Nucleotide Metabolism - ME Flashcards
What are purines and pyrimidines?
Purines: ADENINE GUANINE
Pyrimidines: URACIL, CYTOSINE, THYMINE
What is PRPP and why is it important?
5’-Phosphoribosyl-1-pyrophosphate (PRPP) is an intermediate of major significance in
nucleotide metabolism
How are purines put together, and how is their synthesis regulated?
a. Base. The purine ring is built on a molecule of PRPP.
b. The precursors of the ring are glutamine, glycine, carbon dioxide (CO2), aspartate,
and two one-carbon fragments from the one-carbon folate pool.
How do sulfinamides and azaserine inhibit nucleotide synthesis?
Two steps in IMP synthesis are inhibited by specific drugs:
Azaserine (an analog of glutamine) blocks amide transfer from glutamine.
Sulfonamides (analogs of p-aminobenzoic acid) block the biosynthesis of folic acid in bacteria and prevent its formation. This blocks nucleotide synthesis.
What are salvage pathways?
Salvage pathways for purine nucleotides
1. Ribose phosphate transfer enzymes. There are two specific enzymes that catalyze the transfer of the ribose phosphate from PRPP to free purine bases, which are formed by the degradation of nucleotides.
A. Hypoxanthine-guanine phosphoribosyl transferase (HGPRT)
B. Adenine phosphoribosyl transferase (APRT)
C. Nucleoside kinase
How are pyrimidines assembled, and how is their synthesis regulated?
Synthesis of pyrimidine nucleotides
1. Origin of the carbons and nitrogens of the pyrimidine ring
a. Base. The pyrimidine ring, unlike the purine ring, is not built on a molecule of PRPP.
Instead, the pyrimidine ring is formed, and then it reacts with PRPP to form the
nucleotide.
b. The precursors of the ring are carbamoylphosphate and aspartate.
When are deoxynucleotides made and how are they made?
A. Formation of deoxyribonucleotides. Deoxyribonucleotides are formed by reduction of ribonucleoside diphosphates, ONLY THE DIPHOSPHATES (this helps to prevent dUTP from being formed.
B. Enzyme. The reduction of ribonucleoside diphosphates is catalyzed by ribonucleotide reductase.
What is thymidylate synthase and ribonucleotide reductase?
- dTMP is formed from dUMP in a reaction that is catalyzed by thymidylate synthase.
- The reduction of ribonucleoside diphosphates is catalyzed by ribonucleotide reductase.
• What is 5-fluorouracil and how is it related to THF?
5-Fluorouracil undergoes conversion to the nucleoside 5’-monophosphate F-UMP in cells.
F-dUMP interacts with thymidylate synthase and N5,N10-methylenetetrahydrofolate. This complex resembles the transition state formed during the conversion of dUMP to dTMP .
What methotrexate and how is it related to THF?
Methotrexate is an analog of folic acid that inhibits dihydrofolate reductase. Therefore, the regeneration of tetrahydrofolate is blocked, and synthesis of dTMP is inhibited.
Define Gout
Gout is caused by the precipitation of sodium urate crystals in the joints and kidneys. Sodium urate crystals precipitate because the serum levels of urate exceed its solubility limit.
What is allopurinol?
Allopurinol is an important drug in the treatment of gout: It blocks the production of uric acid. Also colchicine is used.
a. Allopurinol is oxidized by xanthine oxidase to oxypurinol.
b. Oxypurinol binds tightly to xanthine oxidase, inhibiting its ability to oxidize xanthine
or hypoxanthine. This is an example of suicide inhibition.
What is Lesch-Nyhan Syndrome?
Lesch-Nyhan syndrome is a hereditary X-linked recessive condition that is due to a severe or complete deficiency of HGPRT activity.
a. Increased synthesis of purines. Because there is little or no HGPRT activity in people
affected with Lesch-Nyhan syndrome, hypoxanthine and guanine are not salvaged. Also, the intracellular levels of PRPP increase, while those of IMP and GMP decrease. This leads to increased de novo synthesis of purines.
What is adenosine deaminase deficicency?
In the cells of people with ADA deficiency, deoxyadenosine and adenosine
are abundant because they are not degraded to deoxyinosine and inosine. They are, however, efficiently converted to nucleotides in white blood cells. The high levels of dATP inhibit ribonucleotide reductase, which inhibits DNA synthesis. Therefore, white blood cells cannot proliferate. ADA deficiency is associated with severe combined immunodeficiency (SCID).
