61 - Urea Cycle

Liver and Kidney (to lesser extent)

Site of Urea Cycle

Aspartate and Glutamate

sources of NH2 in Urea

Carbamoyl Phosphate Synthetase I (CPS-I)

• Enzyme for First and rate limiting/regulated step of Urea cycle

• allostrically activated by NAG

Ornithine Trancarbamoylase (OTC)

• Enzyme responsible for the second step of the Urea cycle

• Makes Citrulline from Carbomyl phosphate and ornithine, which is then transported to the cytosol

• Deficiency - most common urea cycle defect (X linked)

Malate, Fumarate, OAA

common intermediates found in both the Urea and TCA cycle

Arginase

enzyme that releases free urea that is then transported into the bloodstream and filtered by the kidneys to be excreted in the urine

Ornithine

molecule that is regenrated at the end of the Urea cycle that must be transported to the mitochondria for the next round.

11-23 mg/dL

Normal level of Serum Urea

Glutaminase Reaction

Produces free ammonia in kidney tubular cells

Presentation of all Urea Cycle Deficiencies

• hyperammonia → causing neurotoxicity

• increase in glutamine levels in circulation

OTC deficiency

• most common Urea cycle disorder

• X linked

• causes carbamoyl phosphate to flood the cycle for pyrimidine synthesis → orotic acid from this cycle is then excreted in the urine

  • helpful in diagnosis

Arginine Supplementation

Helpful in Urea Cycle Defects following the synthesis of argininosuccinate, as it helps to regenrate ornithine and continue the cycle

Management of Hyperammonia

• Low protein diet → bc they cannot be degraded

• High dose glucose (IV dextrose) → bc this prevents the breakdown of AA carbon skeletons for GNG

• Hemodialysis

• Liver transplant

• Phenylbiturate