Introduction to Metabolism PDF

# Introducción al Metabolismo ## Unidad II Morfofisiología I - **Metabolismo:** The sum of all chemical reactions occurring in cells. It's a highly coordinated cellular activity, with intentionality, orientation, and involving numerous enzymatic systems. There is also the interchange of matter a...

# Introducción al Metabolismo ## Unidad II Morfofisiología I - **Metabolismo:** The sum of all chemical reactions occurring in cells. It's a highly coordinated cellular activity, with intentionality, orientation, and involving numerous enzymatic systems. There is also the interchange of matter and energy with the environment. ### Functions: - Obtain chemical energy from sunlight or food. - Convert nutrients into cellular components. - Assemble those components into macromolecules. - Form and degrade molecules required for specialized cellular functions. ### Digestion - Transforms carbohydrates, lipids, and proteins into absorbable compounds: - Glucose - Fatty acids - Amino acids ### Absorption - The passage of final digestion products, vitamins, minerals, water, etc., through the digestive system into the organism. ### Phases of metabolism: 1. **Absorption**: Chemical substances and energy enter the protoplasm from the environment. 2. **Transformation**: The protoplasm transforms absorbed substances and energy. This includes secretion, digestion, assimilation, and dissimilation. 3. **Excretion**: Eliminates chemical species that are not incorporated into the protoplasm. ## Stages of metabolism: 1. Breakdown of large molecules into their monomers: - Polysaccharides to monosaccharides (glucose type), - Lipids to glycerol, fatty acids, and other molecules. - Proteins to amino acids. - There is no usable energy released during this stage. 2. Degradation of monomers into simpler molecules: - This leads to a convergence towards the molecule called acetyl-CoA. - A small amount of ATP is produced during this stage. 3. Oxidation of acetyl-CoA: - Generates water and carbon dioxide. - Most ATP production from food is generated in this stage. ## Division of Metabolism: Anabolism and Catabolism ### Anabolism - The metabolic process of building large molecules from smaller ones and consuming energy. - This process is used to form proteins from amino acids and requires energy in the form of ATP generated by catabolism. - It builds components of the cell. ### Catabolism - The metabolic process of breaking down large molecules into smaller ones. - It is used to break down large molecules from food or the cell's own reserves. - Oxidation and energy production occur during this process. - Some energy is not used directly, but stored in special molecules containing lots of energy. This energy is used when the body needs it. <start_of_image> Diagrams: [Description of the diagrams: there are two diagrams: - One is a flow diagram illustrating the relationship between anabolism, catabolism and a third category: "amphbolic". - The second diagram illustrates the anabolism/catabolism pathways of carbohydrates, lipids and proteins.] ### Amphibolic pathways - Mixed pathways: interconversions between metabolic intermediates at the beginning of anabolic pathways or at the end of catabolic pathways. ### Energy: - The ability to do work and cause change in matter. - Forms: heat, light, electricity, and movement. ### Metabolic Pathways - An ordered sequence of reactions in which the final product of one reaction becomes the initial substrate of the following reaction. - Example: glycolysis. ### Types of Metabolic Pathways 1. **Catabolic Pathways:** - Oxidative pathways: These release energy and reducing power while synthesizing ATP. - Examples: glycolysis and beta-oxidation. - They make up catabolism. 2. **Anabolic Pathways:** - Reductive pathways: These consume energy (ATP) and reducing power. - Examples: gluconeogenesis and the Calvin cycle. - They make up anabolism. 