⚗️Biological Chemistry II Unit 1 – Metabolism and Bioenergetics

Key Concepts and Definitions

• Metabolism encompasses all chemical reactions involved in maintaining the living state of cells and organisms
• Bioenergetics studies energy transformations and energy exchanges within living systems
• Catabolism breaks down complex molecules into simpler ones, releasing energy in the process
• Anabolism constructs complex molecules from simpler ones, requiring an input of energy
• Metabolic pathways are series of enzymatic reactions that transform initial reactants into final products
• Enzymes are biological catalysts that speed up chemical reactions without being consumed in the process
• Coenzymes are small, organic, non-protein molecules that carry chemical groups between enzymes (NAD+, FAD, Coenzyme A)
• Adenosine triphosphate (ATP) is the primary energy currency of the cell, storing and releasing energy through its phosphate bonds

Thermodynamics in Biochemistry

• Thermodynamics is the study of energy transformations and the direction of spontaneous processes
• The first law of thermodynamics states that energy cannot be created or destroyed, only converted from one form to another
• The second law of thermodynamics states that entropy (disorder) tends to increase in a closed system over time
• Gibbs free energy (ΔG) predicts the spontaneity of a reaction at constant temperature and pressure
  • Reactions with negative ΔG are spontaneous and release energy
  • Reactions with positive ΔG are non-spontaneous and require an input of energy
• Exergonic reactions release energy and have a negative ΔG (ATP hydrolysis, glucose oxidation)
• Endergonic reactions absorb energy and have a positive ΔG (ATP synthesis, glucose synthesis)
• Coupling of exergonic and endergonic reactions allows for energy transfer and drives metabolic processes

Metabolic Pathways Overview

• Glycolysis is a cytosolic pathway that breaks down glucose into pyruvate, generating ATP and NADH
• The citric acid cycle (Krebs cycle) is a mitochondrial pathway that oxidizes acetyl-CoA, producing CO2, NADH, FADH2, and ATP
• Oxidative phosphorylation is the process by which electrons from NADH and FADH2 are transferred through the electron transport chain to generate a proton gradient, which is used to synthesize ATP
• Fatty acid oxidation breaks down fatty acids into acetyl-CoA units, which can enter the citric acid cycle
• Amino acid metabolism involves the breakdown of amino acids into carbon skeletons that can be used in the citric acid cycle or for gluconeogenesis
• Gluconeogenesis is the synthesis of glucose from non-carbohydrate precursors (amino acids, lactate, glycerol)
• The pentose phosphate pathway generates NADPH for reductive biosynthesis and ribose-5-phosphate for nucleotide synthesis
• Metabolic integration coordinates the activities of various pathways to meet the energy and biosynthetic needs of the cell

Enzymes and Metabolic Regulation

• Enzymes lower the activation energy of reactions, increasing reaction rates by factors of 106 to 1012
• Enzyme activity is regulated by various mechanisms to control metabolic flux
• Allosteric regulation involves the binding of effectors at sites other than the active site, modulating enzyme activity
  • Allosteric activators increase enzyme activity (AMP activating glycogen phosphorylase)
  • Allosteric inhibitors decrease enzyme activity (ATP inhibiting phosphofructokinase)
• Covalent modification, such as phosphorylation or dephosphorylation, can alter enzyme activity (glycogen synthase, pyruvate dehydrogenase)
• Feedback inhibition occurs when the end product of a pathway inhibits the activity of an earlier enzyme in the pathway (CTP inhibiting aspartate transcarbamoylase)
• Compartmentalization of enzymes and substrates in different organelles allows for spatial regulation of metabolic processes
• Hormonal regulation controls metabolic pathways at the organismal level (insulin promoting glucose uptake and storage)

Energy Production and ATP

• ATP is composed of adenosine (adenine + ribose) and three phosphate groups
• The hydrolysis of ATP to ADP + Pi releases ~7.3 kcal/mol of energy under standard conditions
• ATP is synthesized by substrate-level phosphorylation and oxidative phosphorylation
  • Substrate-level phosphorylation directly transfers a phosphate group from a high-energy intermediate to ADP (phosphoenolpyruvate to ATP in glycolysis)
  • Oxidative phosphorylation uses the proton gradient generated by the electron transport chain to drive ATP synthesis via ATP synthase
• The ATP/ADP cycle allows for the storage and release of energy in cells
• The phosphorylation potential ($\Delta G_{p}$) represents the free energy of ATP hydrolysis under intracellular conditions
• The ATP/AMP ratio is a key indicator of cellular energy status and regulates metabolic pathways through allosteric enzymes (AMP-activated protein kinase)

Carbohydrate Metabolism

• Glycolysis is a 10-step pathway that converts glucose into pyruvate
  • Preparatory phase (steps 1-5) consumes 2 ATP to convert glucose into fructose-1,6-bisphosphate
  • Payoff phase (steps 6-10) yields 4 ATP and 2 NADH, resulting in a net gain of 2 ATP and 2 NADH per glucose molecule
• Pyruvate can be further oxidized in the citric acid cycle or converted to lactate under anaerobic conditions
• The pentose phosphate pathway has an oxidative and a non-oxidative branch
  • Oxidative branch generates NADPH and ribulose-5-phosphate
  • Non-oxidative branch interconverts pentose phosphates and glycolytic intermediates
• Glycogen is a storage polysaccharide in animals, synthesized by glycogen synthase and degraded by glycogen phosphorylase
• Gluconeogenesis synthesizes glucose from non-carbohydrate precursors, sharing several enzymes with glycolysis but using unique, irreversible steps (pyruvate carboxylase, phosphoenolpyruvate carboxykinase, fructose-1,6-bisphosphatase, glucose-6-phosphatase)

