Transcript lec 7 Metabolism of purine nucleotides

Metabolism of purine nucleotides
1- Biosynthesis of purine nucleoetides
A- De novo biosynthesis (10 % in liver mainly)
B-
Salvage pathway (90 % in other tissues)
2- Degradation of purine nucleotides
3- Disorders of purine nucleotides
A- Gout
B- Lesch Nyhan syndrome
Remember that purine nucleotides are:
AMP, ADP , ATP: adenosine mono (or di or tri) phosphate
GMP, GDP, GTP: Guanosine mono (or di or tri) phosphate
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A- De Novo synthesis of AMP and GMP
Site: Mainly in the liver (in the cytoplasm)
Sources of the atoms in purine ring:
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•
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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 de novo purine nucleotides biosynthesis:
1. Phosphoribosyl pyrophosphate (PRPP) is the source of ribose 5-phosphate. PRPP is the active form of ribose-5-phosphate
2. Pyrophosphate is removed from PRPP and substituted with
NH2 group of glutamine to form phosphoribosylamine. This
step
is
the
rate
limiting
step
and
catalyzed
by
amidophosphoribosyl transferase
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The rate limiting step in de novo biosynthesis
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3. The ring is then formed from their atoms sources (aspartic,
glutamine, glycine, etc).
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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IMP is converted into AMP by the addition of aspartate. NH2 group
of aspartate replace oxy group in carbon 6 to form AMP.
IMP is converted into GMP through the addition of glutamine. NH2
group of glutamine is added to carbon 2 to form GMP.
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2
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Conversion of IMP to AMP and GMP (for illustration)
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Regulation of the pathway:
amidophosphoribosyl transferase catalyses the rate limiting step
of the pathway.
Activator of the amidotransferase:
This enzyme is activated by PRPP.
So PRPP is an activator of the pathway. Increased PRPP leads to
overproduction of purine nucleotides.
Inhibitors of the amidotransferase:
The enzyme is inhibited by the final products of the pathway (IMP,
AMP and GMP).
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B- Salvage pathway of purines: or resynthesis of purine
nucleotides:
De novo biosynthesis occur in liver due to presence of enzymes. Other
tissues can’t do de novo synthesis. In these organs, free purine bases
(guanine, hypoxanthine and adenine) reacts with PRPP again to
resynthesize purine nucleotides.
These free purine bases are obtained from diet or result during
breakdown of purine nucleotides (see purine catabolism)
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Salvage pathway needs two enzymes:
1- Adenine phosphoribosyl transferase (APRTase)
2- Hypoxanthine-guanine phosphoribosyl transferase
(HGPRTase)
Both enzymes use PRPP as the source of ribose-5-phosphate
The first enzyme catalyze the transfer of ribose-5-P from PRPP to
adenine to synthesize AMP.
→
APRTase
Adenine + PRPP
AMP
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The second salvage enzyme (HGPRTase) catalyzes the transfer of
ribose-5-P into hypoxanthine or guanine to regenerate IMP or
GMP.
→
HGPRTase
Hypoxanthine + PRPP
→
IMP
HGPRTase
Guanine + PRPP
GMP
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Catabolism (breakdown) of purine nucleotides
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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Disorders of purine nucleotides metabolism
A- 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:
Primary causes such as
1- decreased excretion of uric acid by the kidney due to renal disease,
Sometimes it is inherent.
2-defect in purine metabolism: 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. The increased purine lead to increased uric
acid production
Secondary causes: such as diet rich in purines such as red meat, duck,
liver, xanthine beverages like tea, coffee, cola or due to
medication
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.18
3- redness, swelling of big toe.
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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B-Lesch –Nyhan syndrome:
Cause: inherited disease resulting from complete deficiency
(absesnce) of HGPRTase → block (inhibit) salvage pathway of
guanine and hypoxanthine → ↓ use of PRPP in salvage pathway and ↑
its use in purine synthesis leading to overproduction of purine
nucleotides which by catabolism, will give increased levels of uric
acid
Symptoms: appear at age 3-6 months. The first symptom is orange
colored crystals in the diaper of the baby.
1- Hyperuricemia: in aggressive way than in gout.
2- urate kidney stones:
Some symptoms of unknown mechanism are:
3- mental retardation
4- involuntary movements of legs and arms
5- lack of muscle coordination
6- self mutilation (biting of fingers and lips
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leading to lip lesions).