seven reversible steps with glycolysis. ○ Bypasses three irreversible steps (catalyzed by hexokinase, phosphofructokinase-1, and pyruvate kinase) using alternative exergonic reactions. Key Reactions of Gluconeogenesis Bypass 1: Pyruvate → Phosphoenolpyruvate (PEP) Step 1: Pyruvate to Oxaloacetate: ○ Enzyme: Pyruvate carboxylase. ○ Requires ATP and biotin as a coenzyme. ○ Reaction:Pyruvate+HCO3−+ATP→Oxaloacetate+ADP+PiPyruvate+HCO3−​+ATP →Oxaloacetate+ADP+Pi​ Step 2: Oxaloacetate to PEP: ○ Enzyme: Phosphoenolpyruvate carboxykinase (PEPCK). ○ Requires GTP. ○ Reaction:Oxaloacetate+GTP→PEP+CO2+GDPOxaloacetate+GTP→PEP+CO2​+ GDP Alternative Pathway: ○ If lactate is the precursor, oxaloacetate is directly converted to PEP in the mitochondrion. Bypass 2: Fructose 1,6-Bisphosphate → Fructose 6-Phosphate Enzyme: Fructose 1,6-bisphosphatase (FBPase-1). Hydrolyzes the C-1 phosphate bond.  Reaction:Fructose 1,6-bisphosphate+H2O→Fructose 6-phosphate+PiFructose 1,6-bisphosphate+H2​O→Fructose 6-phosphate+Pi​ Regulation: ○ Inhibited by AMP and fructose 2,6-bisphosphate. ○ Activated by ATP. Bypass 3: Glucose 6-Phosphate → Glucose Enzyme: Glucose 6-phosphatase. Found in the ER of hepatocytes, renal, and intestinal cells. Reaction:Glucose 6-phosphate+H2O→Glucose+PiGlucose 6-phosphate+H2​O→Glucose+Pi​ Note: This step does not occur in muscle or brain cells, which lack glucose 6-phosphatase. Energy Requirements Gluconeogenesis is energetically expensive: ○ Requires 4 ATP, 2 GTP, and 2 NADH per molecule of glucose synthesized. ○ Overall reaction:2Pyruvate+4ATP+2GTP+2NADH+2H++4H2O→Glucose+4ADP+2GDP+ 6Pi+2NAD+2Pyruvate+4ATP+2GTP+2NADH+2H++4H2​O→Glucose+4ADP+2G DP+6Pi​+2NAD+ Precursors for Gluconeogenesis Pyruvate: Central precursor. Lactate: ○ Recycled to glucose in the Cori Cycle. Glucogenic Amino Acids: ○ Amino acids like alanine, aspartate, and glutamine can be converted to citric acid cycle intermediates, which feed into gluconeogenesis. Glycerol: ○ Derived from triglycerides, converted to dihydroxyacetone phosphate (DHAP). Special Considerations  Oxaloacetate Transport: ○ No direct transporter for oxaloacetate across the mitochondrial membrane. ○ Converted to malate (via malate dehydrogenase) for export and reoxidized to oxaloacetate in the cytosol. Fatty Acids and Glucose Synthesis: ○ Mammals cannot convert fatty acids to glucose due to the absence of the glyoxylate pathway. ○ Plants and microorganisms can synthesize glucose from fatty acids using this pathway. Regulation of Gluconeogenesis Activated by: ○ High ATP and citrate levels. ○ Glucagon signaling (increases gluconeogenesis enzymes). Inhibited by: ○ Low ATP. ○ Insulin (promotes glycolysis instead). Key Points to Remember 1. Gluconeogenesis is not the reverse of glycolysis but a complementary pathway with unique bypass reactions. 2. It is critical for maintaining blood glucose levels, especially during fasting. 3. Energy cost is significant, emphasizing the role of this pathway in metabolic balance. Study Guide: Chapter 16 - The Citric Acid Cycle Cellular Respiration Overview Definition: Cellular respiration is the complete oxidation of pyruvate (from glycolysis) to CO₂ and H₂O, producing ATP. Stages: 1. Oxidation of fuels to acetyl-CoA: Generates ATP, NADH, and FADH₂. 