Purine Synthesus And Salvage Psthway Flashcards
What are the functions of nucleotides?
- ribonucleotides (contain ribose) building blocks of RNA
- Deoxyribonucletides (contain deoxyribose) building blocks of DNA
- ATP is ‘energy currency ‘ in cells
- components of coenzymes like FAD, NAD, NADP and coenzyme A
- Nucleotudes like cAMP and cGMP are intracellular second messengers
Do the math on how purine and pyrimidine nucleosides are made
N-containing base+ ribose= nucleoside
B-N-glycosidic linkage between base and ribose
N-containing base + ribose+ phosphate= Nucleotide
Purine + ribose= purine nucleoside
Pyrimidine + ribose= pyrimidine nucleoside
What May inhibit purine and pyrimidine biosynthesis ?
Anti cancer or antimicrobial agents
What are the 3 components to purine metabolism?
Purine de-novo synthesis
Salvage/ recycling pathway of purines
Purine degradation
Give an overview of purine de novosynthesis
Precursors
- amino acids(glutamine, Aspartate, glycine)
- formylated tetrahydrofolate (THF)
Each donor donates specific C or N atom
C and N atoms added to ribose phosphate (numbers on purine in diagram is order in which added)
- Energy ( about 6 ATP/ purine synthesis )
- Ribose phosphate from pentose phosphate pathway (HMP shunt)
- Remenber: 2 C-atoms of purine from formyl tetrahydrofolate (folic acid)
Give an k review of purine Nucleotide synthesis
- IMP formation
- PRPP synthetase: regulated enzymes
- Phosphoribosylamidotrabsferase: committed step (regulated step)- N donated by glutamine
- Inosine monophosphate(IMP) (Hypoxanthine ribose phosphate): parent purine Nucleotide -forms AMP and GMP
Explain the conversion of IMP to AMP and GMP
- formation of AMP from IMP requires GTP
- Formation of GMP from IMP requires ATP
- Ensures balance if cellular ATP and GTP concentration
-Mycophenoliccacid inhibits conversion of IMP to
GMP
-inhibits IMP dehydrogenase
-used following transplantation to prevent rejection
-Ribonucleotide reductase forms deoxyribonucletides (dADP/dGDP)
Explain the regulation of purine biosynthesis
- PRPP synthetase and Phosphoribosylamidotrabsferase
- PRPP also used fir pyrimidine biosynthesis and salvage pathway
- Feedback/product inhibition: purine nucleotides inhibit PRPP synthetase and the phosphoribosylamidotrabsferase
- PRPP is feedforward activator of phosphoaminotransferase
- High PRPP activates enzyme to increase purine nuckeotide synthesis
What are the inhibitors of bacterial purine Nucleotide synthesis
In bacteria, the folic acid synthesized from PABA (p-amino benzoic acid)
- PABA analogs (sulfonamides; sulfa drugs) inh8bjt bacterial folate synthesis
- Trimethoprim inhibits bacterial dihydrofolate reductase
- Sulfonamide-trimethoprim: antibacterial agent
- Reduce tetrahydrofolate and purine Nucleotide synthesis
- Humans cannot synthesize folic acid (folic acid obtained in diet), sulfonamide-trimethoprim combination doesn’t affect purine synthesis in humans
Describe inhibition in eukaryotic purine synthesis
- humans obtain folate (vitamin B9) from diet
- methotrexate (folate analog): anti cancer agent
- competitive inhibitor of dihydrofolate reductase
- reduces tetrahydrofolate for purine synthesis and slows down for purine synthesis and slows down DNA replication (cell division) in mammalian cells
- Side effects on all rapidly dividing cell: anemia, GI disturbance, scaly skin, hair loss, immune deficiency
What are thiopurine and azathiopurind?
Thiopurine (mercaptopurine) and azathiopurine metabolized to intermediates that inhibit denovo purine synthesis
-Anticancer agents (leukemia); and immunosuppressive agents
What. Is the consequence of folate (vitamin B9) deficiency?
- formyl THF or methylene THF- used fir purine Nucleotide synthesis and fir thymidine synthesis (dTMP synthesis)
- essential fir DNA synthesis during S phase of the cell cycle
- critical for rapidly dividing cells
- Folate deficiency May macrocytic anemia and decreased cell division
- pre and perinatal folate deficiency in pregnancy
- higher risk of neural. Tube defects in fetus
Explain the conversion of ribonuckeotides to deixyrubonucleotides
- Ribonucleitude reductase
- Converts purine abs pyrimidine ribonucleotides to Deoxy ribonucleotides
- Ribose sugar converted to deoxyribose
- Requires: Thioredoxin(protein coenzyme ) and NADPH+ + H+
- Regulated to ensure equivalent concentrations of dATP, dGTP, dCTP and dUTP during S phase if cell cycle
- Inhibuted by high concentrations if dATP(refer to SCID)
- Hydroxyurea (anticancer afent): inhibits ribonucleotides reductase
Give an Overview the salvage/ recycling pathway of purines
-purines bases recycled (reused) by salavage pathway
- Free purine bases converted to purine nucleotides
- free bases derived from cellular DNA lysus (following cell death) and RNA (cell turnover)
- About 80% of bases are reused
- Uses less energy than Denovo synthesis pathway
- HGPRT and APRT are enzymes of purine salvage pathway
- Salvage pathway is important for brain
- PRPP donates ribose-phosphate to form AMP
What is the importance of HGPRT as an enzyme kf the salvage pathway
- complete enzyme deficiency causes Lisch-nyhan syndrome
- Purine base NOT reused—> increased purine degradation —> uric acid
- High PRPP concentration stimulates denovo synthesis of purine nucleotides
- Hyperurecemia, behavioral disturbances (self mutilation )
