Examples of feedback inhibition:

Carbamoyl phosphate synthetase is feedback – inhibited by CTP.

Aspartate transcarbamoylase (ATCase) is inhibited by CTP.

Furthermore, the concentrations of key enzymes are transcriptionally regulated during the cell cycle, with increased rates of nucleotide synthesis in the late G1/early S phase of the cell cycle preceding DNA replication.

Orotic acid urea: a rare disease associated with defects in pyrimidine biosynthesis

• – Symptoms: anemia, growth retardation, orotic acid excretion in urine.

– Causes: a defect in phosphoribosyl transferase or orotidylate decarboxylase

– Treatment: patients are fed uridine: U ® UMP ® UDP ® UTP UTP inhibits CPS II (regulated step), preventing the biosynthesis of orotic acid

Pyrimidine biosynthesis: Take home message

• 1. Pyrimidines are synthesized using both de novo and salvage pathways.

2. The pyrimidine ring is synthesized from pre-assembled ingredients (carbamoyl phosphate and aspartate) and then attached to ribose.

3. Pyrimidine biosynthesis is tightly regulated via feedback inhibition (CTP synthetase, ATCase) and transcriptional regulation (ATCase).

4. Most of the necessary enzymes are located in the cytosol with the exception of dihydroorotate (localized in the mitochondria).

5. The mammalian enzymes are multifunctional, e.g. CAD (three activities), UMP synthetase (two activities).

 

REFERENCES:

Text Books:

1. Jeffery C. Pommerville. Alcamo's Fundamentals of Microbiology (Tenth Edition). Jones and Bartlett Student edition.

2. Gerard J. Tortora, Berdell R. Funke, Christine L. Case. Pearson - Microbiology: An Introduction. Benjamin Cummings.

Reference Books:

1. Lansing M. Prescott, John P. Harley and Donald A. Klein. Microbiology. Mc Graw Hill companies.