3. **Amphibolic Pathways:** - Mixed pathways: They are both catabolic and anabolic. - Example: the Krebs cycle, generating both energy and reducing power, as well as precursors for biosynthesis. ### Metabolic Intermediates - A set of central metabolic pathways: - They are involved in the synthesis, degradation, and conversion of important metabolites. - They mediate the conversion of energy. ### Glycolysis - (Greek *glycos*, sugar, and *lysis*, rupture) : The metabolic pathway responsible for oxidizing glucose to obtain energy for the cell. - It involves 10 consecutive enzymatic reactions that convert glucose into two pyruvate molecules. - Pyruvate can follow other metabolic pathways, continuing to deliver energy to the organism. ### Function and importance of Glycolysis - It produces molecules that generate energy, like ATP and NADH. - It forms molecules that serve as sources of cellular energy in aerobic respiration (presence of oxygen) and fermentation (absence of oxygen). ### Characteristics: - Also known as the Embden-Meyerhof pathway. - Takes places in the cytosol. - Does not require oxygen. - The initial substrate is a 1 molecule of glucose (6C). - The final product is two pyruvate molecules (pyruvic acid, 3C). - It is an amphibolic pathway. ### The Pentose Phosphate Pathway - The predominant glucose catabolic pathway is glycolysis. - An alternative pathway for glucose catabolism : its known as the phosphogluconate pathway. - This pathway oxidizes glucose to obtain energy, but not in the form of ATP. - It does not consume energy either. - It takes place in the cytoplasm. - It is the primary source of cytoplasmic NADPH in eukaryotic cells. ### Characteristics: - It takes place in the cytoplasm. - Consists of irreversible oxidation reactions and reversible interconversions. - It is more complex than glycolysis. - It does not occur in skeletal muscle. ### Functions of the Pentose Phosphate Pathway - To obtain reducing power in the cytoplasm in the form of NADPH + H+ - This is essential for anabolic reactions and also acts as a very powerful antioxidant in some cells (e.g., red blood cells). - To supply pentoses (ribose) to cells: - They are needed for the synthesis of nucleotides (the bases of nucleic acids) and a large number of enzyme cofactors (coenzymes). ### Stages of the Pentose Phosphate Pathway 1. **Oxidative stage**: It produces NADPH + H+. 2. **Non-oxidative stage**: It produces various monosaccharides, with pentoses (ribose) being one of the most important. ### The Krebs Cycle - A series of metabolic reactions that follow glycolysis and up to the Respiratory Chain. - This cycle allows the production of ATP and CO2. - It takes place in the mitochondria. ### Stages of the Krebs Cycle 1. Oxidation of pyruvate to acetyl-CoA. 2. Krebs Cycle. 3. Electron transport chain. ### Aerobic Respiration - It requires the presence or consumption of oxygen. - Specific to eukaryotic cells ### Anaerobic Respiration - It does not require the presence of oxygen. - Occurs without consuming oxygen. - Specific to prokaryotic cells ### History of the Krebs Cycle This pathway was investigated many years ago by scientist Hans Krebs: - He studied the metabolic reactions occurring in an organism. - In 1937 he proposed that there were metabolic reactions that consumed and produced ATP compounds. - He studied the amino acid malate and the compound lactate to see how phosphorylation occurred in the presence of oxygen and in its absence. - Two years later, he completed the 8 reactions involving the Krebs cycle. - It was widely accepted by the scientific community 30 years later. ### Amphibolic nature of the Krebs Cycle - It is both a catabolic pathway (consumes compounds) and an anabolic pathway (produces compounds). - It consumes compounds but also produces compounds that are used in other metabolic pathways. ### Details of the Krebs Cycle - It is a cycle because it starts with a compound (Oxalacetate) and ends with the same compound (Oxalacetate). - The compound Oxalacetate accepts a 2-carbon compound (acetyl-CoA) during the Krebs cycle. ### Glucogenolysis - It is a catabolic process occurring in the cytosol. - It involves the removal of a glucose molecule, one monomer at a time, from glycogen through phosphorylation to produce glucose 1-phosphate, which is later converted into glucose 6-phosphate, an intermediate of glycolysis. ### Key Points of Glucogenolysis: - It is the synthesis of glucose from glycogen. - It is antagonistic to glucogenesis. - It is stimulated by glucagon in the liver, epinephrine (adrenaline) in muscle, and inhibited by insulin. - It requires the combined action of three enzymes: - Glycogen phosphorylase. - Debranching enzyme. - phosphoglucomutase. **Diagram:** [Description: A diagram of Glucogenolysis showing the main reactions. It shows the breaking of glycogen into glucose-1-phosphate, glucose-6-phosphate, the