🧬Biochemistry Unit 19 – Integration of Metabolism

Key Metabolic Pathways

• Glycolysis breaks down glucose into pyruvate in the cytosol, generating ATP and NADH
  • Consists of two phases: preparatory phase (requires ATP) and payoff phase (produces ATP)
  • Key enzymes include hexokinase, phosphofructokinase, and pyruvate kinase
• Citric acid cycle (Krebs cycle) oxidizes acetyl-CoA to generate NADH, FADH2, and GTP in the mitochondrial matrix
  • Acetyl-CoA is derived from pyruvate, fatty acids, and amino acids
  • Key enzymes include citrate synthase, isocitrate dehydrogenase, and α-ketoglutarate dehydrogenase
• Oxidative phosphorylation produces ATP through the electron transport chain and chemiosmosis in the mitochondrial inner membrane
  • NADH and FADH2 donate electrons to the electron transport chain, creating a proton gradient
  • ATP synthase uses the proton gradient to generate ATP
• Fatty acid synthesis occurs in the cytosol, using acetyl-CoA as a substrate to generate long-chain fatty acids
  • Key enzymes include acetyl-CoA carboxylase and fatty acid synthase
• Fatty acid oxidation (β-oxidation) breaks down fatty acids in the mitochondrial matrix to generate acetyl-CoA, NADH, and FADH2
  • Carnitine shuttle system transports fatty acids into the mitochondria
  • Each cycle of β-oxidation shortens the fatty acid chain by two carbons
• Amino acid metabolism involves the synthesis and degradation of amino acids
  • Transamination reactions transfer amino groups between amino acids and α-ketoacids
  • Deamination removes the amino group, forming ammonia and the corresponding α-ketoacid
• Urea cycle converts ammonia into urea in the liver for excretion, involving a series of enzymes and transporters
  • Key enzymes include carbamoyl phosphate synthetase I, ornithine transcarbamylase, and arginase

Regulatory Mechanisms

• Allosteric regulation modulates enzyme activity through the binding of effectors at sites distinct from the active site
  • Positive effectors (allosteric activators) enhance enzyme activity, while negative effectors (allosteric inhibitors) decrease activity
  • Example: phosphofructokinase is allosterically inhibited by ATP and activated by AMP
• Covalent modification of enzymes, such as phosphorylation and dephosphorylation, can alter their activity
  • Protein kinases add phosphate groups to enzymes, while phosphatases remove them
  • Example: glycogen phosphorylase is activated by phosphorylation and inactivated by dephosphorylation
• Substrate availability influences the flux through metabolic pathways
  • High substrate concentrations drive reactions forward, while low concentrations limit the reaction rate
  • Example: increased glucose availability promotes glycolysis and glycogen synthesis
• Feedback inhibition occurs when the end product of a pathway inhibits the activity of an earlier enzyme in the pathway
  • Helps maintain homeostasis and prevents excessive accumulation of end products
  • Example: ATP inhibits the activity of citrate synthase in the citric acid cycle
• Compartmentalization of enzymes and substrates in different organelles allows for spatial regulation of metabolism
  • Example: fatty acid synthesis occurs in the cytosol, while fatty acid oxidation takes place in the mitochondria
• Gene expression regulation controls the synthesis of enzymes involved in metabolic pathways
  • Transcription factors can activate or repress the expression of genes encoding metabolic enzymes
  • Example: the transcription factor SREBP activates genes involved in lipid synthesis
• Enzyme induction and repression alter the amount of enzyme present in response to environmental or physiological signals
  • Induction increases enzyme synthesis, while repression decreases enzyme synthesis
  • Example: the presence of lactose induces the synthesis of β-galactosidase in E. coli

Energy Production and Utilization

• ATP serves as the primary energy currency in cells, providing energy for various cellular processes
  • Hydrolysis of ATP to ADP and inorganic phosphate (Pi) releases energy
  • ATP is regenerated through substrate-level phosphorylation and oxidative phosphorylation
• Glucose is a major energy source for many cells and can be oxidized through glycolysis and the citric acid cycle
  • Glycolysis generates 2 ATP per glucose molecule, while the citric acid cycle and oxidative phosphorylation yield additional ATP
• Fatty acids are energy-dense molecules that can be oxidized through β-oxidation to generate acetyl-CoA
  • Each cycle of β-oxidation produces NADH, FADH2, and acetyl-CoA, which can enter the citric acid cycle
  • Fatty acids yield more ATP per gram compared to carbohydrates
• Amino acids can be catabolized to generate energy when glucose and fatty acids are limited
  • Glucogenic amino acids can be converted to glucose or intermediates of the citric acid cycle
  • Ketogenic amino acids can be converted to acetyl-CoA or acetoacetate
• Creatine phosphate serves as an energy reserve in muscle cells, rapidly regenerating ATP during high-intensity exercise
  • Creatine kinase catalyzes the transfer of a phosphate group from creatine phosphate to ADP, forming ATP
• Uncoupling proteins (UCPs) in the mitochondrial inner membrane can dissipate the proton gradient without generating ATP
  • UCPs generate heat instead of ATP, contributing to thermogenesis
  • Example: brown adipose tissue expresses high levels of UCP1 for heat production
• Energy balance is maintained by matching energy intake with energy expenditure
  • Excess energy is stored as glycogen and triglycerides, while energy deficits lead to the mobilization of stored fuels

