10-24-11 Nitrogen metabolism Part C: Amino acid degradation and the urea cycle

Amino acid catabolism usually begins with Amino acid catabolism usually begins with the removal of the amino group (used in urea synthesis) The carbon skeletons are then degraded into seven metabolic products Acetyl-CoA, acetoacteyl-CoA, pyruvate, a-ketoglutarate, succinyl-CoA, fumarate and oxaloacetate Metabolic products can then be used to synthesize fatty acids or glucose, or to generate energy Most amino acid catabolism occurs in the liver Deamination cycles, removal of amino group. End up with 7 metabolic products see above, TCA intermediates and can serve anaplurotic reactions. acetyl-CoA and pyruvate intermediates of glycoloysis, two advantages can be used for sythesis or be burned for energy.

Deamination Removal of the a-amino group from amino acids involves two types of reactions: Transamination and oxidative deamination Reversible reactions, so the amino groups can be shifted from abundant amino acids and used to synthesize those that are scarce When amino acids are in excess, the amino groups become available for urea synthesis Oxidative deaminations- amino group comes off as a free amino group. After a protein rich meal or after metabolism and the amino groups are in excess, they go to urea synthesis

2. Serine and threonine dehydrases Ketogenic amino acids can be converted into fatty acids or ketone bodies (from acetyl-CoA and acetoacteyl-CoA) Glucogenic amino acids are degraded into pyruvate or citric acid cycle intermediates, can be used in gluconeogenesis Most of the ammonia (NH4+) generated in amino acid degradation is produced by the oxidative deamination of glutamate Additional ammonia is produced in several other reactions catalyzed by the following enzymes: 1. L-amino acid oxidases 2. Serine and threonine dehydrases 3. Bacterial urease (intestinal bacteria) 4. Adenosine deaminase Ketogenic- fatty acid or ketone bodies Glucogenic- pyruvate or TCA cycle intermediates

Transamination moves an amino group to make gultamate and free ammonia

Replaces carbonyl with amino group

Free ammonia and NADH

In most terrestrial vertebrates NH4 is converted to urea for excretion Excretion of ammonia is in the form urea, glutamate is converted to urea

Peripheral tissues transport nitrogen to the liver Muscle uses branched chain amino acids (leu, ile, val) for fuel Muscle nitrogen is transported in a form that can be absorbed by the liver and converted to urea Alanine and glutamine are the primary transport forms Transamination reactions produce glutamate, which transfers NH3 to pyruvate to form alanine (the alanine cycle) Lue, ile, and val Deaminate the amino acid and use carbon part for fuel creating ammonia as by product

Ammonia binds to pyruvate to create alanine in the muscle goes to the blood and then the liver. Converted to gluatamate if the need for pyruvate doesn’t exist

Urea is water souble because of highly polar water groups

Urea Synthesis Urea is formed from ammonia, CO2 and aspartate in a cyclic cycle referred to as the Urea Cycle The urea cycle disposes of approximately 90% of surplus nitrogen Overall equation: CO2 + NH4+ + Aspartate + 3 ATP + 2 H2O  Urea + Fumarate + 2 ADP + 2 Pi + AMP + PPi + 5 H+ Urea synthesis needs lots of energy

Carbamoyl phosphate reacts with ornithine to form citrulline Urea synthesis (hepatocytes) begins with the formation of carbamoyl phosphate in the mitochondrial matrix Carbamoyl phosphate reacts with ornithine to form citrulline Citrulline is transported to the cytoplasm Happens in the mitochondrial matrix Ornithine is an amino acid not used for protein synthesis, is only used to for citrulline when reacted with carbamoyl phosphate Citrulline then moves to the cytoplasm, mechanism to get the ammonia from inside the matrix outside into the cytoplasm so that it can be synthesised to arginosuccinate The Urea Cycle

Eventually ornithine and urea are generated Ornithine goes back into the cycle to make more citrulline Urea diffuses out of the hepatocytes into the blood stream Urea is eliminated in the urine by the kidney The Urea Cycle

The urea cycle is linked to gluconeogenesis Fumarate is a precursor for gluconeogenesis

Carbon atoms of degraded amino acids emerge as metabolic intermediates The strategy of amino acid degradation is to transform the carbon skeletons into major metabolic intermediates that can be converted into glucose or oxidized by the citric acid cycle Recognize the distinction between gluogenic aa- pyruvate, or intermediates of the tca which can lead to oxaloacetate to make glucose (alpha keto acid, simple) keto aa- produce acetyl CoA can be used for lipid or ketone body synthesis (hydrophobic, long R chains)