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Amino Acid Metabolism Role of Amino Acids • Protein monomeric units • Energy source • Precursors of other biological molecules Protein Monomeric Units R1 + R2 – H3 N C COO H H2O + + – H3 N C COO H R1 O R2 + – H3 N C C NH C COO H H Energy Source ADP + Pi Amino Acids ATP Waste Products Precursors (Nitrogen-containing Compounds) • • • • Heme Nucleotides Amines Nucleotide Coenzymes • Glutathione Precursors (a-ketoacids) Pyruvate Amino Acids Oxaloacetate -Ketoglutarate Glucose Fatty Acids Ketone Bodies Classification (Mammals) • Essential amino acids • Non-essential amino acids Amino Acid Deamination (First Reaction in Amino Acid Breakdown) O R H 3N C H COO– Nitrogen-containing compounds -keto acid R + C COO– Glutamate KG Aminotransferases (Transaminases) Fumarate OAA aKG Aspartate Urea Cycle H2 N O C NH2 Urea Aminotransferases (Transaminases) Amino Acid + -Ketoglutarate Glutamate + Oxaloacetate -Keto Acid + Glutamate -Ketoglutarate + Aspartate Oxidative Deamination Glutamate + NAD(P)+ + H2 O -Ketoglutarate + NH 4+ + NAD(P)H + H+ Glutamate Dehydrogenase Amino Acid Oxidase Amino Acid + FAD + H2 O FADH2 + O2 -Keto Acid + NH 3 + FADH2 FAD + H2 O2 Transamination (Reactions) Amino Acid + Enzyme Enzyme–NH 2 + -Ketoglutarate -Keto Acid + Enzyme–NH Enzyme + Glutamate 2 Summary Amino Acid + -Ketoglutarate -Keto Acid + Glutamate Degradative Fates of Glutamate Regeneration of -Ketoglutarate Carbon and Energy Nitrogen-containing compounds -ketoacid Amino Acid NH4+ Glutamate -KG CO2 Fumarate OAA KG Aspartate Urea Cycle H2 N O C NH2 Urea Glutamate-Aspartate Aminotransferase Glutamate + Oxaloacetate -Ketoglutarate + Aspartate Glutamate Dehydrogenase (Oxidative Deamination) H2C COO – NAD(P) + NAD(P)H + H + H2C CH 2 + H3N C COO – CH 2 COO – H2N C COO NH 4+ H2C -Iminoglutarate COO – CH 2 – H Glutamate H2O O C COO – -Ketoglutarate Formation of Urea Aspartate + HCO3 - + NH4+ Urea Cycle Urea Degradative Fates of Glutamate Regeneration of -Ketoglutarate Carbon and Energy Nitrogen-containing compounds -ketoacid Amino Acid NH4+ Glutamate -KG CO2 Fumarate OAA KG Aspartate Urea Cycle H2 N O C NH2 Urea Urea Cycle Urea Cycle (Introduction) Proteins Fats Carbohy drates (Nutrients) ADP Catabolism ATP NADP+ (Oxidation) (Biosy nthesis) NADPH Intermediates Waste (CO2/Urea/etc.) Anabolism Nitrogen Waste Products O N N O O NH 3 Ammonia H2N C O NH 2 Urea (Vertebrates) N N H Uric Acid (Birds and Reptiles) Require less water for excretion Classification of Organisms (Nitrogen Excretion Patterns) • Ammonotelic: ammonia excreting • Ureotelic: urea excreting • Uricotelic: uric acid excreting Overall Urea Cycle (Liver) 3ATP NH 3 + HCO 3– + H2C COO – C – + H3N COO H Aspartate 2ADP + 2P i + AMP + PP i O H2N C NH 2 Urea + HC –OOC COO – CH Fumarate Glutamate Dehydrogenase (Generation of NH3) Glutamate + NAD(P) + + H2O -Ketoglutarate + NH 3 + NAD(P)H + H + Carbamyl Phosphate Synthetase (CPS) (Mitochondrion) 2ATP 2ADP + Pi O NH3 + HCO3 – H 2N C OP Carbamyl Phosphate Carbamyl Phosphate Synthetase (CPS) • CPSI (Mitochondria) – Uses NH3 – Urea Cycle • CPSII (Cytosol) – Uses Glutamine – Pyrimidine Biosynthesis Ornithine Transcarbamylase (OTC) (Mitochondrion) O NH 2 C NH 3+ O H2N C OP + Carbamoyl P (CH 2)3 +H N 3 C COO – NH Pi (CH 2)3 +H N 3 C COO – H H Ornithine Citrulline Non-standard amino acids (not present in proteins) Glutamate Dehydrogenase Glutamate + NAD + + H2O -Ketoglutarate + NH 3 + NADH + H + Regeneration of Aspartate (Cytosol) NAD+ Fumarate NADH + H + Malate Fumarase Oxaloacetate Malate Dehydrogenase Aspartate Glu-Asp Aminotransferase Oxidation of 2 NADH Yields 6 ATP Activator H2C O H3C C COO – CH 2 N H C H COO – N-Acetylglutamate Products of Amino Acid Breakdown • Glucogenic – – – – – Pyruvate -Ketoglutarate Succinyl-CoA Fumarate Oxaloacetate • Ketogenic – Acetyl-CoA – Acetoacetate Page 995 Degradation of amino acids to one of seven common metabolic intermediates. Animals cannot carryout net synthesis of precursors of gluconeogenesis from acetyl-CoA or acetoacetate Conversion of Pyruvate and Oxaloacetate to PEP (Gluconeogenesis) ATP O H 3C C COOH + Pyruvate HCO 3– (CO 2) ADP + P i Pyruvate Carboxylase COOH CH2 O C COOH Oxaloacetate COOH CH2 O C COOH Oxaloacetate GTP GDP + CO2 PEP Carboxykinase OP H 2C C COO – Phosphoenolpyruvate (PEP) "Gluconeogenesis" Glucose Degradation to Pyruvate Alanine, Cysteine, Glycine, Serine and Threonine Degradation of amino acids • Amino acid breakdown can yield: – Acetyl-CoA --KG – Succinyl-CoA – OAA – fumarate -KG is generated from five amino acids • • • • • Proline Glutamate Glutamine Arginine Histidine Four amino acids are converted to Succinyl-CoA • Methionine – Converted to homocysteine through methyl group transfer, generates cysteine as converted to -ketobutyrate • Isoleucine – Transamination, oxidative decarboxylation to acetyl-CoA and propionyl CoA • Valine – Transamination, decarboxylation to propionyl CoA • Threonine - -ketobutyrate generated and converted to propionyl CoA Propionyl-CoA is a common intermediate for amino acids succinyl-CoA Branched-chain -keto acid dehydrogenase complex • In certain body tissues, this enzyme catalyzes the oxidative decarboxylation of valine, isoleucine, and leucine yielding CO2, and acyl-CoA derivatives. • Shares ancestry with pyruvate dehydrogenase complex, -KG dehydrogenase complex – another example of gene duplication Branched-chain …complex Asparagine and aspartate are degraded to OAA Fate of metabolites derived from amino acids • In addition to feeding the citric acid cycle, amino acids can result in ketone bodies, while others are gluconeogenic Ketone bodies • The six amino acids that are degraded to acetoacetyl-CoA and/or acetyl-CoA) can be converted to acetoacetate and b-hydroxybutyrate Glucogenic amino acids • Amino acids that are degraded to pyruvate, -KG, succinyl-CoA fumarate, and/or OAA can be converted to glucose