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Biochemistry II PHR 375

Nucleotides Metabolism
by

Hassan Mokhamer
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
PRPP Synthase
Ribose-5-Phosphate 5-Phosphoribosyl -1-pyrophosphate

ATP AMP
2. Synthesis of 5’_ phosphoribosylamine
H2O PPi

5-Phosphoribosyl -1-pyrophosphate 5-Phosphoribosylamine

Glutamine Glutamate
• 3. Synthesis of Inosine 5’- Monophosphate (IMP):
O

C N
HN C
Glycine 4
CH
Folic Acid HC C 5

Glutamine N
5-Phosphoribosylamine N
Aspartate 2-
O3P O CH2 O
CO2 H H
H H
OH OH

Inosine Monophosphate (IMP)

• 4. Conversion of IMP to either AMP or GMP

Adenyl succinate AMP ADP ATP

IMP
Xanthosine GMP GDP GTP
Monophosphate
Inhibitors of purines synthesis

Methotrexate
That competitively inhibits the reduction of
dihdrofolate 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. Deoxyribonucleoside diphosphate
Ribonucleoside diphosphate

Ribonucleotide Reductase

Thioredoxin ( Reduced) Thioredoxin ( Oxidized)

Thioredoxin Reductase

NADP+ NADPH + H+
Catabolism of purine nucleotides

• A. Uric acid is the end product of purine


catabolism in man which is excreted in urine.
• B. Net excretion of total uric acid in normal
human is about 500 mg/day.
• C. Normal human plasma uric acid average 2-6
mg/dl in female and 3 – 7 mg/dl.
• D. Uric acid is oxidized into Allantion by the
action of Uricase enzyme which is lacked in
human.
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).

• 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.
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 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.
• 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 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
• CO2 + Glutamine + ATP Carbamoyl phosphate
Carbamoyl phosphate
synthase II

Orotic Acid

CTP UTP

UDP UMP

dTMP dUMP dUDP


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 Cytosolic
Carabamoyl phosphate Carabamoyl phosphate synthase
synthase I II
Function Urea synthesis Pyrimidine synthesis

Site Mitochondrial of liver cells Cytosol of most tissue cells

Substrate NH3, CO2 and ATP Glutamine, CO2 and ATP