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Semester 2: Bioenergetics and Intermediary Metabolism
Bioenergetics: energy transformation, laws of thermodynamics, Gibbs energy, free energy changes, redox potential, ATP as energy currency, electron transport chain, oxidative phosphorylation, inhibitors and uncouplers, shuttle systems
Bioenergetics and Intermediary Metabolism
Energy Transformation
Bioenergetics is the study of energy flow through living systems. It involves the conversion of energy from one form to another within biological systems.
Laws of Thermodynamics
The first law of thermodynamics states that energy cannot be created or destroyed, only transformed. The second law states that entropy of an isolated system always increases, which implies that energy transformations are not 100% efficient.
Gibbs Energy
Gibbs free energy is a thermodynamic potential that measures the maximum reversible work performed by a thermodynamic system at constant temperature and pressure.
Free Energy Changes
Free energy changes indicate the spontaneity of a process. A negative change in Gibbs free energy indicates a spontaneous reaction, while a positive change indicates non-spontaneity.
Redox Potential
Redox potential is a measure of the tendency of a chemical species to acquire electrons and be reduced. It plays a critical role in biological reactions, especially in electron transport chains.
ATP as Energy Currency
Adenosine triphosphate (ATP) is known as the energy currency of the cell. It is utilized by cells to perform work and is produced in processes like cellular respiration.
Electron Transport Chain
The electron transport chain is a series of protein complexes located in the inner mitochondrial membrane. It facilitates the transfer of electrons, ultimately leading to the synthesis of ATP.
Oxidative Phosphorylation
Oxidative phosphorylation is the metabolic pathway through which cells convert nutrients into ATP using oxygen. This process occurs in mitochondria and involves the electron transport chain.
Inhibitors and Uncouplers
Inhibitors block specific steps in the electron transport chain, reducing ATP production. Uncouplers disrupt the proton gradient, leading to decreased ATP synthesis while increasing heat production.
Shuttle Systems
Shuttle systems, such as the malate-aspartate shuttle, transport reducing equivalents from the cytosol into mitochondria, playing a vital role in energy metabolism.
Carbohydrate metabolism: glycolysis, citric acid cycle, gluconeogenesis, glycogen metabolism, hexose monophosphate pathway, uronic acid pathway, metabolism of fructose and galactose, hormonal regulation
Carbohydrate metabolism
Glycolysis
Glycolysis is the metabolic pathway that converts glucose into pyruvate, producing energy in the form of ATP. This process occurs in the cytoplasm of cells and can function under both aerobic and anaerobic conditions. Glycolysis consists of ten enzyme-catalyzed reactions, including energy investment and energy payoff phases.
Citric Acid Cycle
Also known as the Krebs cycle, the citric acid cycle occurs in the mitochondria and is a key component of cellular respiration. It involves the oxidation of acetyl-CoA to produce NADH, FADH2, and GTP. These electron carriers subsequently feed into the electron transport chain, generating additional ATP.
Gluconeogenesis
Gluconeogenesis is the synthesis of glucose from non-carbohydrate precursors, primarily in the liver. This process is crucial during fasting or intense exercise, allowing the body to maintain blood glucose levels. Key substrates include lactate, glycerol, and certain amino acids.
Glycogen Metabolism
Glycogen metabolism encompasses both glycogenesis and glycogenolysis. Glycogenesis is the synthesis of glycogen from glucose, primarily in liver and muscle tissues. Glycogenolysis is the breakdown of glycogen to release glucose-1-phosphate, which can then enter glycolysis or be converted to glucose for blood sugar regulation.
Hexose Monophosphate Pathway
The hexose monophosphate pathway, also known as the pentose phosphate pathway, occurs in the cytoplasm and serves two main functions: generating NADPH for reductive biosynthesis and producing ribose-5-phosphate for nucleotide synthesis. It provides important reducing power for anabolic reactions.
Uronic Acid Pathway
The uronic acid pathway is involved in the metabolism of glucose and other hexoses into glucuronic acid, which is significant for detoxification processes and as a precursor for glycosaminoglycans and glycoproteins.