role of debranching enzyme, and the use of cofactors like PLP.] ### Gluconeogenesis - It is an anabolic pathway responsible for the synthesis of glycogen from a simpler precursor, glucose 6-phosphate. This primarily occurs in the liver and to a lesser extent in the muscles. - It is stimulated by insulin in response to high levels of glucose, often after eating carbohydrates. ### Requirements for Gluconeogenesis: - A molecule of UDP-glucose: This is the active form of glucose required for incorporation onto a growing glycogen molecule. - Three enzymes: - UDP-glucose pyrophosphorylase. - Glycogen synthase. - Branching enzyme. ### The Importance of Glycogen - It is important in most tissues, especially muscles. - It acts as a storage mechanism for glucose, preventing drastic changes in osmotic pressure that free glucose could cause, both inside and outside the cell. - When the body or a cell needs immediate energy, like during a stressful event, glycogen breaks down into glucose, which then becomes available for energy metabolism. ### Glucose Regulation in the Liver - The conversion of stored glucose in the liver into free glucose in the blood is regulated by the hormones glucagon and adrenaline. - Liver glycogen is the main source of blood glucose, especially between meals. - Muscle glycogen provides energy for the contraction of muscle. ### Gluconeogenesis - It is the anabolic metabolic pathway that allows for the biosynthesis of glucose from non-carbohydrate precursors. This includes the use of various amino acids, lactate, pyruvate, glycerol, and any of the intermediates of the citric acid cycle (Krebs cycle) as sources of carbon for the metabolic pathway. - All amino acids, except leucine and lysine, can provide carbon for glucose synthesis. - Even-chained fatty acids do not provide carbon for glucose synthesis, as they are broken down into acetyl-CoA, which is not a glucogenic substrate. However, odd-chained fatty acids will generate acetyl-CoA and succinyl-CoA (which is glucogenic because it is an intermediate of the Krebs cycle). ### Importance of Gluconeogenesis - It allows organisms to get glucose in states where their metabolic needs are high, like during fasting. - It occurs mainly in the liver (10% in the kidneys). - Gluconeogenesis in the liver and kidneys helps maintain blood glucose levels to ensure that the brain and muscles can extract enough glucose to meet their energy demand. - The brain uses glucose as its primary fuel. - Red blood cells require glucose as their sole fuel. - Skeletal muscles require glucose for prolonged exertions. ### Pentose Phosphate Pathway Cont. - It is a linear pathway, unlike glycolysis and the Krebs cycle because only the first half of the process is cyclic. - It is important in providing NADPH. - The Pentose Phosphate Pathway is also important for producing the precursors for biosynthetic pathways for nucleotide synthesis. ### Details of The Pentose Phosphate Pathway Cycle 1. The first part of the process converts glucose to a pentose sugars called ribulose 5-P. 2. It generates 2 molecules of NADPH (reductive power). 3. It uses ribose-5-P in the synthesis of nucleotides and is a source of the cofactor NADPH for detoxification. 4. The second part of the cycle is non-cyclic. It involves a number of enzymes that rearrange sugars and form precursors (like intermediates) for the synthesis of glucose. ### The Cori Cycle - The Cori cycle is a cyclic pathway that maintains the cyclic circulation of glucose and lactate between the muscle and liver. - Muscle cells obtain their energy from glycogen and glucose, primarily from the blood. - During exercise (intense anaerobic conditions), high amounts of lactate are produced due to high activity of glycogen. - Lactate diffuses into the blood and is transported to the liver. - Muscle cells lack the enzyme glucose-6-phosphatase, which is necessary for glucose-6-phosphate to leave the cell, so the phosphorylated glucose cannot enter the circulation. ### The Importance of the Cori Cycle: - It enables the rapid production of energy within muscle tissue, especially under conditions of high intensity and limited oxygen availability. - It prevents lactic acidosis in muscle cells. ### The Cori Cycle Integrates Several Metabolic Pathways - It links glycolysis, glycogenolysis, gluconeogenesis, and lactic acid fermentation. - It was first described in animal and human metabolism, where extensive hormonal regulation occurs. - Its main function is to maintain muscular activity during intense exertion. ### The Cori Cycle has two main phases: **Phase 1 (Muscle):** 1. Glucose derived from glycogen or gluconeogenesis is anaerobically oxidized by glycolysis to pyruvate, ATP, and NADH. 2. Pyruvate is converted into lactate using NADH with the help of the lactate dehydrogenase enzyme, producing NAD+ that allows further glycolysis. 