1. The Urea Cycle بسم الله الرحمن الرحيم Dr. Mahmoud Sirdah Dr. Mahmoud Sirdah

3. Amino acid and Protein Catabolism Disposal of nitrogen Transamination and/or deamination is usually the first step in metabolism of amino acid not used for synthesis of proteins or nitrogen- containing compounds Disposal of carbon skeletons

4. Key reactions Transamination Deamination Glutamine synthesis Some amino acids that are more commonly deaminated include glutamate, histidine, serine, glycine and threonine. But many of these may also be transaminated Disposal of Amino Acid Nitrogen

5. Involve the transfer of an amino group from one amino acids to an amino acid carbon skeleton This carbon skeleton then becomes an amino acid The original amino acid then becomes an α-keto acid Transamination reactions are catalyzes by aminotransferases Typically require vitamin B 6 in its coenzyme form (pyridoxal phosphate) Tyrosine aminotransferase Branched-chain aminotransferase Alanine aminotransferase (most active) Aspartate aminotransferase (most active) Transamination Reactions

6. Transamination reactions tend to channel amino groups on to glutamate Glutamate plays a central role in amino acid N metabolism Transaminase reactions are reversible Alanine aminotransferase In liver, reverse reaction moves amino acid nitrogen back on glutamate Muscle amino acid nitrogen is transported out as alanine to the liver Aspartate aminotransferase ASP important in liver since half of urea-N is from ASP Alanine aminotransferase Alanine + α-ketoglutarate pyruvate + glutamate Aspartate aminotransferase Aspartate + α-ketoglutarate oxaloacetate + glutamate Transamination Reactions

7. Transamination

8. Removal of an amino group with no direct transfer to another compound Key enzymes Lyases Dehydratases Dehydrogenases Threonine dehydratase Threonine α-ketobutyrate + ammonium Ammonia/ammonium used by hepatocyes for urea synthesis Deamination Reactions

9. Detoxification of ammonia Liver glutamine synthestase Glutamate + NH 4 + ATP glutamine + ADP Glutamine Synthetase

10. Major products of amino acid catabolism is CO 2, H 2 O and urea Urea Main nitrogen-excretory compound Formed in the Urea cycle The urea cycle functions in the liver to remove ammonia from the body Ammonia formed from deamination Ingested and absorbed ammonia Intestinal ammonia from bacterial lysis of urea and amino acids The Urea Cycle – Disposal of Ammonia

11. Flow of Nitrogen from Amino Acids to Urea in Liver Amino acid flow to the liver from muscle Amino acid flow to the liver from muscle Alanine and glutamine Alanine and glutamine In the liver In the liver Transfer of nitrogen to glutamate Transfer of nitrogen to glutamate Glutaminase & glutamate dehydrogenase Glutaminase & glutamate dehydrogenase Transaminases Transaminases Transfer of glutamate nitrogen Transfer of glutamate nitrogen Aspartate Aspartate Aspartate transaminase Aspartate transaminase Ammonium/ammonia Ammonium/ammonia Glutamate dehydrogenase Glutamate dehydrogenase Glutamine synthetase Glutamine synthetase Nitrogen is transferred to urea Nitrogen is transferred to urea

12. As with most biochemical pathways, the urea cycle should be mastered by working backwards. We will start by drawing the last component in the pathway …Arginine. As you study the structure of arginine try to imagine all of the intermediates in the pathway built into this one molecule. Arginine is the immediate source of urea. Can you see urea in arginine. The oxygen is obtained from H 2 O H2NH2NNH 2 C O COO CH 2 H 3 N-C-H NH HN=C NH 2 – + + Urea Ornithine O Citrulline After the urea is removed by hydrolysis, what remains is ornithine. Ornithine reacts with carbamoyl-PO 4 to form citrulline. Now the three compounds fit into the arginine molecule, Now the three compounds fit into the arginine molecule,

21. Thank you with my best wishes for a very fruitful and successful life