The Urea Cycle

الرحمن الله الرحمن بسم الله بسمالرحيمالرحيم

Dr. Mahmoud SirdahDr. Mahmoud Sirdah

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

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

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 B6 in its coenzyme form (pyridoxal phosphate)

Tyrosine aminotransferase Branched-chain aminotransferase Alanine aminotransferase (most active) Aspartate aminotransferase (most active)

Transamination Reactions

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 aminotransferaseAlanine + α-ketoglutarate pyruvate + glutamate

Aspartate aminotransferaseAspartate + α-ketoglutarate oxaloacetate + glutamate

Transamination Reactions

TransaminationTransamination

Transamination

Removal of an amino group with no direct transfer to another compound Key enzymes

Lyases Dehydratases Dehydrogenases

Threonine dehydrataseThreonine α-ketobutyrate + ammonium

Ammonia/ammonium used by hepatocyes for urea synthesis

Deamination Reactions

Detoxification of ammonia Liver

glutamine synthestase

Glutamate + NH4 + ATP glutamine + ADP

Glutamine Synthetase

Major products of amino acid catabolism is CO2, H2O 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

Flow of Nitrogen from Amino Acids to Urea in LiverFlow of Nitrogen from Amino Acids to Urea in Liver

Amino acid flow to the liver from muscleAmino acid flow to the liver from muscle Alanine and glutamineAlanine and glutamine

In the liver In the liver Transfer of nitrogen to glutamateTransfer of nitrogen to glutamate

Glutaminase & glutamate dehydrogenaseGlutaminase & glutamate dehydrogenase TransaminasesTransaminases

Transfer of glutamate nitrogenTransfer of glutamate nitrogen AspartateAspartate

Aspartate transaminaseAspartate transaminase Ammonium/ammoniaAmmonium/ammonia

Glutamate dehydrogenaseGlutamate dehydrogenase Glutamine synthetaseGlutamine synthetase

Nitrogen is transferred to ureaNitrogen is transferred to urea

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 H2O

H2N NH2

C

O COO

CH2

CH2

CH2

H3N-C-H

NHHN=C

NH2

–

+

+

UreaUrea

OrnithineOrnithine

OCitrullineCitrulline

After the urea is removed by After the urea is removed by hydrolysis, what remains is hydrolysis, what remains is ornithine. ornithine. Ornithine reacts with Ornithine reacts with carbamoyl-POcarbamoyl-PO44 to form to form

citrulline.citrulline. Now the three compounds fit Now the three compounds fit into the arginine molecule, into the arginine molecule,

Thank you Thank you with my best wishes for with my best wishes for

a very fruitful and successful life a very fruitful and successful life