Metabolism of Fructose and Galactose
Fructose and galactose are metabolized through different pathways compared to glucose. Fructose is phosphorylated by fructokinase, while galactose is converted to glucose-1-phosphate via galactose-1-phosphate uridyltransferase. This metabolism is important for energy production and glycogen synthesis.
Hormonal Regulation
Carbohydrate metabolism is tightly regulated by hormones such as insulin, glucagon, and epinephrine. Insulin promotes glucose uptake, glycogenesis, and lipogenesis, while glucagon and epinephrine stimulate glycogenolysis and gluconeogenesis, ensuring homeostasis in blood sugar levels.
Lipid metabolism: fatty acid biosynthesis and oxidation, metabolism of triacylglycerols, phospholipids, sphingolipids, cholesterol biosynthesis and regulation, lipoprotein metabolism, ketone bodies
Lipid metabolism
Fatty Acid Biosynthesis
Fatty acid biosynthesis primarily occurs in the cytoplasm and utilizes acetyl-CoA as a building block. The process begins with the carboxylation of acetyl-CoA to form malonyl-CoA, catalyzed by acetyl-CoA carboxylase. The fatty acid synthase complex then elongates the fatty acid chain through a series of condensation, reduction, dehydration, and another reduction reaction, ultimately producing palmitate, a 16-carbon saturated fatty acid. The synthesis of unsaturated fatty acids involves additional enzymes that modify the palmitate.
Fatty Acid Oxidation
Fatty acid oxidation occurs in the mitochondria, beginning with the process of beta-oxidation. Long-chain fatty acids are activated to acyl-CoA before entering the mitochondria. The acyl-CoA undergoes sequential removal of two-carbon units, producing acetyl-CoA, NADH, and FADH2. The acetyl-CoA produced can enter the citric acid cycle for energy production. Regulation of fatty acid oxidation involves the availability of substrates, the energy state of the cell, and the levels of malonyl-CoA.
Triacylglycerol Metabolism
Triacylglycerols, also known as triglycerides, are formed by the esterification of glycerol with three fatty acids. They serve as primary energy storage in adipose tissue. During energy demands, triacylglycerols are hydrolyzed by hormone-sensitive lipase into glycerol and free fatty acids, which can then be utilized for energy through beta-oxidation. The regulation of triacylglycerol metabolism involves hormonal control by insulin, glucagon, and epinephrine.
Phospholipid Metabolism
Phospholipids are essential components of cell membranes and consist of a glycerol backbone, fatty acids, and a phosphate group. Their biosynthesis takes place in the endoplasmic reticulum via the CDP-diacylglycerol pathway and the phosphatidylcholine pathway. These pathways utilize precursors like diacylglycerol and serine. Phospholipids play crucial roles in maintaining membrane integrity, cell signaling, and lipid metabolism.
Sphingolipid Metabolism
Sphingolipids, characterized by a sphingoid base, play vital roles in signal transduction and cell membrane structure. The biosynthesis of sphingolipids starts with ceramide, which can be further modified to form sphingomyelin or glycosphingolipids. Regulation of sphingolipid metabolism involves various enzymes, including ceramide synthase and sphingomyelinase.
Cholesterol Biosynthesis and Regulation
Cholesterol is synthesized from acetyl-CoA via the mevalonate pathway in the liver. The key regulatory enzyme in cholesterol biosynthesis is HMG-CoA reductase. Feedback inhibition by cholesterol levels and the regulation by statins (cholesterol-lowering drugs) plays a significant role in controlling biosynthesis. Cholesterol is essential for membrane fluidity, steroid hormone synthesis, and bile acid formation.
Lipoprotein Metabolism
Lipoproteins are complexes of lipids and proteins that transport lipids in the bloodstream. They include chylomicrons, VLDL, LDL, and HDL. Their metabolism involves the synthesis in the liver and intestines, transport in the cardiovascular system, and the uptake by various tissues. The balance of lipoprotein types is crucial for cardiovascular health.
Ketone Bodies
Ketone bodies (acetoacetate, β-hydroxybutyrate, and acetone) are produced in the liver from acetyl-CoA during periods of low carbohydrate availability, such as fasting or prolonged exercise. They serve as an alternative energy source for peripheral tissues, especially the brain, during times of glucose scarcity. Regulation of ketogenesis is influenced by the availability of fatty acids and the energy status of the cell.
