Orotic aciduria and pyrimidine metabolism

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