3. Lactate accumulates in the muscle, and later diffuses into the blood to be transported to the liver. 4. Each muscle cell produces 2 pyruvate molecules, 2 ATP, and 2 NADH molecules per glucose molecule consumed. However, the 2 NADH molecules are used to turn the 2 pyruvate molecules into 2 lactate molecules. **Phase 2 (Liver):** - The liver is the main site for glycogen synthesis (glucose storage) and gluconeogenesis (glucose synthesis). - When lactate arrives in the liver, it is converted back into pyruvate by the lactate dehydrogenase enzyme in the cytosol. - Pyruvate then enters the mitochondria and is used as a substrate by the pyruvate carboxylase enzyme, converting it to oxaloacetate. - Oxaloacetate is reduced to Malate by a mitochondrial enzyme, NAD malate dehydrogenase. - Malate leaves the mitochondria and is oxidized back to oxaloacetate by a cytosolic isoform of NAD malate dehydrogenase. - In the cytosol of liver cells, oxaloacetate is decarboxylated to produce phosphoenolpyruvate (PEP) by the phosphoenolpyruvate carboxykinase (PEPCK) enzyme. - Phosphoenolpyruvate is processed via the reverse of the glycolytic pathway until it becomes fructose 1,6-bisphosphate (F1,6BP). - Fructose 1,6-bisphosphate is converted to fructose 6-phosphate by the enzyme fructose 1,6-bisphosphatase. - Finally, the enzyme glucose 6-phosphatase converts glucose 6-phosphate (G6P) into free glucose, which is transported back into the bloodstream to be returned to the muscles. ### Amino acid Metabolism - Free amino acids in the cell can come from protein hydrolysis or from the absorption of intracellular fluid. - These simple amino acids make up the amino acid pool, from which the cell obtains the units to synthesize new proteins. - Interesting fact: amino acids come from various sources, such as: - Food sources - Protein catabolism - *De novo* synthesis from carbon chains and NH3 in the liver. - Amino acids undergo transamination and deamination reactions. ### Transamination Reactions - The transfer of the α-amino group from an amino acid to an α-ketoacid. - The amino acid becomes a ketoacid, and the ketoacid accepting the amino group becomes the corresponding amino acid. - It is a reversible reaction catalyzed by transaminases, which use the coenzyme pyridoxal phosphate (vitamin B6), firmly bound to the enzyme (covalent bond). - Pyridoxal phosphate forms an intermediate compound with an amino acid, a Schiff base. - Pyridoxal phosphate acts as an acceptor and transporter of the amino group. - When the amino acid donating the amino group binds to the transaminase, its amino group is transferred to the pyridoxal phosphate, now called pyridoxamine. - Hydrolysis releases the α-ketoacid corresponding to the amino acid that was created. - The enzyme's prosthetic group (pyridoxal phosphate) becomes pyridoxamine. - Later, when the enzyme binds to an α-ketoacid, it will transfer the amino group, regenerates pyridoxal phosphate, and releases the corresponding amino acid. - The most commonly used amino acid donors are: glutamate, alanine, and aspartate. - The most commonly used ketoacids are: α-ketoglutarate, pyruvate, and oxaloacetate. - Two very abundant transaminases are GPT or ALT, and GOT or AST: - These are especially abundant in the liver and are present in a smaller percentage in the heart. - Their gene expression is induced by cortisol. - **GPT or ALT (Glutamic Pyruvic Transaminase or Alanine Aminotransferase): ** - It is a cytosolic enzyme. - It catalyzes the transamination of glutamate acting as an α-amino acid donor with pyruvate, making alanine and α-ketoglutarate as the product of the reaction. - **GOT or ASAT (Glutamic Oxaloacetic Transaminase or Aspartate Aminotransferase):** - Both a cytosolic and mitochondrial enzyme. - It catalyzes the transamination of glutamate (α-amino acid donor) together with oxaloacetate, transferring the amino group from glutamate to