Amino Acid Degradation and the Urea Cycle 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 α-keto acids.** **Amino acids synthesized by hu...

# 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 α-keto acids.** **Amino acids synthesized by humans:** - **Cysteine** - **Glycine** - **Serine** - **Asparagine** - **Aspartate** - **Proline** - **Glutamate** - **Alanine** - **Threonine** - **Cystathionine** - **Lysine** - **Methionine** - **Isoleucine** - **Leucine** - **Valine** - **Ornithine** - **Glutamine** - **Citrulline** - **Histidine** - **Arginine** - **Tryptophan** - **Tyrosine** - **Phenylalanine** ## 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.** **Two main fates for amino acids:** 1. **Recycled into new proteins.** 2. **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 - The **National Academy of Medicine recommends that adults get about 0.8 grams of protein a day for every kilogram they weigh.** - This is about **7 grams for every 20 pounds.** - **Babies and children need a bit more**, ranging from 1.2 grams per kilogram for infants to 0.85 grams per kilogram for teens. **Special Considerations:** - **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.** - **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.** - **Branched-chain α-keto acid + NAD⁺ + CoA → CoA derivative + CO₂ + NADH + H⁺** ## The Carbon Skeletons of the Amino Acids Are Metabolized to Seven Major Metabolic Intermediates - **Acetoacetyl CoA, acetyl CoA, pyruvate, succinyl CoA, fumarate, α-ketoglutarate, 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.** ## 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.** - **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.** - **Net result: high NH₄⁺ in mitochondria.** ## 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:** 1. **Free NH₄⁺ is incorporated into carbamoyl phosphate by carbamoyl phosphate synthetase.** 2. **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.** ## 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.** ## 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 than 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.** ## Nitrogen from Pyrimidine Degradation Is Incorporated into Glutamate - **Uridine → Dihydrouracil → β-Alanine → β-Ureidopropionate → β-Ureidoisobutyrate → Glutamate.** ## Nitrogen from Purine Degradation Is Excreted as Urate - **AMP → Adenosine → Inosine → Hypoxanthine → Xanthine → Urate → Uric acid.** ## 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 crystal 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.** ## 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.**