PYRIMIDINE SYNTHESIS

NUCLEOTIDE
METABOLISM
PREPARED BY; MISS RABIA KHAN BABER
COURSE TITLE : BIOCHEMISTRY IV

LEARNING OBJECTIVES OF
CLASS
PYRIMIDINE
SYNTHESIS
DENOVO
SYNTHESIS
REGULATION SIGNIFICANCE

 Thymine,cytosineanduracilarepyrimidinebases.
 Thepyrimidine ring issynthesized as free
pyrimidine &it isincorporated into the nucleotide.
 Aspartate, glutamine (amide group) &CO2
contribute to atoms in the formation of pyrimidine
ring.
PYRIMIDINE BASES

DE NOVO PYRIMIDINE
SYNTHESIS
 Biosynthesis of pyrimidine nucleotides can occur by
a de novo pathway or by the reutilization of
preformed pyrimidine bases or ribonucleosides
(salvage pathway).
 The pyrimidine synthesis is a similar process than
that of purines. In the de novo synthesis of
pyrimidines, the ring is synthesized first and then it is
attached to a ribose-phosphate to for
a pyrimidine nucleotide.

LOCATION
 De novo pyrimidine synthesis occurs in the cytosol of
cells in all tissues.
SUBSTRATES
 CO2; glutamine; ATP; Aspartate; H2O; NAD+;
Phosphoribosyl pyrophosphate (PRPP).
PRODUCTS
 UTP; CTP; glutamate; NADH; CO2

STEPS OF SYNTHESIS
Pyrimidines are synthesized from carbamoyl
phosphate and aspartate. Ribose-5-phosphate is then
attached to yield pyrimidine ribonucleotides.
Cytosine is found in both DNA and RNA. Uracil is
found only in RNA

Synthesisofcarbomylphosphate
 Thereaction occursin cytoplasm
 Glutamine transfers its amido nitrogen to CO2 to
produce carbamoyl phosphate.
 This reaction is catalyzed by ATP dependent enzyme
carbamoyl phosphate synthetase II (CPS II).
 CPS-Iisinvolved in urea cycle.
STEP#1

Rate limiting step
 Carbamoyl phosphate condenses with aspartate
to form carbamoyl aspartate.
 This reaction is catalysed by aspartate
transcarbamoylase.
 The atoms C2 & N3 are derived from
carbamoyl phosphate & the rest are from aspartate.
STEP#2

Formation of pyrimidine ring
 Dihydroorotase catalyses the pyrimidine ring
closure with a loss of H2O.
Oxidation
 NAD+ dependent dehydrogenation, leading to the
formation of orotate.
 The enzyme is dihydro orotate
dehydrogenase (DHODH).
STEP#3 & STEP#4

Formation of OMP
 Ribose 5-phosphate isnow added to orotate to
produce orotidine monophosphate (OMP).
 Thisreaction iscatalysed by orotate
phosphoribosyltransferase.
 PRPPisthe donor of ribose 5-phosphate.
STEP#5

Decarboxylation
 OMP undergoes decarboxylation to uridine mono-
phosphate (UMP).
 The enzyme isOMP decarboxylase (OMPDC).
 Thisisthe first pyrimidine that issynthesized.
 6-aza-uridine inhibits this step &used as an
anticancer drug.
STEP#6

 Orotate phosphoribosyl transferase &OMP
decarboxylase are domains of a single protein.
 A defect in this bifunctional enzyme causes orotic
aciduria.
CLINICAL CORELATION

STEP#7
Synthesis of triphosphates
 By an ATP-dependent UMP kinase reaction, UMP
is converted to UDP which serves as a precursor for
the synthesis of dUMP, dTMP, UTP&CTP.
 UDPisphosphorylated to UTP(uridine
triphosphate) with the help of ATP.
 Theenzyme isnucleoside diphosphate kinase.

STEP#8
Formation of CTP
 Cytidine triphosphate (CTP)issynthesized from UTP
byamination.
 CTPsynthetase isthe enzyme &glutamine provides
the nitrogen.
 CTPsynthetase needsATP.

REGULATION OF PYRIMIDINE
SYNTHESIS
 In bacteria, aspartate transcarbamoylase (ATCase)
catalyses a committed step in pyrimidine biosynthesis.
 ATCaseisa good example of an enzyme controlled by
feedback mechanism by the end product CTP.
 Carbamoyl phosphate synthetase II (CPSII) is the
regulatory enzyme of pyrimidine synthesis in animals.
 It isactivated by PRPPand ATP&inhibited by UDP
& UTP.
 OMP decarboxylase, inhibited by UMP & CMP,
also controls pyrimidine formation.

SIGNIFICANCE OF
PYRIMIDINE SYNTHESIS
 Pyrimidine nucleotides, in common with purine
nucleotides, are required for the synthesis of DNA
and RNA.
 They also participate in intermediary metabolism. For
example, pyrimidine nucleotides are involved in the
biosynthesis of glycogen and of phospholipids.
 Pyrimidines have diverse biological activities such as
antimicrobial, CNS depressant, anti-inflammatory,
analgesic, anti-convulsant, anticancer, antihelmentic,
antioxidant and herbicidal.

REFERENCES
 Textbook of Biochemistry-U Satyanarayana
 Textbook of Biochemistry-DM Vasudevan
 Text book of medical biochemistry, MN Chatterjee
 Fundamentals of biochemistry, J.L Jain, Sunjay Jain,
Nitin Jain

PYRIMIDINE SYNTHESIS

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