1634-biochem (2) biossynthesis of pyrimidine

biochemistry
Biosynthesis of pyreimidine

1. BIOSYNTHESIS OF PYRIMIDINE
(CYTOSINE & THYMINE)
Presented by: Buraira Iftikhar
Presented to: Dr. Shaukat Ali
Roll no:1634-BS-Z-21
Semester:6
th
(morning)

2. TABLE OF CONTENTS
•Introduction
•Pathways for biosynthesis of nucleotides
•De-Novo synthesis of pyrimidines (cytosine & thymine)
•Steps of pyrimidine biosynthesis
•Synthesis of CTP
•Synthesis of thymine
•Synthesis of deoxyribonucleotides
•Salvage pathway
•Regulation of pyrimidine biosynthesis
•Conclusion

3. INTRODUCTION:
•Pyrimidine biosynthesis is the process by which cells generate pyrimidine
nucleotides, essential for DNA and RNA synthesis.
•The de novo synthesis pathway produces uridine monophosphate (UMP) from
simple precursors in six enzymatic steps. UMP is then converted to other
pyrimidine nucleotides, including cytidine triphosphate (CTP) and thymidine
triphosphate (dTTP).
•The salvage pathway recycles pyrimidine bases and nucleosides from degraded
RNA and DNA. Understanding pyrimidine biosynthesis is crucial for insights into
cellular metabolism, DNA replication, and gene expression.

4. DE-NOVO SYNTHESIS
•Synthesis from scratch
•It is a biochemical pathway in which
nucleotides are synthesized new from
simple precursor molecules .
•Recycle pathway
•It is used to recover bases and
nucleosides formed during the
degradation of RNA and DNA.
SALVAGE PATHWAY
PATHWAYS FOR BIOSYNTHESIS OF
NUCLEOTIDES

5. Nucleotide biosynthesis
De novo
synthesis
Salvage pathway

6. DE- NOVO SYNTHESIS OF PYRIMIDINES
(CYTOSINE AND THYMINE)
•Biosynthesis of pyrimidines is simple than that of purines.
•Aspartate, glutamine and bicarbonate contributes pyrimidine nucleus.
•Uridine monophosphate (UMP) also acts as precursor of CTP and dTTP.
•De- Novo synthesis of UMP is completed in 6 enzymatic steps from simple precursor.
•De- Novo synthesis of pyrimidines occur in cytosol of cells in all tissues.

7. STEP1: SYNTHESIS OF CARBAMOYL
PHOSPHATE
•With the hydrolysis of two
ATP molecules, bicarbonate
and amide nitrogen of
glutamine combine to form
carbamoyl phosphate in the
presence of enzyme
carbamoyl phosphate
synthestase II.

8. STEP 2: SYNTHESIS OF CARBAMOYL ASPARTATE
STEP 3: RING CLOSURE AND DIHYDROOROTATE
FORMATION
•Step2: carbamoyl phosphate reacts
with aspartate to yield carbamoyl
aspartate catalyzed by the enzyme
aspartate
transcarbamoylase(ATCase).
•Step 3: By the elimination
(Condensation reaction) of one
molecule of water , the carbamoyl
aspartate catalyzed to
Dihydroorotate.

9. STEP 4: OXIDATION OF
DIHYDROOROTATE
•Dihydroorotate is dehydrogenated to form orotate with
enzyme dihydroorotate dehydrogenase.
•In eukaryotes dihydroorotate dehydrogenase is located
in outer surface of inner mitochondrial membrane. All
other enzymes for pyrimidine biosynthesis are located in
cytosol. Inhibition of dihydroorotate dehydrogenase will
inhibit pyrimidine synthesis in T lymphocytes, thereby it
attenuate the autoimmune disease rheumatoid arthritis.
Since the enzyme is not in cytosol, the oxidizing power
required for conversion of dihydroorotate is provided by
Quinone.

10. STEP 5: ACQUISITION OF RIBOSE PHOSPHATE
MOIETY
STEP 6: DECARBOXYLATION TO FORM UMP

11. •Step 5: Orotate reacts with PRPP to produce orotidine-5-
monophosphhate (OMP) with enzymes Orotate phosphoribosyl
transferase.
•Step 6: OMP undergoes decarboxylation with assistance of enzymes
OMP decarboxylase (ODCase) to form uridine monophosphate
(UMP).

12. SYNTHESIS OF UTP FROM UMP
•UMP is converted in two step kinase reaction with 2 molecules of ATP

13. SYNTHESIS OF CTP
•CTP is synthesized by animation of UTP by the enzyme CTP synthase.
•In animals amino group is donated by glutamine whereas in bacteria amino group is
donated directly by ammonia .

14. SYNTHESIS OF THYMINE
•The synthesis of thymidine begins with deoxyuridine monophosphate (dUMP) which is
the product of the action of ribonucleotide reductase on UDP forming dUDP followed
its dephosphorylation to dUMP.
•Thymidylate synthetase utilizes an active folate derivative, N5,N10-methylene
tetrahydrofolate (THF), as the methyl group donor in the synthesis of dTMP. In the
process of thymidine synthesis the THF derivative is converted to dihydrofolate, DHF.
•Conversion of DHF back to active THF require the action of dihydrofolate reductase,
DHFR. DHFR is the same enzyme that is required to convert dietary folate to DHF and
then to THF. Both thymidylate synthetase and DHFR are targets for anticancer drugs.

16. SALVAGE PATHWAY
•Pyrimidines can be salvaged from orotic acid, uracil, and thymine but not from
cytosine.

17. SALVAGE PATHWAY

18. REGULATION OF PYRIMIDINE
SYNTHESIS
•Regulation of pyrimidine biosynthesis is a complex process that involves multiple
mechanisms to ensure proper control of nucleotide production.
•Feedback Inhibition: The end products of pyrimidine biosynthesis, UTP and
UDP, inhibit the enzyme CAD (carbamoyl-aspartate synthetase), which catalyzes
the first step of the pathway. This prevents excessive pyrimidine production.
•Hormonal Regulation: Hormones like insulin and glucagon play a role in
regulating nucleotide biosynthesis. Insulin stimulates pyrimidine synthesis, while
glucagon inhibits it.
•These regulatory mechanisms ensure that pyrimidine biosynthesis is balanced and
adjusted according to cellular needs, preventing excessive or insufficient nucleotide
production.

20. DISORDER RELATED TO PYRIMIDINE
BIOSYNTHESIS

22. CONCLUSION
•In conclusion, pyrimidine biosynthesis is a vital cellular process that
plays a central role in the synthesis of nucleotides, DNA, and RNA. The
de novo biosynthesis pathway, which involves the conversion of
glutamine and aspartate to UMP, is tightly regulated to ensure proper
nucleotide production.
• Understanding the regulation of pyrimidine biosynthesis provides
valuable insights into cellular metabolism and has important
implications for the development of therapeutic strategies to modulate
nucleotide metabolism and treat related diseases.

23. THANK YOU