1. Pyrimidine metabolism
Sources of carbon and nitrogen atoms in pyrimidine ring:
N1, C4, C5 and C6 → from aspartate
C2 from CO2
N3 → from amide group of glutamine

2. Pyrimidine bases:
Cytosine = 2-oxy-4-amino pyrimidine: present in both DNA and RNA
Thymine = 2,4-dioxy-5-methyl pyrimidine: present only in DNA
Uracil = 2,4-dioxy pyrimidine: present in RNA only 2

3. RNA contains the same bases as DNA with the exception of thymine
RNA contains the same bases as DNA with the exception of thymine. Instead, RNA contains the pyrimidine uracil: 3

4. De no vo biosynthesis of pyrimidine nucleotides (UTP, CTP):
pyrimidine nucleotides are synthesized by a stepwise series of reactions to form UMP.
Pyrimidine ring is formed first then ribose-5- phosphate is added via PRPP.
NB. In purine synthesis, ribose-5-P is added from the first step, then, the ring is formed.
The rate limiting step in de novo synthesis of pyrimidine is the first step which is the formation of carbamoyl phosphate from glutamine and CO2 in the presence of 2ATP and carbamoyl phosphate synthetase II (CPSII)which is the rate limiting enzyme.

5. Pyrimidine biosynthesis:1- 3 2 4 2- 1 5

6. UMP kinase
UDP kinase
CTP synthetase 6

7. Conversion of UTP into CTP
CTP synthetase works only on nucleoside triphosphate level

8. Regulation of UTP de novo biosynthesis
Carbamoyl phosphate synthetase II (CPS II) the key enzyme in the biosynthesis is stimulated by ATP and inhibited by UTP (feed back inhibition)

9. Orotic aciduria (very rare disease)
Causes:
Deficiency in one of the last two enzymes in UTP de novo biosynthesis; Orotate Phosphoribosyl transferase (OPRT) OR OMP decarboxylase
Sypmtoms:
Increased excretion of orotic acid in urine
Retarded growth

10. Conversion of ribonucleotides into deoxyribonucleotides
In the de novo biosynthesis (of either purine or pyrimidine nucleotides) PRPP is the source of ribose-5-phoshate and lead to the formation of ribonucleotides (RNA nucleotides). These ribonucleotides could be converted into deoxyribonucleotides (DNA nucleotides) by the action of ribonucleotide reductase enzyme (RR) which reduce ribose into deoxyribose.
RR enzyme works only on nucleoside diphosphate level i.e. act on ADP , GDP or CDP (and even on UDP for biosynthesis of dTMP which will be explained later)

11. ADP → dADP GDP → dGDP CDP → dCDP RR enzyme RR enzyme
Ribonucleotide reductase (RR)
RR enzyme
RR enzyme

12. Thymidylate synthase works only on nucleoside monophosphate level
Biosynthesis of dTMP
UDP → dUDP → dUMP
RR enzyme
Thymidylate synthase works only on nucleoside monophosphate level

13. Tetrahydrofolic acid (THF or FH4)

14. Anticancer drugs from dTMP synthesis pathway:
5-flurouracil is a competitive inhibitor of thymidylate synthetase
Methotrexate is an inhibitor of dihydrofolate reductase (DHFR)
These drugs interfere with dTMP biosynthesis and so prevent DNA synthesis in cancer cells.
Cancer cells will be affected by these drugs more than healthy cells because they divide more rapidly.

15. Salvage pathway of pyrimidine nucleotides:
By two enzymes
1- Pyrimidine + Ribose-1-P → Pyrimidine nucleoside + Pi
Enzyme: Nucleoside Phosphorylase
Nucleoside + ATP → Pyrimidine nucleotide +ADP
Enzyme: Nucleoside kinase

16. Pyrimidine Catabolism
1- Ring Cleavage:
pyrimidine ring can be opened and degraded to highly soluble β-amino acids such as β- alanine and β-aminoisobutyrate

17. Functions of purine and pyrimidine nucleotides
1. Building units of nucleic acids
DNA is a polymer of deoxyribonucleotides (d-AMP, d-GMP
d-CMP, d-TMP)
RNA is a polymer of ribonucleotides (AMP, GMP, CMP, UMP)
2- Energy carriers
Nucleoside triphosphates (ribonucleotides) are the “energy
carriers” in cells
ATP is general energy source
GTP is specific for protein synthesis
UTP is specific for carbohydrate synthesis
CTP is specific for lipid synthesis

18. 3. Components of many of the coenzymes
Adenine nucleotides (ribonucleotides) are components of
many of the coenzymes
Examples: NAD+, FAD, Coenzyme A
FAD
NAD

19. 4. Second messenger
Cyclic nucleotides (ribonucleotides) act as second messenger
Examples: cAMP and cGMP
Second messengers are intracellular molecules released by the cell (e.g. in response to hormonal action) to trigger physiological changes
Cyclic nucleotides

20. cAMP
cGMP
In cAMP and cGMP: a phosphodiester bond is formed between the 3'and 5' carbons of ribose 20

21. Synthesis of cAMP and cGMP
cAMP is synthesized from ATP by the enzyme adenylyl cyclase
cGMP is synthesized from GTP by the enzyme guanylyl cyclase

22. cAMP as second messenger (for understanding)
Phosphorylate enzymes

23. Degradation of cAMP and cGMP:
By the enzyme phosphodiesterase that breaks the phosphodiester bond to give AMP from cAMP and GMP from cGMP