2. PYRIMIDINE INTRODUCTION
• A heterocyclic aromatic compound that presents as a pyrimidine ring, and
servesas a component of nucleic acids (e.g.DNA and RNA), certain
proteins, starches, etc.
• Pyrimidine is a heterocyclic aromatic organic compound.It has a single
ring (called a pyrimidine ring) with alternating carbon and nitrogen atoms.
The molar mass of pyrimidine is 80.088g/mol and its melting point is at
20-22 °C.
• Cytosine, thymine, and uracil are pyrimidine nucleobases.
• Cytosine has a chemical formulaof C4H5N3O.
• Thymine has a chemical formula of C5H6N2O2.
• Uracil is similar to thymine in terms of structure except for the methyl
group at position 5 in the heterocyclic aromatic ring present in thymine. It
has a chemical formula of C4H4N2O2
3. NUCLEOTIDE BIOSYNTHESIS
Pathways for the biosynthesis of
nucleotides
Nucleotidebiosynthesis in the cell
can be groupedinto two broad
classes.
1. De novo synthesis
2. Salvage pathways
De novo synthesis(synthesis from
scratch): it is a biochemical
pathway in which nucleotides are
synthesized new from simple
precursor molecules.
Salvage pathways: used to recover
bases and nucleosidesformed
during the degradation of RNA and
DNA.
5. DE NOVO SYNTHESYS OF PYRIMIDINES
• Biosynthesisof pyrimidines is simple than that of purines.
• Unlike purine synthesis, pyrimidines are synthesizedas bases and
later it is added to ribose sugar, i.e.,the ring is completed before
being it is linked to ribose-5- phosphate.
• Following diagram shows the source of different atoms in a
pyrimidine skeletonidentified by radio labelling studies.
• N1, C6, C5 AND C4 are derived from aspartate.
• N3 is derivedfrom glutamine.
• C2 is derived from HCO3-(bicarbonate)
7. DE NOVO SYNTHESYS OF UMP
Step 1: synthesis of
carbamoyl phosphate:
With the hydrolysisof
two ATPs, bicarbonate
and amide nitrogen of
glutamine combine to
form carbamoyl
phosphate.
8. DE NOVO SYNTHESYS OF UMP
Step 2: synthesis of
carbamoyl aspartate:
Carbamoyl phosphate
reacts with aspartate to
yield carbamoyl
aspartate.
9. DE NOVO SYNTHESYS OF UMP
Step 3: Ring closureand
dihydroorotate
formation:
By the elimination
reaction, the carbamoyl
aspartate is converted to
a ring compound
dihydroorotate.
One moleculeof water is
eliminated in this step
10. DE NOVO SYNTHESYS OF UMP
Step 4: Oxidation of
dihydroorotate:
Dihydroorotate is
dehydrogenatedto
form orotate.
11. DE NOVO SYNTHESYS OF UMP
Step 5: Acquisition of
the ribose phosphate
moiety:
Orotate reacts with
PRPP to produce
orotidine-5’-
monophosphate(OMP)
12. DE NOVO SYNTHESYS OF UMP
Step 6:
Decarboxylation
to form UMP:
OMP undergoes
decarboxylation
to form UMP
13. DE NOVO SYNTHESYS OF PYRIMIDINES
Synthesis of UTP from UMP
UMP is converted to UTP in two step
kinase reaction with 2 moleculesof ATP.
Synthesis of CTP
CTP is synthesized by the amination of
UTP by the enzyme CTP synthase.
In animals amino group is donated by
glutamine whereas in bacteria, the
amino group is donated directly by
ammonia
14. DE NOVO SYNTHESYS OF PYRIMIDINES
Synthesis of deoxyribonucleotide.
Deoxyribonucleotidesare synthesizedfrom their corresponding ribonucleotidesby the reduction
of ribose sugar at position C2. enzymesinvolvedin the formation of deoxyribonucleotidesby the
reduction of the corresponding ribonucleotidesare called ribonucleotide reductases (RNRs).
There are three classes of RNRs so far describedin the living world and they all differ in their
prosthetic groups.All of them replace the c2-OH group of ribose with –H via free radical
mechanism.
15. DE NOVO SYNTHESYS OF PYRIMIDINES
Synthesis of dTTP from dUMP
• The dUMP is added with CH3 (methyl
group) to form dTMP catalysed by
the enzyme thymidylate synthetase.
• The dTMP is then phosphorylatedin
two step reaction forming dTDP and
finally dTTP catalysed by kinase
enzymeshydrolysingtwo ATPs,
16. DE NOVO SYNTHESYS OF PYRIMIDINES
Regulation of Pyrimidine synthesis
• In bacteria, aspartate transcarbamoylase (ATCase)
catalyses a committed step in pyrimidine
biosynthesis.ATCase is a good example of an enzyme
controlled by feedbackmechanism by the end
product of CTP. In certain bacteria, UTP also inhibits
ATCase. ATP, however, stimulates ATCase activity.
• The second enzyme CTP synthetase is activated by
GTP while inhibited by CTP.
20. DEGRADATION OF PYRIMIDINES
• The pyrimidine nucleotides undergo similar reactions
(dephosphorylation,deamination and cleavage of glycosidic bond)
like that of purine nucleotides to liberate the nitrogenous bases-
cytosine, uracil and thymine.
• The bases are then degraded to highly solubleproducts- beta alanine
and beta aminoisobutyrate.
• These are the amino acids which undergo transamination and other
reaction to finally produce acetyl CoA and succinyl CoA.
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