Synthetic inhibitors of purine synthesis, Salvage pathway for purines, Clinical application Salvage pathway for purines (Lesch-Nyhan syndrome),Synthesis and Regulation of Deoxyribonucleotides , CPS 1 vs CPS 2
Last lecture we discussed the De novo pathway of purines and today we will continue the Salvage pathway and pyrimidine
synthesis before that we will discuss Synthetic inhibitors of purine synthesis.
Synthetic inhibitors of purine synthesis
Synthetic inhibitors of purine synthesis (the sulfonamides1), are designed to inhibit the growth of
rapidly dividing microorganisms without interfering with human cell functions. (like antibiotics)
Other purine synthesis inhibitors, such as structural analogs of folic acid (such as, methotrexate2),
are used as drugs that control the spread of cancer by interfering with the synthesis of nucleotides
and, therefore, of DNA and RNA.
Remember that we need N10-Formyl-tetrahydrofolate (folic acid) in 2 reactions in the De novo
pathway of purines so if we interfere these reactions, purine synthesis will stop thus inhibit the
growth of rapidly dividing microorganisms.
Inhibitors of human purine synthesis are extremely toxic to tissues, especially to developing
structures such as in a fetus, or to cell types that normally replicate rapidly, including those of
bone marrow, skin, GI tract, immune system, or hair follicles.
Thus, anticancer drugs result in adverse effects, including anemia, scaly skin, GI tract disturbance,
immunodeficiencies, and hair loss.
Salvage pathway for purines
Salvage pathway for purines is purine synthesis from:
1. The normal turnover of cellular nucleic acids
2. Diet purines that are not degraded (small amounts)
Conversion of purine bases to nucleotides:
Here we have Guanine and by the action of HGPRT enzyme,
it takes the ribose 5-phosphate group from PRPP and
produce GMP, same thing applies to IMP but it uses
Hypoxanthine as well as AMP but the enzyme is APRT as
well as the AA is Adenine.
❖ Both APRT and HGPRT use PRPP as the source of the ribose 5-phosphate group.
❖ PP is released and hydrolyzed by pyrophosphatase making these reactions irreversible.
❖ Adenosine is the only purine nucleoside to be salvaged. It is phosphorylated to AMP by
adenosine kinase.
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, Clinical application Salvage pathway for purines-Lesch-Nyhan syndrome
A rare, X-linked, recessive disorder associated with HGPRT deficiency.
Notice the AMP salvage pathway isn’t affected since it has its own enzyme,
so AMP level is higher than GMP which will activate degradation of AMP
Inability to salvage hypoxanthine or guanine resulting in high amounts of
uric acid (the end product of purine degradation)
Increased PRPP levels and decreased IMP and GMP levels.
The committed step in purine synthesis has excess substrate and decreased
inhibitors available, and de novo purine synthesis is increased.
When de novo purine synthesis increase this we result in both increasing
AMP and GMP. The decreased purine reutilization and increased purine
synthesis results in increased degradation of purines and the production of
large amounts of uric acid (hyperuricemia)
Lesch-Nyhan syndrome
Hyperuricemia results in:
1. Uric acid stones in the kidneys (urolithiasis)
2. The deposition of urate crystals in the joints (gouty arthritis) and
soft tissues.
The syndrome is characterized by:
Motor dysfunction
Cognitive deficits
Behavioral disturbances that include self-mutilation (biting of lips
and fingers).
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