There are six steps of the urea cycle:
- Bicarbonate ion, NH4+ and 2 ATP necessary to form carbamoyl phosphate via carbamoyl phosphate synthetase I (found in mitochondrial matrix).
- 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
- Citruilline is transported out of mitochondrial matrix in exchange for ornithine
- Citruilline condenses with aspartate --> arginosuccinate via an ATP-dependent reaction via arginosuccinate synthetase
- Arginosuccinate cleaved to form fumarate and arginine via arginosuccinate lyase
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
- Two -NH2 groups and terminal carbon of arginine cleaved to form ornithine and urea via arginase
Ornithine is transported into mitochondrion to repeat cycle(Figure)
Overall reaction:
Inherited defects in urea cycle:
-
Blockage of carbamoyl phosphate synthesis leads to hyperammonemia (elevated levels of ammonia in blood)
- argininosuccinase deficiency
Providing surplus of arginine in diet and restricting total protein intake
Nitrogen is excreted in the form of argininosuccinate
- 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.
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