2.3 Metabolism

Metabolism is the cornerstone of life, encompassing all chemical reactions that sustain cells and organisms. It's divided into anabolism (building complex molecules) and catabolism (breaking them down). Understanding metabolism is crucial in medicinal chemistry, influencing how drugs interact with the body.

Metabolic pathways form intricate networks, efficiently using energy and resources within cells. Key pathways include glycolysis, the citric acid cycle, and oxidative phosphorylation. These processes are tightly regulated, and disruptions can lead to various metabolic disorders and impact drug effectiveness.

Metabolism overview

• Metabolism encompasses all chemical reactions involved in maintaining the living state of cells and organisms
• Anabolism and catabolism are two broad categories of metabolism that work together to sustain life and enable growth and reproduction
• Metabolism is a critical consideration in medicinal chemistry as it influences drug absorption, distribution, metabolism, and excretion (ADME)

Anabolism vs catabolism

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• Anabolism refers to constructive metabolism, which involves the synthesis of complex molecules from simpler ones
  • Examples include the synthesis of proteins from amino acids and the formation of nucleic acids from nucleotides
• Catabolism is destructive metabolism, which breaks down complex molecules into simpler ones, often releasing energy in the process
  • Examples include the breakdown of glucose during glycolysis and the oxidation of fatty acids to generate ATP
• Anabolism and catabolism are tightly regulated and balanced to maintain homeostasis and support growth and repair

Energy requirements of metabolism

• Metabolism requires a constant supply of energy, primarily in the form of adenosine triphosphate (ATP)
• ATP is generated through catabolic processes such as cellular respiration and is consumed by anabolic reactions and other cellular processes
• The energy balance of a cell is regulated by various mechanisms, including allosteric regulation of enzymes and hormonal control of metabolic pathways
• Disruptions in energy balance can lead to metabolic disorders and cellular dysfunction

Metabolic pathways

• Metabolic pathways are series of enzymatic reactions that transform one molecule into another
• These pathways are organized into networks that enable the efficient use of energy and resources within cells
• Key metabolic pathways include glycolysis, the citric acid cycle, oxidative phosphorylation, and the synthesis and degradation of fatty acids and amino acids

Glycolysis

• Glycolysis is a central pathway in glucose metabolism that takes place in the cytosol
• It involves the breakdown of one molecule of glucose into two molecules of pyruvate, generating ATP and reducing equivalents (NADH)
• Glycolysis is a crucial source of energy for cells and provides precursors for other metabolic pathways
• The rate of glycolysis is regulated by the activity of key enzymes such as hexokinase and phosphofructokinase

Citric acid cycle

• The citric acid cycle, also known as the Krebs cycle or tricarboxylic acid (TCA) cycle, is a central metabolic pathway that takes place in the mitochondrial matrix
• It involves the oxidation of acetyl-CoA, derived from the breakdown of carbohydrates, fats, and proteins, to generate reducing equivalents (NADH and FADH2) and ATP
• The citric acid cycle is a key source of precursors for biosynthetic pathways, such as the synthesis of amino acids and nucleotides
• The cycle is regulated by the availability of substrates and the activity of enzymes such as citrate synthase and isocitrate dehydrogenase

Oxidative phosphorylation

• Oxidative phosphorylation is the process by which cells generate ATP using the reducing equivalents (NADH and FADH2) produced by the citric acid cycle and other catabolic pathways
• It takes place in the inner mitochondrial membrane and involves the electron transport chain and ATP synthase
• The electron transport chain consists of a series of protein complexes that transfer electrons from NADH and FADH2 to oxygen, creating a proton gradient across the inner mitochondrial membrane
• ATP synthase uses the proton gradient to drive the synthesis of ATP from ADP and inorganic phosphate

Pentose phosphate pathway

• The pentose phosphate pathway is an alternative route for glucose metabolism that takes place in the cytosol
• It generates reducing equivalents in the form of NADPH, which is essential for reductive biosynthesis and antioxidant defense
• The pathway also produces ribose-5-phosphate, a precursor for nucleotide synthesis
• The pentose phosphate pathway is particularly active in tissues with high requirements for NADPH, such as the liver and red blood cells

