Lecture 31, Amino Acid Degradation - PDF

# Amino Acid Biosynthesis and Catabolism ## Amino Acid Biosynthesis - **Glycolysis and the TCA cycle provide carbon skeletons for amino acid biosynthesis**. - **Alanine, glutamate, and aspartate are synthesized by transamination of the corresponding a-keto acids**. - **Amino acids synthesized by h...

# Amino Acid Biosynthesis and Catabolism ## Amino Acid Biosynthesis - **Glycolysis and the TCA cycle provide carbon skeletons for amino acid biosynthesis**. - **Alanine, glutamate, and aspartate are synthesized by transamination of the corresponding a-keto acids**. - **Amino acids synthesized by humans** are shown in the diagram with a circle around their name. ## Overview of Amino Acid Catabolism - **Once broken down to amino acid, all types of protein are treated the same way dependent on the organism's energy needs:** - **Recycled into new proteins** - **Oxidized for energy:** - Removal of amino group (urea cycle) - Entry into central metabolism (glycolysis, citric acid cycle) ## The Use of Amino Acids as Fuel Varies Greatly by Organism - **About 90% of energy needs of carnivores can be met by amino acids immediately after a meal.** - **Microorganisms scavenge amino acids from their environment for fuel when needed.** - **Only a small fraction of energy needs of herbivores are met by amino acids.** - **Plants do not use amino acids as a fuel source but can degrade amino acids to form other metabolites.** ## Metabolic Circumstances of Amino Acid Oxidation - **Leftover amino acids from normal protein turnover** (e.g., proteolysis and regeneration of proteins) - **Dietary amino acids that exceed body's protein synthesis needs** - **Proteins in the body can be broken down to supply amino acids for energy when carbohydrates are scarce** (starvation, diabetes mellitus). ## You are not protein deficient - A chart shows the protein intake (g/day) in the Adventist Health Study 2. - Non-vegetarian - Semi-vegetarian - Pesco-vegetarian - Lacto-ovo vegetarian - Strict vegetarian - **The National Academy of Medicine recommends that adults get about 0.8 grams of protein a day for every kilogram they weigh.** That's about 7 grams for every 20 pounds. - **It suggests babies and children get a bit more,** ranging from 1.2 grams per kilogram for infants to 0.85 grams per kilogram for teens. - **Vegans should eat grains and beans to get enough methionine and lysine.** ## Degradation of all amino acids begins with removal of the amino nitrogen by transaminases or direct deamination - **Alanine aminotransferase and aspartate aminotransferase transfer amino groups to glutamate**. - Alanine + α-ketoglutarate <=> pyruvate + glutamate - Asparate + α-ketoglutarate <=> oxaloacetate + glutamate - **Pyruvate and oxaloacetate can enter metabolism directly** - gluconeogenesis or TCA cycle - **Some amino acids can be directly deaminated.** - Serine -> pyruvate + NH₄⁺ - Threonine -> α-ketobutyrate + NH₄⁺ ## The two major sites of amino acid degradation are muscle and liver - **Muscle, especially during prolonged fasting, can use branched chain amino acids as a major energy source.** - **However, muscle lacks the enzymes of the urea cycle so cannot process NH₄⁺ released by deamination of amino acids.** - **Liver is the principal site of breakdown of other amino acids, and also for processing of NH₄⁺ by the urea cycle.** ## In muscle, α-ketoacid dehydrogenase processes branched-chain amino acids - The branched-chain amino acids - leucine, isoleucine, and valine are used as fuels by muscle tissue. - They are converted into acetyl CoA, succinyl CoA and acetoacetyl CoA using reactions similar to those of the citric acid cycle and fatty acid oxidation. - The branched-chain α-ketoacid dehydrogenase complex, which is similar to the pyruvate dehydrogenase complex and the α-ketoglutarate dehydrogenase complex, processes these amino acids. - A chemical reaction diagram shows the process. ## The carbon skeletons of the amino acids are metabolized to seven major metabolic intermediates - **Acetoacetyl CoA, acetyl CoA, Pyruvate, α-ketoglutarate, succinyl CoA, fumarate, oxaloacetate** - **When amino acids are metabolized to acetyl CoA and acetoacetyl CoA they are called ketogenic amino acids** because they can form fats but not glucose. - **When amino acids are degraded to the remaining major intermediates they are called gluconeogenic amino acids** because they can be used to synthesize glucose. - **Only leucine and lysine are solely ketogenic.** - **Other amino acids can be glucogenic OR ketogenic.** ## Ammonia Is Safely Transported in the Bloodstream as Glutamine - **Free ammonia is very toxic**. - **Glutamine synthetase traps free ammonia** (from serine and threonine for example) into glutamine. - **Excess glutamine is processed in the intestines, kidneys, and liver.** - A chemical reaction diagram shows the process. ## Muscle lacks the enzymes of the urea cycle - **The nitrogen from branched-chain amino acid degradation is transported to the liver by the glucose-alanine cycle.** - A diagram shows the process: - Active Pathways: - Glycogen breakdown - Chapter 24 - Glycolysis - Chapter 16 - Citric acid cycle - Chapter 18 - Oxidative phosphorylation - Chapter 20 - Gluconeogenesis - Chapter 17 - Urea cycle - Chapter 30 - Liver: - Glucose - Glutamate - Pyruvate - Alanine - Urea - Muscle: - Glucose - Glycogen - Pyruvate - Alanine - Branched-chain amino acids - Carbon skeletons for cellular respiration - **Transamination of pyruvate produces alanine in the muscle.