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Metabolism of purine nucleotides
A- De Novo synthesis: of AMP and GMP
Sources of the atoms in purine ring:
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N1:
derived from NH2 group of aspartate
C2 and C8: from formate group
N3 and N9 : amide group of glutamine
C4, C5 , N7: glycine amino acid
C6:
from CO2
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Notes on purine nucleotides biosynthesis:
1. Phosphoribosyl pyrophosphate (PRPP) is the source of ribose 5-phosphate. Pyrophosphate is removed.
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2- The ring is then formed from their atoms sources (aspartic,
glutamine, glycine, etc).
3- PRPP is an activator to pathway i.e, increased PRPP leads to
overproduction of purine nucleotides
4- The pathway ends with the formation of a purine nucleotide
called : Inosine monophosphate (IMP) which is the precursor
of AMP and GMP which then converted into ATP and GTP,
respectively
AMP and GMP
←
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NB: IMP is a nucleotide contain purine base which is hypoxanthine
(6 –oxy purine). Hypoxanthine is a purine base not enter in DNA or
RNA structure
hypoxanthine
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Catabolism ( breakdown) of purine nucleotides
Synthesis of uric acid:
Uric acid is the end product of purine metabolism in human.
AMP or GMP is metabolized to give hypoxanthine which is then
converted into xanthine and finally into uric acid as in the next slide.
Most of uric acid is excreted by the kidney. The remaining uric acid
travels through the intestines, where bacteria help break it down.
Normally these actions keep the level of uric acid in the blood plasma
at a healthy level, which is below 6.8 mg/dL. But under certain
circumstances, the body produces too much uric acid or removes too
little. In either case, concentrations of uric acid increase in the blood.
This condition is known as hyperuricemia.
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Gout: is a disorder characterized by high levels of uric acid in blood
(hyperuricemia), with deposition of
monosodium urate
crystals in special sites in the body like joints, and
surrounding tissues and sometimes in the kidney. Gout is a
type of arthritis
Urate crystals are detected in synovial
fluid of the joint
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Causes:
1- decreased excretion of uric acid by the kidney due to renal disease,
acidic urine that decrease uric acid excretion, some drugs inhibit
uric acid excretion such as thiazide diuretics. Sometimes it is
inherent.
2- Diet rich in purines such as red meat, duck, liver, xanthine beverages
like tea, coffee, cola.
3-Overproduction of uric acid due to increased synthesis of purine
nucleotides which may be idiopathic (with unknown cause) or
due to increased levels of PRPP that stimulate synthetic pathway
of purine nucleotides.
Symptoms:
1- Hyperuricemia: increased uric acid levels in blood
2- arthritis, inflammation especially in joints due to deposition of urate
crystals leading to hot red and swollen joints with severe pain.
3- redness, swelling of big toe.
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4- it may also present as tophi (masses of urate crystals deposited
under skin) appears after several years.
5- It may lead to kidney stones,
Tophi, in chronic cases, lumpy
deposits of urate just under the
skin
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Treatment: Allopurinol, analogue of hypoxanthine (structurally
similar). It competitively inhibits xanthine oxidase, so
prevents the conversion of hypoxanthine to xanthine and
xanthine to uric acid.
Uricosuric agents: drugs used to increase excretion of uric acid by
the kidney such as probenecid.
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Anti-inflammatory drugs is recommended also.
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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
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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 cabamoyl phosphate from glutamine and
CO2 in the presence of 2ATP and carbamoyl phosphate synthetase II
which is the rate limiting enzyme.
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Pyrimidine Catabolism
1- Ring Cleavage:
pyrimidine ring can be opened and degraded to highly soluble βamino acids such as β- alanine and β-aminoisobutyrate
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Some Functions of nucleotides:
1- Enter in the structure of DNA and RNA.
2- ATP and GTP are sources of energy
3- CTP is required for synthesis of phosphlipids that enter in the
structure of cell membrane
4- enter in the synthesis of some coenzymes such as NAD, FAD,
FMN.
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