2. Citric Acid Cycle (TCA/Krebs cycle): Oxidizes acetyl groups to CO₂. Produces NADH, FADH₂, and GTP. 3. Electron Transport and Oxidative Phosphorylation:  Uses NADH and FADH₂ to generate the majority of cellular ATP. 16.1 Production of Acetyl-CoA Acetyl-CoA: ○ Contains a reactive thiol group (-SH) in coenzyme A, forming high-energy thioester bonds. ○ Central metabolite linking glycolysis, the TCA cycle, and fatty acid metabolism. The Pyruvate Dehydrogenase (PDH) Complex Role: Converts pyruvate into acetyl-CoA and CO₂ via oxidative decarboxylation. Location: Mitochondrial matrix. Importance: ○ Regulates catabolism and metabolic flux between pathways. Components of the PDH Complex Three Enzymes: 1. E1: Pyruvate dehydrogenase (decarboxylates pyruvate; transfers the hydroxyethyl group to TPP). 2. E2: Dihydrolipoyl transacetylase (transfers acetyl group to CoA). 3. E3: Dihydrolipoyl dehydrogenase (regenerates FAD and lipoate to oxidized states). Five Coenzymes: 1. Thiamine Pyrophosphate (TPP): Decarboxylates pyruvate. 2. Lipoate: Acts as a swinging arm transferring intermediates. 3. Coenzyme A (CoA): Accepts the acetyl group. 4. FAD: Accepts electrons. 5. NAD⁺: Final electron acceptor. Steps of Oxidative Decarboxylation by PDH 1. E1 - Step 1: ○ Pyruvate decarboxylation to hydroxyethyl-TPP (rate-limiting step). 2. E1 - Step 2: ○ Hydroxyethyl-TPP oxidized to acetyl group; transferred to lipoate on E2. 3. E2 - Step 3:  ○ Acetyl group transferred from lipoate to CoA, forming acetyl-CoA. 4. E3 - Step 4: ○ Lipoate regenerated by electron transfer to FAD. 5. E3 - Step 5: ○ FADH₂ oxidized back to FAD; electrons transferred to NAD⁺, forming NADH. Substrate Channeling in the PDH Complex Definition: Direct transfer of intermediates between enzyme active sites without diffusion. Benefits: ○ Increases efficiency by minimizing intermediate loss. ○ Reduces side reactions. Regulation of the Citric Acid Cycle and PDH Complex Allosteric Regulation: ○ Activated by: AMP, CoA, NAD⁺ (indicators of low energy). ○ Inhibited by: ATP, acetyl-CoA, NADH (indicators of high energy). Covalent Regulation: ○ PDH kinase phosphorylates and inactivates PDH. ○ PDH phosphatase removes the phosphate, activating PDH. Metabolic Significance The PDH complex links glycolysis and the TCA cycle. Mutations or dysregulation in PDH can lead to: ○ Metabolic disorders. ○ Tumor formation (due to impaired respiration and reliance on glycolysis). Key Points to Remember 1. The PDH complex is critical for energy metabolism, converting pyruvate to acetyl-CoA. 2. The five-reaction sequence relies on substrate channeling for efficiency. 3. Regulation ensures metabolic homeostasis and balances energy supply with demand. Study Guide: The Citric Acid Cycle (16.2) Overview of the Citric Acid Cycle Purpose: ○ Oxidizes acetyl-CoA to CO₂. ○ Generates high-energy electron carriers NADH, FADH₂, and GTP/ATP. ○ Intermediates are used in both catabolic (breakdown) and anabolic (biosynthetic) pathways. Location: Mitochondrial matrix in eukaryotes. Energy Conservation: ○ Energy from oxidation is conserved in: 3 NADH, 1 FADH₂, and 1 GTP/ATP per acetyl-CoA. Eight Steps of the Citric Acid Cycle 1. Formation of Citrate: ○ Enzyme: Citrate synthase. ○ Acetyl-CoA condenses with oxaloacetate to form citrate. ○ Reaction is irreversible and highly exergonic (ΔG′°