Professional Documents
Culture Documents
Metabolism of Purine and Pyrimidine
Metabolism of Purine and Pyrimidine
Know these!
The biosynthetic origins of Purine ring
atoms
Sources of atoms in Purine ring
A. Amino acids:
1. Aspartate: gives N1
2. Glycine : gives C4,C5 and N7.
3. Glutamine : gives N3 and N9
B. CO2 : gives C6
C. FH4 (tetrahydrofolate): gives C2 and C8.
• The Purines are built upon a pre-existing ribose 5-phosphate.
• Liver is the major site for purine nucleotide synthesis.
• Erythrocytes, polymorphonuclear leukocytes and brain
cannot produce purines
Biosynthesis of Purine nucleotides
Requires 11 steps
over all
Steps of purine nucleotides
1. Synthesis of 5’-phosphoribosyl-1-
pyrophosphate (PRPP):
• The transfer of pyrophosphate (PP) from ATP to C-1 of
ribose 5-phosphate form 5-phosphoribosyl-1-
pyrophosphate (PRPP).
• PRPP also participates in the synthesis of pyrimidines and
in the salvage reactions of purine.
• Enzyme catalyzed this step is phosphoribosyl-
pyrophosphate kinase
Step 1:
• Step 2: acquisition of purine atom 9 or synthesis of 5’-
phosphoribosylamine:
• Enzyme: amidophosphoribosyl transferase
• Displacement of pyrophosphate group by glutamine amide
nitrogen (inversion of configuration – a to b).
• The enzyme PRPP glutamyl aminotransferase
• Product: β-5-phosphoribosylamine
• Step 7: acquisition of C6
• C6 is introduced as HCO3-
• Enzyme: AIR carboxylase (aminoimidazole ribotide
carboxylase)
• Product: CAIR (carboxyaminoimidazole ribotide)
Step 7: purine synthesis
Steps 8
• Step 8: acquisition of N1
• N1 is acquired from aspartate in an amide condensation
reaction
• Enzyme: SAICAR synthetase
• Product: 5-aminoimidazole-4-(N-
succinylocarboxamide)ribotide (SAICAR)
• reaction is driven by hydrolysis of ATP
Step 8: Purine
synthesis
• Step 9: elimination of Fumarate
• Enzyme: adenylosuccinate lyase
• Product: 5-aminoimidazole-4-carboxamide ribotide (AICAR)
• Step 10: acquisition of C2
• Another formylation reaction catalyzed by AICAR
transformylase
• Product: 5-formaminoimidazole-4-carboxamide ribotide
(FAICAR).
Step 9:
Step 10: purine
synthesis
Step 11
A. Hyperuricemia:
• Definition : hyperuricemia is a condition in which serum urate level is
increased above normal level (2-7 mg/dl) and exceeds its solubility limit
• Causes of hyperuricemia:
I. Over activity of PRPP synthase: this leads to purine overproduction and
excretion.
II. Decreased HGPRTase (hypoxanthine guanine phosphoribosyl transferase)
enzyme (lesch Nyhan syndrome): this enzymatic defect leads to
hyperuricemia
III. Increase-Glucose 6-phosphate (von Gierke,s disease): it is one type of
glycogen storage diseases due to deficiency of glucose-6-phosphatase. This
enzymatic defect leads to hyperuricemia
• Treatment of hyperuricemia:
a. Treatment of the cause
b. Allopurinol : it is a structural analogue of the
hypoxanthine that competitively inhibits xanthine
oxidase enzyme then decreasing formation of uric acid.
B. Hypouricemia:
• It is rare condition associated with xanthine oxidase
deficiency. It is due to either genetic defect or severe
liver damage.
• It resulting in excess excretion of xanthine and
hypoxanthine and patient may show xanthine renal stone
Effect of hyperuricemia/Gout
a. Tophi formation: increased insoluble urate leads to
crystallization of sodium urate in soft tissues and joints,
which results in formation of deposits called : tophi .
b. The tophi causes an inflammatory reaction called gouty
arthritis.
c. The joints that firstly affected are small joints especially
those of big toes
d. Renal stone: deposition of urate crystals in renal tubules
may lead to stone formation e.g kidney stone.
e. Lesch Nyhan syndrome: is characterized by
hyperuricemia, uric acid renal stone, neurological
disorders and mental retardation
Gout
Biosynthesis of Pyrimidine
• Sources of atoms in pyrimidine ring:
a. Aspartate: gives N1, C4, C5 and C6
b. Carbamoyl phosphate: gives C2 and N3
Synthesis of pyrimidine:
• It begins with the formation of carbamoyl phosphate from
glutamine, ATP and CO2.
• This reaction is catalyzed by cytosolic carbamoyl phosphate
synthase II.
• Pyrimidine rings is first synthesis where in purine ring is built upon
a pre-existing ribose 5-phosphate.
Nucleotide bases in nucleic acids are pyrimidines or purines.
Steps
• Glutamine transfers its amido nitrogen to CO2 to produce
carbamoyl phosphate.
• This reaction is ATP-dependent and is catalysed by cytosomal
enzyme carbamoyl phosphate synthetase ll (CPSII).
• CPS ll is activated by ATP and PRPP and inhibited by UTP.
• Carbamoyl phosphate synthetase| (CPSl ) is a mitochondrial
enzyme which synthesizes carbamoyl phosphate from
ammonia and CO2 and, in turn urea protein metabolism.
• Carbamoyl phosphate condenses with aspartate to
form carbamoyl aspartate.
• This reaction is catalysed by aspartate
transcarbamoylase.
• Dihydroorotase catalyses the pyrimidine ring
closure with a loss of H2O.
• The three enzymes-CPS ll, aspartate
transcarbamoylase and dihydroorotase are the
domains (functional units) of the same protein.
• This is a good example of a multifunctional
enzyme.
• The next step in pyrimidine synthesis is an NAD+ dependent
dehydrogenation, leading to the formation of orotate.
• Ribose5 –phosphate is now added to orotate to produce
orotidine monophosphate (OMP).
• This reaction is catalysed by orotate
phosphoribosyltransferase, and enzyme comparable with
HGPRT in its function.
• OMP undergoes decarboxylation to uridine mono-phosphate
(UMP).
• Orotate phosphoribosyltransferase and OMP decarboxylase
are domains of a single protein.
• A defect in this bifunctional enzyme causes orotic Aciduria .
• By an ATP-dependent kinase reaction, UMP is converted to
UDP which serves as a precursor for the synthesis of dUMP,
dTMP, UTP and CTP.
• Ribonucleotide reductase converts UDP to dUDP by a
thioredoxin-dependent reaction.
• Thymidylate synthetase catalyses the transfer of a methyl
group from N5, N10-methylene tetrahydrofolate to produce
deoxythymidine monophosphate( dTMP).
• UDP undergoes an ATP-dependent kinase reaction to produce
UTP.
• Cytidine triphosphatase (CTP) is synthesized from UTP by
amination.
• CTP synthetase is the enzyme and glutamine provides the
nitrogen
Pyrimidine synthesis
Regulation of pyrimidine
synthesis
• Carbamoyl phosphate synthetase II (CPS II)
is the regulatory enzyme of pyrimidine
synthesis in animals.
• It is activated by PRPP and ATP and
inhibited by UDP and UTP.
• OMP decarboxylase, inhibited by UMP and
CMP, also controls pyrimidine formation.
Salvage pathways