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Biochemistry II PHR 375Biochemistry II PHR 375
Nucleotides Metabolism
Hassan MokhamerHassan MokhamerHassan MokhamerHassan Mokhamer
bybybyby
Sources Of Atoms in purines
Synthesis Of Purines nucleotides
De Novo Pathway(Steps)
• 1. Synthesis of 5’_ phosphoribosyl-1-pyrophosphate(PRPP)
The key regulatory enzyme is phosphoribosyl pyrophosphate synthase
Ribose-5-Phosphate
PRPP Synthase
5-Phosphoribosyl -1-pyrophosphate
2. Synthesis of 5’_ phosphoribosylamine ATP AMP
5-Phosphoribosyl -1-pyrophosphate 5-Phosphoribosylamine
Glutamine Glutamate
H2O PPi
• 3. Synthesis of Inosine 5’- Monophosphate (IMP):
5-Phosphoribosylamine
Glycine
Folic Acid
Glutamine
Aspartate
CO2
Inosine Monophosphate (IMP)
HN
HC
N
C
C
C
N
CH
N
O
4
5
HH
CH2
OH OH
H HO
O2-O3P
• 4. Conversion of IMP to either AMP or GMP
IMP
Inosine Monophosphate (IMP)
Adenyl succinate
Xanthosine
Monophosphate
AMP
GMP
ADP ATP
GDP GTP
Inhibitors of purines synthesis
Methotrexate
That competitively inhibits the reduction of
dihdrofolate to tetrahydrofolate . Thus this drugdihdrofolate to tetrahydrofolate . Thus this drug
will limit the amount of tetrahydrofolate available
for use in purine synthesis
Conversion of ribonucleotides to deoxyribonucleotides
• The nucleotides synthesized by de novo and salvage
pathways are ribonucleotides and can be used as building
blocks in RNA synthesis.
• The cellular level of deoxyribonucleotides is usually very
low, they are increased only at the time of DNA
replication.replication.Ribonucleoside diphosphate Deoxyribonucleoside diphosphate
Thioredoxin ( Oxidized)Thioredoxin ( Reduced)
NADPH + H+NADP+
Ribonucleotide Reductase
Thioredoxin Reductase
Catabolism of purine nucleotides
• A. Uric acid is the end product of purinecatabolism in man which is excreted in urine.
• B. Net excretion of total uric acid in normalhuman is about 500 mg/day.
• C. Normal human plasma uric acid average 2-6mg/dl in female and 3 – 7 mg/dl.
• D. Uric acid is oxidized into Allantion by theaction of Uricase enzyme which is lacked inhuman.
Uric acid crystals and stones
• The solubility of uric acid depends upon pH .
• Uric acid becomes insoluble (Crystals) at the
site of urine acidification ( the distal tubules).site of urine acidification ( the distal tubules).
• The more acidity the more crystals formation
Uric acid stone
Disorders of purine catabolism
• A. Hyperuricemia :
1. Definition: it is a condition in which serum urate
level is increased above normal level and exceeds
its solubility limit.its solubility limit.
2. Causes of hyperuricemia
a) Primary hyperuricemia
1. Increased activity of PRPP synthase : this
leads to purine overproduction and excretion.
2. Decreased the activity of HGPRTase (hypoxanthine guanine
phosphoribosyl transferase)
( Lesch Nyhan syndrome)
• HGPRTase Block salvage pathway PRPP
Purine synthesis (de novo synthesis) Uric acidPurine synthesis (de novo synthesis) Uric acid
Hyperuricemia
3. Glucose -6- phosphatase (Von Gierke’s disease)
• b) Secondary hyperuricemia :
1. It is due to increase the rate of cell division
and tissue turnover as in cancer and
Leukemia.
2. Decreased renal excretion of uric acid: as
in renal failure or due to drugs as
diuretics or lead poisoning.
3.Effect of hyperuricemia (Gout)
• a) Tophi formation : increased insoluble urate leads
to crystallization of sodium urate in soft tissue and
joints, which results in formation of deposits called
Tophi.
• 1. the tophi cause an inflammatory reaction
called gouty arthritis.called gouty arthritis.
• 2. the joints that firstly affected are small joints
specially those of big toes
b) Renal stones: deposition of urate crystals in
renal tubules may leads to stone formation e.g
kidney stones.
c) Lesch Nyhan Syndrome:
this syndrome is characterized by :-
1. Hyperuricemia and gout1. Hyperuricemia and gout
2. Uric acid renal stone
3. Neurological disorders and mental
retardation.
4.Treatment of hyperuricemia
• a) Treatment of the cause.
• b) Allopurinol:
it is a structural analogue of hypoxanthine that
competitively inhibits xanthine oxidase enzyme
decreasing formation of uric acid
Metabolism of pyrimidine nucleotides
• 1. Sources of atoms in pyrimidine ring
Biosynthesis of pyrimidine
• + + CO2CO2 GlutamineGlutamine ATP Carbamoyl phosphate
CarbamoylCarbamoyl phosphate phosphate
synthase II synthase II
Orotic AcidOrotic AcidOrotic AcidOrotic Acid
UMPUMPUDPUDP
UTPUTP
dUDPdUDP
CTPCTP
dUMPdUMPdTMPdTMP
Regulation of Pyrimidine synthesis
• Carbamoyl phosphate synthase II is the key
enzyme in this pathway:
• 1. It is stimulated by PRPP
• 2. it is inhibited by uracil nucleotides
Mitochondrial
Carabamoyl phosphate
synthase I
Cytosolic
Carabamoyl phosphate synthase
II
Function Urea synthesis Pyrimidine synthesisFunction
Site Mitochondrial of liver cells Cytosol of most tissue cells
Substrate NH3, CO2 and ATP Glutamine, CO2 and ATP
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