Hormonal Control

• Insulin is a key anabolic hormone secreted by pancreatic β-cells in response to elevated blood glucose levels
  • Promotes glucose uptake by tissues (muscle, adipose) through GLUT4 translocation
  • Stimulates glycogen synthesis, lipogenesis, and protein synthesis
  • Inhibits gluconeogenesis, glycogenolysis, and lipolysis
• Glucagon is a catabolic hormone secreted by pancreatic α-cells in response to low blood glucose levels
  • Stimulates glycogenolysis and gluconeogenesis in the liver to raise blood glucose levels
  • Promotes lipolysis in adipose tissue and ketogenesis in the liver
• Catecholamines (epinephrine and norepinephrine) are released by the adrenal medulla during stress or exercise
  • Stimulate glycogenolysis and lipolysis to provide energy substrates
  • Increase heart rate and blood pressure to enhance oxygen and nutrient delivery
• Thyroid hormones (T3 and T4) regulate basal metabolic rate and energy expenditure
  • Increase the expression of genes involved in glucose and lipid metabolism
  • Stimulate mitochondrial biogenesis and oxidative phosphorylation
• Cortisol is a glucocorticoid hormone released by the adrenal cortex in response to stress
  • Promotes gluconeogenesis and lipolysis to provide energy substrates
  • Suppresses immune function and inflammation
• Growth hormone, secreted by the anterior pituitary gland, promotes protein synthesis and lipolysis
  • Stimulates IGF-1 production in the liver, which mediates many of its anabolic effects
• Adipokines, such as leptin and adiponectin, are secreted by adipose tissue and regulate energy balance and insulin sensitivity
  • Leptin signals satiety to the hypothalamus and reduces food intake
  • Adiponectin enhances insulin sensitivity and promotes fatty acid oxidation

Organ-Specific Metabolism

• Liver plays a central role in glucose and lipid metabolism, as well as detoxification
  • Performs gluconeogenesis, glycogenolysis, and glycogen synthesis to regulate blood glucose levels
  • Synthesizes and secretes lipoproteins (VLDL) and ketone bodies
  • Detoxifies ammonia through the urea cycle
• Skeletal muscle is a major site of glucose disposal and energy utilization
  • Insulin stimulates glucose uptake and glycogen synthesis in muscle
  • Oxidizes glucose and fatty acids to generate ATP for contraction
• Adipose tissue stores energy as triglycerides and secretes adipokines
  • White adipose tissue primarily stores energy, while brown adipose tissue generates heat through thermogenesis
  • Insulin promotes lipogenesis and inhibits lipolysis in adipose tissue
• Brain relies primarily on glucose for energy production
  • Maintains a constant supply of glucose through tight regulation of blood glucose levels
  • Can utilize ketone bodies during prolonged fasting or starvation
• Kidney filters blood and reabsorbs glucose and amino acids
  • Performs gluconeogenesis during prolonged fasting
  • Excretes urea, the end product of amino acid catabolism
• Intestine absorbs nutrients from the diet and performs local metabolism
  • Enterocytes express enzymes for glucose and lipid metabolism
  • Gut microbiota ferment undigested carbohydrates to produce short-chain fatty acids
• Heart has a high energy demand and relies on fatty acids and glucose for ATP production
  • Preferentially oxidizes fatty acids under normal conditions
  • Can switch to glucose oxidation under ischemic or hypoxic conditions

Metabolic Adaptations

• Fasting and starvation lead to a shift in energy substrate utilization
  • During short-term fasting, glycogenolysis and lipolysis provide glucose and fatty acids
  • Prolonged fasting induces ketogenesis in the liver, providing ketone bodies for the brain and other tissues
• Exercise alters fuel selection based on intensity and duration
  • Low-intensity exercise primarily relies on fatty acid oxidation
  • High-intensity exercise shifts towards glucose utilization through glycogenolysis and glycolysis
• Pregnancy and lactation require metabolic adaptations to support fetal growth and milk production
  • Increased insulin resistance facilitates glucose transfer to the fetus
  • Lipid metabolism is enhanced to provide substrates for fetal development and milk synthesis
• Circadian rhythms influence metabolic processes, with variations in hormone levels and enzyme activities throughout the day
  • Disruption of circadian rhythms (e.g., shift work) can lead to metabolic disorders
• Caloric restriction and intermittent fasting can improve metabolic health and longevity
  • Reduced insulin levels and increased insulin sensitivity
  • Enhanced autophagy and cellular repair mechanisms
• High-altitude adaptation involves changes in energy metabolism to cope with reduced oxygen availability
  • Increased reliance on glucose oxidation and lactate production
  • Enhanced oxygen delivery through increased red blood cell production and capillary density
• Hibernation in some mammals is characterized by a dramatic reduction in metabolic rate and body temperature
  • Decreased insulin secretion and increased insulin sensitivity
  • Utilization of stored lipids as the primary energy source

