Metabolism 11: Purine and Pyrimidine Nucleotide Metabolism Flashcards
Which bases are purines?
Adenine
Guanine
Which bases are pyrimidines?
Cytosine
Urasil
Thymine
Where do the atoms in the purine ring structure come from?
3 amino acids (glycine, glutamine, aspartate)
CO2
FH4 (tetrahydrofolate) derivative
What is the precursor for purine biosynthesis and where does it come from?
Ribose-5-phosphate from the pentose phosphate pathway
How is the purine ring built?
Built up atom by atom on top of ribose
What is the first step in purine biosynthesis
Activation of R5P to get PRPP (Pyrophosphate from ATP)
What is the second step in purine biosynthesis?
Formation of 5-phosphoribosylamine using the amino group of glutamine
What enzyme catalyzes the second step in purine biosynthesis
Glutamine PRPP Amidotransferase
What is the committed and major regulated step in purine biosynthesis
The 2nd step using glutamine PRPP amidotransferase to generate 5-phosphoribosylamine
What is eventually formed in step 11 of the purine biosynthesis pathway?
Nucleotide IMP (inosinic acid) that is the precursor for both AMP and GMP
Once we create AMP and GMP via purine biosynthesis, how do we get the di and tri phosphate derivatives?
Through phosphorylation -> ADP,GDP -> ATP,GTP
How is the enzyme glutamine PRPP amidotransferase regulated?
+: PRPP (feed forward activation)
-: IMP, GMP, AMP (Negative feedback inhib)
How are normal tissues and tumors different with regards to purine biosynthesis?
Tumors are highly dependent on purine biosynthesis to produce purine nucleotides for DNA/RNA synthesis
Normal tissue are less dependent on de novo synthesis and prefer recycling existing purine bases by a salvage pathway
What is the idea of a drug inhibiting purine biosynthesis?
It will be more toxic to tumor cells than most normal cells due to their dependent on purine biosynthesis for DNA/RNA syntehsis
What is 6-mercaptopurine?
Antitumor agent that is converted to a nucleotide and then inhibits enzymes in the purine biosynthetic pathway.
Used to treat acute lymphocytic leukemia
What are the sources of the atoms in the pyrimidine ring structure?
Glutamine, aspartate, CO2
What is the regulated step in pyrimidine biosynthesis?
Carbamoyl Phosphate Synthetase II
How is the pyrimidine nucleotide formed?
Pyrimidine ring structure formed first and then added to ribose-5-phosphate
What is the precursor for synthesis of all the other pyrimidine nucleotides?
UMP
What is Leflunomide?
Immunosuppressive drug for treating rheumatoid arthritis.
Blocks pyrimidine biosynthesis by inhibiting dihydroorotate dehydrogenase
How is dTMP synthesized?
From dUMP and N5N10 methylene tetrahydrofolate using the enzyme thymidylate synthase
What enzyme catalyzes the conversion of dUMP to dTMP?
Thymidylate Synthase
What is a byproduct of dTMP synthesis that is toxic?
dihydrofolate: it is toxic and must be converted back to tetrahydrofolate by dihydrofolate reductase for use again in purine/pyrimidine biosynthesis
What enzyme converts dihydrofolate back to tetrahydrofolate?
dihydrofolate reductase
What is methotrexate?
Antitumor drug that acts as a Competitive inhibitor of dihydrofolate reductase that causes a buildup of the toxic byproduct dihydrofolate leading to tetrahydrofolate deficiency in cells
What is 5-fluorouracil?
Antitumor drug that is converted to f-dUMP and acts as a pseudosubstrate to covalently bind and inhibit thymidylate synthase
What does ribonucleotide reductase do?
Acts on ADP, GDP, CDP, or UDP to form the deoxyribonucleoside forms (dADP, dGDP, dCDP, dUDP) by replacing 2’ OH group with H
What cofactor is needed for ribonucleotide reductase
Thioredoxin
What phase of the cell cycle does DNA synthesis occur?
S Phase
When do concentrations of the deoxyribonucleotides rise?
During S Phase
When do the enzymes of purine/pyrimidine biosynthesis increase?
Late G1/Early S1 phases
Which enzymes increase in levels during late G1 Early S phase and correlate with tumor growth rate?
Ribonucleotide Reductase
Thymidilate Synthase
What degrades DNA/RNA from diet and mRNA in cells to bases?
Nucleases ->nucleotidases ->nucleosidephosphorylases -> Bases (uracil, thymine, guanine, hypoxanthine)
What happens to most free purine bases produced in cell from the degradation of mRNA?
90% are reused rather than degraded
What is the salvage pathway?
pathway used to reutilize bases instead of having them degraded
What causes Lesch-Nyhan Syndrome?
Deficiency in HGPRTase leading to neurological problems and gout
What does the HGPRTase enzyme do?
Convert hypoxanthine and guanine to IMP and GMP using PRPP (Activated form of R5P)
10% of purine base formed from mRNA catabolism forms what?
Uric Acid
What is uric acid?
Final product of purine degradation that is excreted
What does xanthine oxidase do?
Convert hypoxanthine and xanthine to uric acid
What is the predominant form of uric acid in blood pH?
Urate
What is the predominant form of uric acid in urine pH?
Uric Acid
Which is more soluble urate or uric acid?
Urate
How does gout occur?
Due to overproduction or underexcretion of uric acid
What is hyperuricemia?
Elevated urate in blood. Can lead to deposition of sodium urate crystals in joints and cause painful inflammatory response
What is hyperuricosuria?
Elevated uric acid in urine. Can lead to deposition of uric acid stones in kidney
What is allopurinol and what does it treat?
Treats gout by inhibiting xanthine oxidase
Inhibits formation of xanthing from hypoxanthine and uric acid from xanthine This reduces urate and uric acid levels in blood and urin