Gluconeogenesis

• Gluconeogenesis is the synthesis of glucose from non-carbohydrate precursors, such as amino acids, lactate, and glycerol
• It takes place primarily in the liver and kidney and is essential for maintaining blood glucose levels during fasting or prolonged exercise
• Gluconeogenesis shares several steps with glycolysis but is not simply the reverse of glycolysis, as it requires additional enzymes and energy input
• The process is regulated by hormones such as glucagon and cortisol, which promote gluconeogenesis, and insulin, which inhibits it

Fatty acid synthesis

• Fatty acid synthesis is the anabolic pathway that generates long-chain fatty acids from acetyl-CoA
• It takes place in the cytosol and involves the sequential addition of two-carbon units to a growing fatty acid chain
• The process is catalyzed by the multi-enzyme complex fatty acid synthase and requires NADPH as a reducing equivalent
• Fatty acid synthesis is regulated by the availability of substrates and the activity of enzymes such as acetyl-CoA carboxylase

Fatty acid oxidation

• Fatty acid oxidation, also known as beta-oxidation, is the catabolic pathway that breaks down fatty acids to generate acetyl-CoA, which can be further oxidized in the citric acid cycle
• It takes place in the mitochondrial matrix and involves the sequential removal of two-carbon units from the fatty acid chain
• Fatty acid oxidation is a major source of energy for tissues such as the heart, skeletal muscle, and liver during fasting or prolonged exercise
• The process is regulated by the availability of fatty acids and the activity of enzymes such as carnitine palmitoyltransferase I (CPT-I)

Amino acid metabolism

• Amino acid metabolism involves the synthesis and degradation of amino acids, which serve as building blocks for proteins and precursors for various bioactive compounds
• The catabolism of amino acids generates ammonia, which is converted to urea in the liver and excreted by the kidneys
• Amino acids can also be converted to glucose (glucogenic amino acids) or ketone bodies (ketogenic amino acids) depending on their structure
• Disorders of amino acid metabolism, such as phenylketonuria and maple syrup urine disease, can lead to the accumulation of toxic metabolites and require dietary management

Regulation of metabolism

• Metabolic regulation ensures that cells and organisms can adapt to changing environmental conditions and maintain homeostasis
• Regulation occurs at multiple levels, including the control of enzyme activity, gene expression, and the availability of substrates and cofactors
• Key mechanisms of metabolic regulation include hormonal control, allosteric regulation, and enzyme compartmentalization

Hormonal control

• Hormones are signaling molecules that regulate metabolism by binding to specific receptors on target cells
• Insulin, for example, is a key anabolic hormone that promotes the uptake and storage of glucose, amino acids, and fatty acids
• Glucagon, on the other hand, is a catabolic hormone that stimulates the breakdown of glycogen and the synthesis of glucose during fasting
• Other hormones involved in metabolic regulation include cortisol, thyroid hormones, and catecholamines

Allosteric regulation

• Allosteric regulation involves the modulation of enzyme activity by the binding of effectors at sites other than the active site
• Allosteric effectors can be either activators or inhibitors and can change the affinity of the enzyme for its substrate or its catalytic efficiency
• Examples of allosteric enzymes include phosphofructokinase, which is inhibited by ATP and activated by AMP, and glutamine synthetase, which is inhibited by multiple end products of glutamine metabolism
• Allosteric regulation allows for rapid and reversible control of enzyme activity in response to changes in metabolite concentrations

Enzyme compartmentalization

• The compartmentalization of enzymes within cells allows for the spatial separation of metabolic processes and the creation of local microenvironments with distinct metabolite concentrations
• For example, the enzymes of the citric acid cycle are localized to the mitochondrial matrix, while those of the pentose phosphate pathway are found in the cytosol
• Compartmentalization also enables the regulation of enzyme activity by controlling the access of substrates and effectors to the enzyme
• The permeability of membranes and the presence of specific transport proteins can regulate the flow of metabolites between compartments