Lipid Metabolism

• Fatty acids are activated to acyl-CoA thioesters before being catabolized or synthesized
• Fatty acid oxidation (β-oxidation) occurs in the mitochondrial matrix and breaks down fatty acids into acetyl-CoA units
  • Each cycle of β-oxidation shortens the fatty acid by two carbons and generates NADH, FADH2, and acetyl-CoA
  • Odd-chain fatty acids yield propionyl-CoA in the final step, which is converted to succinyl-CoA and enters the citric acid cycle
• Ketone bodies (acetoacetate, β-hydroxybutyrate) are synthesized from acetyl-CoA in the liver during prolonged fasting or low-carbohydrate states
• Fatty acid synthesis occurs in the cytosol and uses acetyl-CoA as a substrate
  • Acetyl-CoA carboxylase catalyzes the rate-limiting step, converting acetyl-CoA to malonyl-CoA
  • Fatty acid synthase is a multienzyme complex that condenses acetyl-CoA and malonyl-CoA to form palmitate
• Triacylglycerols are stored in adipose tissue and hydrolyzed by lipases to release fatty acids during energy demand
• Cholesterol is synthesized from acetyl-CoA through the mevalonate pathway, with HMG-CoA reductase as the rate-limiting enzyme

Amino Acid Metabolism

• Amino acids are classified as glucogenic (can be converted to glucose), ketogenic (can be converted to ketone bodies or fatty acids), or both
• Transamination reactions transfer the amino group from an amino acid to an α-ketoacid, forming a new amino acid and α-ketoacid
• Deamination removes the amino group from an amino acid, releasing ammonia (NH3) or ammonium (NH4+)
• The urea cycle converts ammonia into urea in the liver, preventing ammonia toxicity
  • Carbamoyl phosphate synthetase I, ornithine transcarbamoylase, argininosuccinate synthetase, argininosuccinate lyase, and arginase are the key enzymes in the urea cycle
• Amino acid carbon skeletons can enter the citric acid cycle or be used for gluconeogenesis
• Specific amino acids have unique metabolic fates (glycine in heme synthesis, phenylalanine and tyrosine in neurotransmitter synthesis)

Integration of Metabolic Pathways

• Metabolic pathways are interconnected and regulated to maintain homeostasis
• The fed state is characterized by high blood glucose, insulin secretion, and anabolic processes (glycogen synthesis, fatty acid synthesis, protein synthesis)
• The fasting state is characterized by low blood glucose, glucagon secretion, and catabolic processes (glycogenolysis, gluconeogenesis, fatty acid oxidation, ketogenesis)
• The Cori cycle shuttles lactate from anaerobic tissues (muscles) to the liver for gluconeogenesis
• The glucose-alanine cycle transports amino groups from muscle to the liver in the form of alanine, which is then used for gluconeogenesis
• The Cahill cycle (glucose-fatty acid cycle) describes the reciprocal regulation of glucose and fatty acid metabolism
  • Fatty acid oxidation inhibits glucose utilization in tissues (glucose-fatty acid cycle)
  • Elevated acetyl-CoA levels from fatty acid oxidation inhibit pyruvate dehydrogenase and activate pyruvate carboxylase, promoting gluconeogenesis
• Metabolic flexibility allows organisms to adapt to changes in nutrient availability and energy demands

Clinical and Real-World Applications

• Diabetes mellitus is characterized by impaired glucose homeostasis due to insulin deficiency (type 1) or insulin resistance (type 2)
  • Complications include hyperglycemia, ketoacidosis, and long-term tissue damage (retinopathy, neuropathy, nephropathy)
• Inborn errors of metabolism are genetic disorders that affect specific metabolic pathways
  • Phenylketonuria (PKU) is caused by a deficiency in phenylalanine hydroxylase, leading to elevated phenylalanine levels and neurological damage if untreated
  • Maple syrup urine disease (MSUD) is caused by a defect in branched-chain α-ketoacid dehydrogenase, resulting in the accumulation of branched-chain amino acids and their toxic metabolites
• Metabolic syndrome is a cluster of conditions (obesity, insulin resistance, hypertension, dyslipidemia) that increase the risk of cardiovascular disease and type 2 diabetes
• Atherosclerosis is the buildup of plaque in arteries, often driven by dyslipidemia (high LDL cholesterol, low HDL cholesterol) and chronic inflammation
• Cancer cells exhibit altered metabolism, such as increased aerobic glycolysis (Warburg effect) and glutamine addiction, to support rapid proliferation
• Athletic performance can be enhanced by optimizing nutrient intake and training to improve metabolic efficiency and maximize energy production
• Fasting and calorie restriction have been shown to induce metabolic adaptations (ketogenesis, autophagy) that may have health benefits, such as improved insulin sensitivity and longevity
• Biotechnology applications leverage metabolic pathways for the production of biofuels, pharmaceuticals, and other valuable compounds (engineered microorganisms, cell-free systems)