oxaloacetate. - When oxaloacetate accepts the amino group, it is called aspartate. Glutamate becomes α-ketoglutarate. - This reaction is reversible, and its direction depends on the amount of substrate. ### Oxidative Deamination - The nitrogen group from glutamate can be separated through oxidative deamination, a reaction catalyzed by **glutamate dehydrogenase**: - This enzyme is found in most tissues and is very active. - It uses the coenzymes NAD and NADP: - ADP, GDP: activate it. - ATP, GTP: inhibit it. - When ADP levels in the cell are high, the enzyme is activated. - The increase in α-ketoglutarate production fuels Krebs Cycle activity and generates ATP. - When ATP and GTP levels are high, glutamate dehydrogenase is inactive. - The reaction is reversible, acting both in catabolism and in glutamate synthesis. ### The fate of NH3 - NH3 produced by the body comes primarily from the tissues, through the reaction: - NH3 + α-ketoglutarate → glutamate + ammonium (NH4+) - The body has mechanisms to dispose of NH3: - **Synthesis of glutamate**. - **Synthesis of glutamine**. - High levels of NH3 are toxic because it is uncharged and can readily cross the blood-brain barrier. - The end product of protein metabolism is urea. ### The Urea Cycle - It processes protein derivatives and produces urea as its terminal product. - It is a hepatic process. ### Types of Organisms based on the excretion of the excess of nitrogen: **Animals that excrete ammonia as a waste product** - **Ammonotelic:** These predominantly include aquatic animals, like fish and amphibian larvae. **Animals that excrete urea as a waste product** - **Ureotelic:** This includes humans, mammals, amphibians, and sharks. **Animals that excrete uric acid as a waste product** - **Uricotelic:** Examples include birds and reptiles. ### Key Steps of the Urea Cycle 1. The first reaction (condensation and phosphorylation) - It occurs in two steps: - the bicarbonate is activated with ATP to form carbonil phosphate and ADP. - The ammonia displaces the ADP, forming carbamate and phosphate. - The carbamate is phosphorylated for a second time using ATP to form carbamoyl phosphate and ADP. - It is irreversible and the main rate-limiting step. - The enzyme involved is **carbamoyl phosphate synthetase I** (CPS1), which requires the hydrolysis of two molecules of ATP. - This enzyme is activated allosterically by N-acetylglutamate. 2. The second reaction (condensation) - The enzyme involved is **ornithine transcarbamylase**. - Carbamoyl phosphate gives its carbamoyl group to ornithine to form citrulline, releasing inorganic phosphate. Citrulline exits the mitochondria through specific transporter proteins. Ornithine is made in the cytosol and enters the mitochondria via other specific transporters. 3. The third reaction (condensation and phosphorylation): - The enzyme involved is **argininosuccinate synthetase**. - This step condenses the second amino group from aspartate with citrulline to form argininosuccinate. - It requires the hydrolysis of one ATP molecule, which includes an intermediate called **citrulil-AMP**. 4. The fourth reaction (lysis) - The reaction involves the enzyme **argininosuccinase**. - This enzyme breaks down argininosuccinate into arginine (it retains the amino group from aspartate) and fumarate. - Fumarate is the preserved form of aspartate's carbon skeleton; it can then be used in the Krebs cycle. 5. The fifth reaction (hydrolysis): - This reaction involves the enzyme **arginase**. - The enzyme hydrolyzes the guanidino group from arginine, releasing urea and ornithine, which cycles back to the mitochondria in the liver. ### The importance of the Urea Cycle - It eliminates waste products and toxic ammonia from the body. - It works for a variety of organisms: - Terrestrial vertebrates excrete nitrogen as urea. - Fish excrete ammonia directly. - Birds and reptiles (and insects) excrete uric acid. ### Key Points about Metabolism - Metabolism is a highly coordinated set of reactions that occurs in all living organisms. - It is essential for life, providing the energy needed to support all of the processes that occur within the cell. - Metabolic pathways are interconnected and regulated, ensuring that a constant supply of energy and building blocks are available to the cell when needed. - Disruptions in metabolism can lead to multiple health problems, including diabetes and cancer.