Urea cycle

Lesson 25 : Amino Acid Metabolism

Urea cycle

There are six steps of the urea cycle:

  1. Bicarbonate ion, NH4+ and 2 ATP necessary to form carbamoyl phosphate via carbamoyl phosphate synthetase I (found in mitochondrial matrix).
  2. Carbamoyl phosphate and ornithine (carrier or carbon and nitrogen atoms; an amino acid, but not a building block of proteins) combine to form citrulline via ornithine transcarbamoylase
  3. Citruilline is transported out of mitochondrial matrix in exchange for ornithine
  4. Citruilline condenses with aspartate --> arginosuccinate via an ATP-dependent reaction via arginosuccinate synthetase
  5. Arginosuccinate cleaved to form fumarate and arginine via arginosuccinate lyase

  6. Fumarate --> malate--> oxaloacetate --> gluconeogenesis

    Oxaloacetate has four possible fates:

    • Transamination to aspartate
    • Conversion into glucose via gluconeogenesis
    • Condensation with acetyl CoA to form citrate
    • Conversion into pyruvate

  7. Two -NH2 groups and terminal carbon of arginine cleaved to form ornithine and urea via arginase
  8. Ornithine is transported into mitochondrion to repeat cycle(Figure)

    Overall reaction:


Inherited defects in urea cycle:

  1. Blockage of carbamoyl phosphate synthesis leads to hyperammonemia (elevated levels of ammonia in blood)

  2. argininosuccinase deficiency
  3. Providing surplus of arginine in diet and restricting total protein intake

    Nitrogen is excreted in the form of argininosuccinate

  4. Carbamoyl phosphate synthetase deficiency or ornithine transcarbamoylase deficiency

    Excess nitrogen accumulates in glycine and glutamine; must then get rid of these amino acids

    Done by supplementation with benzoate and phenylacetate (both substitute for urea in the disposal of nitrogen)

    Benzoate --> benzoyl CoA --> hippurate

    Phenylacetate --> phenylacetyl CoA --> phenylacetylglutamine

Fate of Carbon Skeleton of Amino Acids

Used to form major metabolic intermediates that can be converted into glucose or oxidized by citric acid cycle.

All 20 amino acids are funneled into seven molecules:

  • Pyruvate
  • Acetyl CoA
  • Acetoacetyl CoA
  • ? -ketoglutarate
  • Succinyl CoA
  • Fumarate
  • Oxaloacetate

Those that are degraded to acetyl CoA or acetoacetyl CoA are termed ketogenic because they give rise to ketone bodies.

Those that are degraded to pyruvate or citric acid cycle intermediates are termed glucogenic.

Leucine and lysine are only ketogenic --> cannot be converted to glucose

Isoleucine, phenylalanine, tryptophan, tyrosine are both.

All others are glucogenic only.

C3 family (alanine, serine, cysteine) ---> pyruvate

C4 family (aspartate and asparagine) ---> oxaloacetate

C5 family (glutamine, proline, arginine, histidine) ---> glutamate ---> ?-ketoglutarate

Methionine, isoleucine, valine, threonine --> succinyl CoA

Leucine --> acetyl CoA and acetoacetate

Phenylalanine and tyrosine --> acetoacetate and fumarate

Tryptophan --> pyruvate

Regulation of the Urea Cycle

The main allosteric enzyme is glutamate dehydrogenase.

It is inhibited by high GTP and ATP levels.

It is stimulated by high GDP and ADP levels.

Last modified: Monday, 30 January 2012, 8:15 AM