Disorders of pyrimidine metabolism

Orotic aciduria and pyrimidine metabolism

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

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

NN
NN

NN
NN
NN
NN
HH
PyrimidinePyrimidine PurinePurine

3. Important Pyrimidines
•Pyrimidines that occur in DNA are cytosine
and thymine. Cytosine and uracil are the
pyrimidines in RNA.

HHNN
NN
HH
OO
OO
UracilUracil

HHNN
NN
HH
OO
OO
CHCH
33
ThymineThymine
HHNN
NN
HH
NNHH
22
OO
CytosineCytosine

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)
Salvage Pathwayde novo 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
•Pyrimidine rings are synthesized independent of
the ribose and transferred to the PRPP (ribose)
•Generated as UMP (uridine 5’-monophosphate)
•Synthesized
from:
–Glutamine
–CO
2
–Aspartic acid
–Requires ATP
N
C
C
C
HN
C
O
CH
3
H
O
H
N
C
C
C
N
C
H
O
H
H
NH
2
Uracil Cytosine

8. How is Pyrimidine Biosynthesis
regulated?
•Regulation occurs at first step in the pathway
(committed step)
•2ATP + CO2 + Glutamine = carbamoyl phosphate
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;
X

9. Biosynthesis: Purine vs Pyrimidine
•Synthesized on PRPP
•Regulated by GTP/ATP
•Generates IMP
•Requires Energy
•Synthesized then added to
PRPP
•Regulated by UTP
•Generates UMP/CMP
•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
UMP
Synthetase
X
Feedback
Inhibition•Disease (-UMP)
–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. P
a
g
e

1
0
9
8

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