Amino acid metabolism: biosynthesis and degradation of key amino acids, transamination, deamination, urea cycle, metabolic integration
Amino acid metabolism
Biosynthesis of Key Amino Acids
Key amino acids like alanine, glutamate, and aspartate are synthesized through metabolic pathways involving substrates such as pyruvate and α-ketoglutarate. Enzymatic processes facilitate the conversion of simple molecules into complex structures, enabling the creation of non-essential amino acids. The regulation of these pathways ensures the availability of amino acids for protein synthesis and other metabolic needs.
Degradation of Amino Acids
Amino acids undergo degradation through various pathways that lead to the production of metabolic intermediates. The catabolism of amino acids results in the formation of urea in the liver, which is then excreted by the kidneys. The process ensures the removal of excess nitrogen and maintains nitrogen balance in the organism.
Transamination
Transamination is a key reaction in amino acid metabolism, involving the transfer of an amino group from an amino acid to a keto acid. This reversible reaction is catalyzed by transaminases and is crucial for the synthesis of non-essential amino acids. It plays a significant role in nitrogen metabolism and the interchangeability of amino acids within metabolic pathways.
Deamination
Deamination refers to the removal of the amino group from amino acids, leading to the production of ammonia and a corresponding α-keto acid. This process is vital for the energy production from amino acids and the elimination of excess nitrogen, primarily through oxidative deamination by enzymes such as glutamate dehydrogenase.
Urea Cycle
The urea cycle is a series of biochemical reactions that occur in the liver, converting ammonia, a toxic byproduct of amino acid catabolism, into urea for excretion. Key enzymes involved in the urea cycle include carbamoyl phosphate synthetase, ornithine transcarbamylase, and arginase. The cycle integrates various amino acid metabolic pathways, demonstrating metabolic interconnectivity.
Metabolic Integration
Amino acid metabolism is interconnected with various metabolic pathways including carbohydrate and lipid metabolism. The pathways for amino acid catabolism can feed into the citric acid cycle. This integration highlights the importance of amino acids not only as building blocks for proteins but also as vital contributors to energy metabolism.
Nucleotide metabolism: purine and pyrimidine metabolism, de novo synthesis, salvage pathways, regulation, RNA synthesis
Nucleotide metabolism: purine and pyrimidine metabolism, de novo synthesis, salvage pathways, regulation, RNA synthesis
Purine Nucleotide Metabolism
Purines are synthesized de novo from simple molecules like ribose-5-phosphate, amino acids, and CO2. Key enzymes include PRPP synthetase and amidophosphoribosyltransferase. Salvage pathways involve recycling hypoxanthine and guanine through HGPRT enzyme to form nucleotides.
Pyrimidine Nucleotide Metabolism
Pyrimidine synthesis starts with the formation of carbamoyl phosphate from glutamine and CO2. Enzymes like dihydroorotase and orotate phosphoribosyltransferase play a key role. Pyrimidines can also be salvaged using uridine and cytidine kinases to regenerate nucleotides.
De Novo Synthesis of Nucleotides
De novo synthesis pathways for both purines and pyrimidines are vital for cell growth and division. Involves multiple enzymatic steps, producing nucleotides from basic substrates. This process is orchestrated by feedback inhibition and substrate availability.
Salvage Pathways for Nucleotides
Salvage pathways are crucial for reusing nucleotides. They provide an energy-efficient method to regenerate nucleotides from free bases and nucleosides. Important enzymes in these pathways include adenine phosphoribosyltransferase and nucleoside kinases.
Regulation of Nucleotide Metabolism
Nucleotide metabolism is tightly regulated by substrate availability and feedback mechanisms. Enzymes like ribonucleotide reductase are regulated by the levels of dNTPs, ensuring balanced nucleotide pools.
RNA Synthesis
RNA synthesis, or transcription, involves the formation of RNA from DNA templates. RNA polymerases facilitate this process, using nucleotides synthesized through the aforementioned pathways. Regulation of transcription is critical for gene expression and cellular function.
