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28 Cards in this Set
- Front
- Back
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What form of nucleotides is the most stable in the cell?
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The triphosphate form
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Describe the basic mechanism of purine synthesis
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1-glutamine and PRPP form IMP, with THF adding 1 carbon fragments
2-IMP can then form GMP or AMP 3-Monophosphate forms are then kinased to triphosphate forms |
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Which products inhibit which enzymes in purine biosynthesis?
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GMP and AMP feedback inhibit the 1st enzyme in the pathway.
-IMP also feedback inhibits the 1st enzyme in the pathway *1st enzyme=an aminotransferase |
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What are the 2 ways of making nucleotides?
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1-de novo synthesis. Can make nucleotides from scratch
2-uptake pathway-precursor must be present. Patients w/impaired pathway are given a supplement that can act as a precursor in this pathway. |
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What is Lesch-Nyhan syndrome?
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-Deficiency of HGPRT
-leads to buildup of uric acid all over the body "juvenile gout" -x-linked recessive -allopurinol somewhat effective as a treatment |
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Rank the following molecules in terms of solubility:
hypoxanthine, xanthine, uric acid |
uric acid < xanthine < hypoxanthine
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What is the main product of nucleic acid metabolism?
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Uric acid
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What are 2 drugs that are hypoxanthine analogs?
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6-mercaptopurine
Allopurinol -inhibit steps in purine synthesis and catabolism -used clinically to treat acute lymphocytic leukemia |
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Why is a side effect of treatment w/6-mercaptopurine crystalluria?
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B/c it blocks the purine synthesis pathway and results in a buildup of uric acid
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What enzyme is inhibited by allopurinol?
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Xanthine Oxidase
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What enzyme does 6-mercaptopurine inhibit?
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Xanthine oxidase
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After allopurinol administration, what are the principal purine metabolites in the urine?
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Xanthine and Hypoxanthine.
-very little uric acid |
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Why is allopurinol used in the treatment of gout?
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Gout=deposition of uric acid in the joints.
Allopurinol reduces uric acid formation. |
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Why is there a potentially fatal interaction b/w allopurinol and 6-mercaptopurine?
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Tumor cells are apoptosing and degrading their DNA and RNA. There will be a very high [] of uric acid in the kidney tubules. Since uric acid is very insoluble, it will not be excreted and will cause problems.
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6-mercaptopurine is inactive as an inhibitor; it has to be metabolized to the active inhibitory form. What enzymes will use 6-mercaptopurine as a substrate? What are the products of the rxns?
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will be acted on the same way that hypoxanthine would be. 6-MP+PRPP -> Thio-IMP +Pi
-active form of the drug is Thio-IMP |
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What is the mechanism by which 6-mercaptopurine exerts its inhibitory effect?
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-metabolized to active thio-IMP form.
-then, b/c molecule thinks it's IMP it will block the last enzyme in the synthesis pathway |
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A relapse after clinical remission of ALL can occur leading to tumor cells that are resistant to 6-mercaptopurine action. What is the mechanism of this resistance?
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Cancer cells inactivate the HPRTase. Can no longer take up 6-MP. Cells that don't have HPRTase are viable.
-B/c there are multiple mechanisms to make NTPs you can KO one of the pathways and still be fine |
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Describe the synthetic process of pyrimidines.
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1. Carbamyl phosphate and aspartate are combined, along w/PRPP to form OMP.
2. OMP releases CO2 and becomes UMP. 3. UMP is phosphorylated to UTP. 4. UTP is converted to CTP. |
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What is hereditary orotic aciduria?
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=autosomal rec. disorder due to decreased orotidine 5' phosphate decarboxylase
-biosynthetic pathway is blocked, but patients can take uracil supplements to use their uptake pathway |
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Why must nucleotides be reduced?
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to be used in DNA instead of RNA
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Describe the reaction of nucleotide reduction.
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NTP->NDP->dNDP->dNTP.
-catalyzed by RR (ribonucleoside diphosphate reductase) -uses NADPH |
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What does the cell do with dUTP?
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-It is converted to dUMP by deoxyuridine triphosphatase
-must be converted as soon as it is made b/c DNA polymerase loves dUTP |
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What is hydrourea?
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=potent inhibitor of RR
-Powerful inhibitor of DNA synthesis -does NOT inhibit RNA synthesis b/c all substrates needed for RNA are already present |
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What is hydrourea used for?
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-treatment of some leukemias in combo w/other drugs
-Resistance can occur by increased RR activity via gene amplification |
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Describe the rxn to make TMP.
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dUMP is converted to TMP by thymidine synthase.
-req that THF.C1 is converted to DHF -TMP is then kinased to TTP and all building blocks for DNA synthesis are present |
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What is 5'-Fluorodeoxyuridine?
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=potent inhibitor of TS
-must be kinased to its active form -covalently binds to TS which inhibits DNA synthesis -used in combination w/other drugs for breast cancer treatment |
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What is 5'-Fluorouracil?
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=Analog of uracil
-metabolized in 2 ways: 1-rec as uracil by uridine phosphorylase and converted to a form where it is rec by thymidine phosphorylase. Then kinased, and incorporated into RNA. 2-can be converted to the monophosphate by deoxyuridine triphosphatase |
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Drug resistance to 5'-fluorouracil would be expected to occur by mutation in the gene for:
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Thymidylate synthase
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