** This is transported to the liver, and the amino group transferred to α-ketoglutarate to give glutamate. The resulting pyruvate is converted back to glucose, and released by the liver. ## Ammonia Collected in Glutamine is liberated by glutaminase ## Ammonia collected in glutamate is liberated by Glutamate Dehydrogenase - **Nitrogen enters the liver as:** - Alanine (from muscle). Transaminated to generate pyruvate and glutamate. - Glutamine (from muscle and other tissues). NH₄⁺ is liberated in mitochondria by the enzyme glutaminase. - Or as dietary amino acids from ingested protein. Undergo transamination to generate glutamate and the α-ketoacid. Glutamate then undergoes an oxidative deamination by glutamate dehydrogenase. - A diagram shows the process. - **Net result: high NH₄⁺ in mitochondria** ## Ammonia is converted to urea in the liver by the enzymes of the urea cycle - **The free NH₄⁺ generated by glutaminase and glutamate dehydrogenase must be transformed into a less toxic compound for excretion.** - **Nitrogen enters the cycle at two points:** - Free NH₄⁺ is incorporated into carbamoyl phosphate by carbamoyl phosphate synthetase. - The carbamoyl group is transferred to ornithine by ornithine transcarbamolyase to form citrulline. - **Citrulline is transported out of the mitochondria into the cytoplasm in exchange for ornithine.** - **Nitrogen from aspartate is incorporated by a transamination reaction to form argininosuccinate.** - **Argininosuccinate is cleaved to form arginine and fumarate.** - **Arginine is cleaved by arginase into urea, which is excreted, and ornithine, which is transported into the mitochondria to begin another cycle.** - A diagram shows the process. - **You need to know the structures of urea and carbamoyl phosphate.** ## The urea cycle, citric acid cycle, and the transamination of oxaloacetate are linked by fumarate and aspartate - **The stoichiometry of the urea cycle is:** CO₂ + NH₄⁺+ 3 ATP + aspartate + 2 H₂O → urea + 2 ADP + 2 P_i + AMP + PP_i + fumarate. - **Fumarate can be converted into oxaloacetate by the citric acid cycle and then into glucose by the gluconeogenic pathway.** - A diagram shows the process. ## Fates of Nitrogen in various organisms - **Plants conserve almost all of their nitrogen.** - **Many aquatic vertebrates release ammonia to their environment:** - Passive diffusion from epithelial cells - Active transport via gills - **Many terrestrial vertebrates and sharks excrete nitrogen in the form of urea:** - Urea is far less toxic that ammonia. - Urea has very high solubility - **Some animals such as birds and reptiles excrete nitrogen as uric acid:** - Uric acid is least toxic, but has the disadvantage of requiring more energy for its synthesis. - Uric acid is rather insoluble. - Excretion as paste allows the animals to conserve water. - **Humans and great apes excrete both urea (from amino acids) and uric acid (from purines).** ## Phenylketonuria is caused by a defect in the first step of Phe degradation - **A buildup of phenylalanine and phenylpyruvate impairs neurological development leading to intellectual deficits.** - **Controlled by limiting dietary intake of Phe.** - A chemical reaction diagram shows the process ## Nitrogen from pyrimidine degradation is incorporated into glutamate - A chemical reaction diagram shows the process ## Nitrogen from purine degradation is excreted as urate - A chemical reaction diagram shows the process. ## Disruptions in nucleotide metabolism can cause pathological conditions - **Xanthine oxidase catalyzes the conversion of xanthine into uric acid, the final common pathway for the degradation of purine nucleotides.** - **Uric acid ionizes to form urate.** - **High blood levels of urate induce gout, a painful disease that results from the accumulation of urate crystals in the joints.** - **Administration of allopurinol, a suicide inhibitor of the oxidase, relieves the symptoms of gout.** - **Purines are then excreted as xanthine and hypoxanthine.** - **Urate is a potent antioxidant, and urate in the blood may prevent oxidative damage.** - A chemical reaction diagram shows the process. ## What you need to know - Amino acids from protein are an important **energy source** in carnivorous animals. - Ammonia generated by amino acid catabolism in muscle tissues is transported to the liver as alanine (transamination of pyruvate generated by glycolysis). - The first step of AA catabolism is transfer of the NH₃ via PLP-dependent aminotransferase usually to α-ketoglutarate to yield glutamate. Transferring a second NH₃ yields glutamine. - In most mammals, toxic ammonia is quickly recaptured into carbamoyl phosphate and passed into the **urea cycle**. - Amino acids are degraded to pyruvate, acetyl-CoA, α-ketoglutarate, succinyl-CoA, and/or oxaloacetate. - Amino acids yielding acetyl-CoA are ketogenic. - Amino acids yielding other end products are glucogenic. - Genetic defects in amino degradation pathways result in a number of human diseases. - Nitrogen from pyrimidine degradation is incorporated into glutamate. - Nitrogen from purine degradation is excreted as uric acid. - Excess uric acid production leads to gout.