Metabolic disorders

• Metabolic disorders are conditions that disrupt normal metabolism, leading to the accumulation of toxic intermediates or the deficiency of essential products
• These disorders can be classified as inborn errors of metabolism, which are genetic disorders present from birth, or acquired metabolic disorders, which develop later in life due to environmental factors or underlying diseases
• The study of metabolic disorders is crucial for understanding disease mechanisms and developing targeted therapies

Inborn errors of metabolism

• Inborn errors of metabolism are genetic disorders caused by mutations in genes encoding metabolic enzymes or transport proteins
• These disorders are typically inherited in an autosomal recessive manner and can affect multiple organ systems
• Examples include phenylketonuria (PKU), which is caused by a deficiency of phenylalanine hydroxylase, and galactosemia, which results from a deficiency of galactose-1-phosphate uridyltransferase
• The management of inborn errors of metabolism often involves dietary restriction of the accumulating substrate and supplementation of the deficient product

Acquired metabolic disorders

• Acquired metabolic disorders develop later in life and can be caused by environmental factors, such as diet and toxins, or underlying diseases, such as diabetes and cancer
• Examples include obesity, which results from an imbalance between energy intake and expenditure, and metabolic syndrome, which is characterized by insulin resistance, dyslipidemia, and hypertension
• The management of acquired metabolic disorders typically involves lifestyle modifications, such as diet and exercise, and pharmacological interventions to target specific metabolic pathways
• The study of acquired metabolic disorders is essential for understanding the complex interplay between genetics, environment, and disease risk

Metabolism in drug design

• Understanding metabolism is crucial for the design and development of safe and effective drugs
• Metabolic stability, prodrug strategies, and drug-drug interactions are key considerations in drug design and optimization
• The study of metabolism in drug design involves a multidisciplinary approach, integrating knowledge from medicinal chemistry, pharmacology, and toxicology

Metabolic stability of drugs

• Metabolic stability refers to the ability of a drug to resist biotransformation by metabolic enzymes, such as cytochrome P450 (CYP) enzymes and UDP-glucuronosyltransferases (UGTs)
• High metabolic stability is generally desirable, as it can prolong the half-life of the drug and reduce the potential for drug-drug interactions
• However, in some cases, metabolic instability can be advantageous, as it can facilitate the rapid clearance of the drug and minimize the risk of accumulation and toxicity
• The metabolic stability of a drug can be optimized through structural modifications, such as the introduction of electron-withdrawing groups or the blocking of metabolically labile sites

Prodrugs and metabolic activation

• Prodrugs are inactive compounds that are converted to active drugs by metabolic enzymes in the body
• Prodrug strategies can be used to improve the solubility, bioavailability, or targeting of drugs, or to reduce the risk of adverse effects
• Examples of prodrugs include enalapril, which is converted to the active angiotensin-converting enzyme (ACE) inhibitor enalaprilat by esterases, and cyclophosphamide, which is activated by CYP enzymes to form cytotoxic metabolites
• The design of prodrugs requires a detailed understanding of the metabolic pathways involved in their activation and the potential for interindividual variability in enzyme activity

Drug-drug interactions in metabolism

• Drug-drug interactions can occur when one drug alters the metabolism of another drug, leading to changes in its pharmacokinetics or pharmacodynamics
• These interactions can be mediated by the induction or inhibition of metabolic enzymes, such as CYP enzymes, or by competition for the same metabolic pathways
• Examples of drug-drug interactions include the increased risk of bleeding with the concomitant use of warfarin and antibiotics that inhibit CYP2C9, and the decreased efficacy of oral contraceptives with the use of enzyme-inducing antiepileptic drugs
• The prediction and management of drug-drug interactions require a comprehensive understanding of the metabolic pathways involved and the use of in vitro and in vivo models to assess the potential for interactions

Analytical techniques in metabolism

• Analytical techniques are essential tools for studying metabolism and identifying metabolic biomarkers of disease and drug response
• These techniques range from targeted approaches, such as enzyme kinetics assays, to untargeted approaches, such as metabolomics
• The choice of analytical technique depends on the specific research question and the nature of the metabolites of interest

