This document summarizes pyrimidine nucleotide metabolism, including the de novo synthesis, degradation, and salvage pathways. It discusses the key steps and enzymes involved in synthesizing the pyrimidine ring from glutamine, CO2, and aspartate. It then covers the attachment of the ring to ribose-5-phosphate to form the nucleotide orotidine monophosphate. The pathways that generate the other pyrimidine nucleotides, CTP and dTMP, are also outlined. The document concludes by briefly mentioning pyrimidine degradation and salvage, as well as some disorders related to pyrimidine metabolism.

1. XIANG
ZHUXING
NUCLEOTIDE
METABOLISM

2. Synthesis of Purine Nucleotides
Degradation of Purine Nucleotides
Synthesis of Pyrimidine Nucleotides
Degradation of Pyrimidine Nucleotides
INTRODUCTION

4. The pyrimidine ring is synthesized before being
attached to ribose 5- phosphate(PRPP).
The sources of the atoms in the pyrimidine ring
are glutamine, CO2, and aspartate.
PYRIMIDINE SYNTHESIS
Aspartate
CO2

5. The regulated step of this pathway is the synthesis
of carbamoyl phosphate from glutamine and CO2,
catalyzed by carbamoyl phosphate synthetase
(CPS) II.
CPS II is inhibited by UTP
activated by PRPP.
A. SYNTHESIS OF CARBAMOYL
PHOSPHATE

6. Synthesis of Carbamoyl Phosphate

7.  The second step is the formation of carbamoyl
aspartate, catalyzed by aspartate transcarbamoylase.
 The pyrimidine ring is then closed by dihydroorotase.
The resulting dihydroorotate is oxidized to produce
orotic acid (orotate) .
 The enzyme that produces orotate, dihydroorotate
dehydrogenase, is a flavoprotein associated with the
inner mitochondrial membrane.
 All other enzymes in pyrimidine biosynthesis are
cytosolic.
B. SYNTHESIS OF OROTIC ACID

9.  The completed pyrimidine ring is converted to the
nucleotide orotidine monophosphate (OMP) in the
second stage of pyrimidine nucleotide synthesis
 PRPP is the ribose 5-phosphate donor.
 The enzyme is orotate phosphoribosyltransferase.
 Both purine and pyrimidine synthesis require glutamine,
aspartate, and PRPP as essential precursors.
 OMP, the parent pyrimidine mononucleotide, is
converted to uridine monophosphate (UMP) by
orotidylate decarboxylase
 UMP is sequentially phosphorylated to UDP and UTP.
C. FORMATION OF A PYRIMIDINE
NUCLEOTIDE

12. CTP is produced by amination of UTP by CTP
synthetase. with glutamine providing the nitrogen.
Some CTP is dephosphorylated to CDP, which is a
substrate for ribonucleotide reductase. dCDP
D. SYNTHESIS OF CYTIDINE
TRIPHOSPHATE
CTP Synthetase

14. REGULATION OF PYRIMIDINE
SYNTHESIS

15. dUMP is converted to dTMP by thymidylate
synthase, which uses N5,N10-methylene THF as
the source of the methyl group.
This is an unusual reaction in that THF contributes
not only a one-carbon unit but also two H atoms,
resulting in the oxidation of THF to DHF
E. SYNTHESIS OF dTMP

16. E. SYNTHESIS OF dTMP

17.  Inhibitors of thymidylate synthase include thymine
analogs such as 5-fluorouracil, which serve as
antitumor agents.
 Converted to 5-FdUMP, which becomes permanently
bound to the inactivated thymidylate synthase, making
the drug a “suicide” inhibitor.
INHIBITORS OF PYRIMIDINE
SYNTHESIS

18.  DHF can be reduced to THF by dihydrofolate reductase,
an enzyme that is inhibited by folate analogs such as
methotrexate.
 By decreasing the supply of THF, these drugs not only
inhibit purine synthesis, but, by preventing
methylation of dUMP to dTMP, they also decrease the
availability of this essential component of DNA.
 DNA synthesis is inhibited and cell growth slowed.
 Thus, these drugs are used to decrease the growth
rate of cancer cells.
INHIBITORS

19. Site of Action of
Antineoplastic
Drugs

20. Pyrimidine bases can be salvaged to
nucleosides, which are phosphorylated to
nucleotides.
However, their high solubility makes pyrimidine
salvage less significant clinically than purine
salvage.
The salvage of pyrimidine nucleosides is the
basis for using uridine in the treatment of
hereditary orotic aciduria.
F. Salvage of Pyrimidines

22. The pyrimidine ring is opened and
degraded to highly soluble products, β-
alanine (from the degradation of CMP
and UMP) and β-aminoisobutyrate (from
TMP degradation), with the production of
NH3 and CO2.
G. Degradation of Pyrimidines

23. DEGRADATION
OF PYRIMIDINES

24. Disorders of pyrimidine metabolism
includes:
Orotic aciduria
Reye’s syndrome
DISORDERS OF PYRIMIDINE
METABOLISM

25. Is a rare metabolic disorder characterized by
the excretion of orotic acid in urine, severe
anemia and retarded growth.
It is due to the deficiency of the enzymes
orotate phosphoribosyl transferase and OMP
decarboxylase of pyrimidine synthesis.
Both these enzymes activities are present on
a single protein as domains (bifunctional
enzyme).
OROTIC ACIDURIA

27. Orotic Aciduria

28. Orotic Aciduria

29. Considered as a secondary orotic aciduria.
It is believed that a defect in ornithine
transcarbamoylase (of urea cycle) causes
the accumulation of carbamoyl
phosphate.
This is then diverted for the increased
synthesis and excretion of orotic acid.
REYE’S SYNDROME

30. COMPARE/CONTRAST
Purine biosynthesis
Salvage is a major pathway
Base synthesized while
attached to R5P
IMP is common
intermediate for AMP and
GMP, but itself is not a
typical nucleotide
Pyrimidine biosynthesis
De novo is a major pathway
Base is synthesized, then
attached to R5P
UMP, a typical nucleic acid,
is converted into other
pyrimidines

32.  Lehninger Principles of Biochemistry: David L. Nelson (University of Wisconsin -Madison) ,
Michael M. Cox (University of Wisconsin -Madison) : ISBN-10: 1-4641-2611-9; ISBN-13: 978-1-
4641-2611-6; Format: Cloth Text
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REFERENCE