This document discusses disorders of pyrimidine metabolism. It provides an overview of pyrimidine synthesis pathways including de novo and salvage pathways. It describes one specific disorder, hereditary orotic aciduria, which is caused by a defect in UMP synthetase, resulting in excess orotic acid excretion. Treatment involves supplementing with UMP, which downregulates the pathway via feedback inhibition. The document contrasts pyrimidine and purine synthesis, regulation, catabolism, and salvage pathways.

1. Disorders of Pyrimidine
Metabolism
Lecturer:
Dr. G. K. Maiyoh
Department of Medical
Biochemistry, School of Medicine,
MU
March 21, 2013 GKM/MUSOM/NSP 210:PATH.2012.2013 1

2. Pyrimidines and Purines
• Pyrimidine and purine are the names of the
parent compounds of two types of
nitrogen-containing heterocyclic aromatic
compounds.
N N N
N N N
H
Pyrimidine Purine

3. Important Pyrimidines
• Pyrimidines that occur in DNA are cytosine
and thymine. Cytosine and uracil are the
pyrimidines in RNA.
O O NH2
CH3
HN HN HN
O N O N O N
H H H
Uracil Thymine Cytosine

4. Synthesis Pathways
• For both purines and pyrimidines there are two means
of synthesis (often regulate one another)
– de novo (from bits and parts)
– salvage (recycle from pre-existing nucleotides)
de novo Pathway Salvage Pathway

5. Many Steps Require an Activated
Ribose Sugar (PRPP)
5’

6. de novo Synthesis
• Committed step: This is the point of no
return
– Occurs early in the biosynthetic pathway
– Often regulated by final product (feedback
inhibition)
X

7. Raw materials for biosynthesis
O NH 2
• Synthesized C CH3 C H
HN C N C
from:
– Glutamine O C C O C C
N H N H
– CO2 H H
– Aspartic acid
– Requires ATP
Uracil Cytosine
• Pyrimidine rings are synthesized independent of
the ribose and transferred to the PRPP (ribose)
• Generated as UMP (uridine 5’-monophosphate)

8. How is Pyrimidine Biosynthesis
regulated?
• Regulation occurs at first step in the pathway
(committed step)
• 2ATP + CO2 + Glutamine = carbamoyl phosphate
X
Inhibited by UTP
If you have lots of UTP around this means you won’t
make more that you don’t need. This is referred to as;

9. Biosynthesis: Purine vs Pyrimidine
• Synthesized on PRPP • Synthesized then added to
PRPP
• Regulated by GTP/ATP • Regulated by UTP
• Generates IMP • Generates UMP/CMP
• Requires Energy • Requires Energy

10. Hereditary Orotic Aciduria
• Is a defect in de novo synthesis of pyrimidines
• Loss of functional UMP synthetase
– Gene located on chromosome III
• Characterized by excretion of orotic acid
• Results in severe anemia and growth
retardation
• Extremely rare (15 cases worldwide)
• Treated by feeding UMP

11. Why does UMP Cure
Orotic Aciduria?
Carbamoyl
Phosphate Orotate
XUMP
Synthetase
Feedback
• Disease (-UMP) Inhibition
– No UMP/excess orotate
• Disease (+UMP)
– Restore depleted UMP
– Downregulate pathway via feedback inhibition (Less orotate)

12. Catabolism of pyrimidines
• Animal cells degrade pyrimidines to their
component bases.
• Happen through dephosphorylation,
deamination, and glycosidic bond cleavage.
• Uracil and thymine broken down by
reduction (vs. oxidation in purine
catabolism).

13. Page 1098

14. Pyrimidine Degradation/Salvage
• Pyrimindine rings can be fully degraded to
soluble structures (Compare to purines that
make uric acid)
• Can also be salvaged by reactions with PRPP
– Catalyzed by Pyrimidine
phosphoribosyltransferase
Degradation pathways are quite distinct for purines and
pyrimidines, but salvage pathways are quite similar