Metabolomics

• Metabolomics is the comprehensive analysis of small molecule metabolites in biological systems
• It involves the use of high-throughput analytical techniques, such as mass spectrometry and nuclear magnetic resonance (NMR) spectroscopy, to profile the metabolome
• Metabolomics can be used to identify biomarkers of disease, monitor drug response, and elucidate metabolic pathways
• The data generated by metabolomics studies require advanced bioinformatics tools for processing, normalization, and interpretation

Isotope labeling studies

• Isotope labeling studies involve the use of stable isotopes, such as 13C and 15N, to trace the flow of metabolites through metabolic pathways
• These studies can provide information on the rates of metabolic reactions, the contribution of different substrates to metabolite pools, and the compartmentalization of metabolic processes
• Examples of isotope labeling studies include the use of 13C-glucose to study glycolysis and the citric acid cycle, and the use of 15N-glutamine to study nitrogen metabolism
• The analysis of isotope labeling data requires specialized software and mathematical modeling approaches

Enzyme kinetics assays

• Enzyme kinetics assays are used to study the activity and regulation of metabolic enzymes
• These assays involve the measurement of the rate of product formation or substrate depletion over time, using spectrophotometric or fluorometric methods
• Enzyme kinetics data can be used to determine the Michaelis-Menten constants (Km and Vmax), the mode of inhibition, and the effects of allosteric regulators
• The design and interpretation of enzyme kinetics assays require a solid understanding of enzyme kinetics theory and the use of appropriate controls and data analysis methods

Metabolism in different tissues

• Metabolism varies significantly across different tissues and organs, reflecting their specific functions and energy requirements
• The liver, muscle, and brain are among the most metabolically active tissues in the body and play critical roles in the regulation of whole-body metabolism
• The study of tissue-specific metabolism is essential for understanding the pathophysiology of metabolic diseases and the development of targeted therapies

Liver metabolism

• The liver is the central organ of metabolism, playing a key role in the synthesis, storage, and breakdown of carbohydrates, lipids, and proteins
• It is the main site of glycogen synthesis and storage, as well as the primary site of gluconeogenesis during fasting
• The liver is also the main site of lipid synthesis and the packaging of lipids into lipoproteins for transport to other tissues
• The liver is responsible for the detoxification of xenobiotics and the synthesis of bile acids, which are essential for the absorption of dietary lipids

Muscle metabolism

• Skeletal muscle is the largest metabolic organ in the body, accounting for up to 40% of total body mass
• It is a major site of glucose uptake and glycogen storage, as well as the primary site of fatty acid oxidation during exercise
• Muscle metabolism is highly responsive to insulin and exercise, which stimulate glucose uptake and glycogen synthesis
• Disorders of muscle metabolism, such as McArdle disease (glycogen storage disease type V), can lead to exercise intolerance and muscle weakness

Brain metabolism

• The brain is one of the most energy-demanding organs in the body, consuming up to 20% of total body glucose despite accounting for only 2% of body weight
• It relies almost exclusively on glucose for energy production, although it can also use ketone bodies during prolonged fasting or starvation
• The brain has a limited capacity for energy storage and requires a constant supply of glucose from the bloodstream
• Disorders of brain metabolism, such as Alzheimer's disease and Parkinson's disease, are associated with impaired glucose utilization and mitochondrial dysfunction

Metabolism and disease

• Metabolic dysregulation is a hallmark of many chronic diseases, including cancer, metabolic syndrome, and diabetes
• The study of metabolism in disease states can provide insights into the underlying pathophysiology and identify potential targets for therapeutic intervention
• The development of metabolic therapies, such as metformin for diabetes and statins for hypercholesterolemia, has revolutionized the treatment of metabolic diseases

Cancer metabolism

• Cancer cells exhibit altered metabolism, characterized by increased glucose uptake and lactate production (the Warburg effect)
• This metabolic reprogramming supports the rapid proliferation and survival of cancer cells in the hypoxic and nutrient-deprived tumor microenvironment
• Targeting cancer metabolism, such as by inhibiting glycolysis or glutaminolysis, is an emerging strategy for cancer therapy
• The use of metabolic imaging techniques, such as positron emission tomography (PET) with 18F-fluorodeoxyglucose (FDG), can aid in the diagnosis and monitoring of cancer

Metabolic syndrome

• Metabolic syndrome