Interconnections Between Pathways

• Glucose-alanine cycle shuttles amino groups from muscle to liver
  • Pyruvate is transaminated to form alanine in muscle, which is transported to the liver
  • In the liver, alanine is deaminated to form pyruvate, which can be used for gluconeogenesis
• Cori cycle (glucose-lactate cycle) transfers lactate from anaerobic tissues (e.g., muscle) to the liver
  • Lactate is produced by anaerobic glycolysis in muscle and released into the bloodstream
  • The liver takes up lactate and converts it back to glucose through gluconeogenesis
• Ketone bodies (acetoacetate, β-hydroxybutyrate) are produced by the liver during fasting or low-carbohydrate diets
  • Acetyl-CoA from fatty acid oxidation is converted to ketone bodies when glucose is limited
  • Ketone bodies serve as an alternative fuel source for the brain, heart, and skeletal muscle
• Glyceroneogenesis is the synthesis of glycerol 3-phosphate from precursors other than glucose
  • Important for triglyceride synthesis and fatty acid re-esterification in adipose tissue
  • Helps maintain triglyceride-fatty acid cycling and regulates fatty acid release
• Pentose phosphate pathway generates NADPH and ribose 5-phosphate
  • NADPH is used for reductive biosynthesis (e.g., fatty acid synthesis) and antioxidant defense
  • Ribose 5-phosphate is a precursor for nucleotide and nucleic acid synthesis
• Malate-aspartate shuttle transfers reducing equivalents (NADH) from the cytosol to the mitochondria
  • Allows the regeneration of NAD+ in the cytosol for continued glycolysis
  • Provides NADH for the electron transport chain and ATP production in the mitochondria
• Glutamine serves as a major nitrogen carrier and energy source for rapidly dividing cells
  • Glutaminolysis converts glutamine to α-ketoglutarate, which enters the citric acid cycle
  • Supports the biosynthesis of nucleotides, amino acids, and other important metabolites

Clinical Relevance and Disorders

• Diabetes mellitus is characterized by hyperglycemia due to insulin deficiency (type 1) or insulin resistance (type 2)
  • Leads to impaired glucose utilization and increased glucose production
  • Associated with long-term complications such as cardiovascular disease, nephropathy, and neuropathy
• Obesity results from an imbalance between energy intake and expenditure, leading to excessive fat accumulation
  • Increases the risk of metabolic disorders such as type 2 diabetes, dyslipidemia, and cardiovascular disease
  • Adipose tissue dysfunction contributes to systemic inflammation and insulin resistance
• Metabolic syndrome is a cluster of conditions that increase the risk of cardiovascular disease and type 2 diabetes
  • Includes abdominal obesity, insulin resistance, hypertension, and dyslipidemia
  • Lifestyle modifications (diet, exercise) and pharmacological interventions can help manage the condition
• Inborn errors of metabolism are genetic disorders that affect specific metabolic pathways
  • Examples include phenylketonuria (PKU), maple syrup urine disease (MSUD), and medium-chain acyl-CoA dehydrogenase (MCAD) deficiency
  • Early diagnosis and management (e.g., dietary restrictions, enzyme replacement therapy) are crucial to prevent severe complications
• Mitochondrial disorders result from mutations in mitochondrial or nuclear DNA that affect mitochondrial function
  • Can present with a wide range of symptoms, including myopathy, encephalopathy, and lactic acidosis
  • Treatment is often supportive and may include antioxidants, cofactor supplementation, and dietary modifications
• Cancer cells exhibit altered metabolism, known as the Warburg effect
  • Increased glucose uptake and aerobic glycolysis, even in the presence of oxygen
  • Supports rapid cell proliferation and biosynthesis of macromolecules
  • Targeting cancer metabolism is an emerging strategy for cancer therapy
• Metabolic acidosis occurs when there is an accumulation of acid or loss of bicarbonate in the body
  • Can be caused by increased production of lactic acid (lactic acidosis) or ketone bodies (ketoacidosis)
  • Treatment involves addressing the underlying cause and correcting the acid-base imbalance