Purines and Pyrimidines Chemotherapy
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- What are the five nitrogenous bases? (purines and pyrimidines)
- guanine, adenine, thymine (uracil), and cytosine.
- Name the purines and pyrimidines (hint: pyrmidines have a "y" in them)
- pyrimidines: thymine, cytosine⬦ purines: adenine, guanine
- What is a nucleoside?
- nitrogenous base + (deoxy) ribose
- What is a nucleotide?
- nucleoside + phosphate
- which carbon is deoxy in deoxyribose of DNA?
- #2 carbon
- How is thymine made? (HInt:It's a modification of a pyrimidine)
- First uracil is made then a 1-carbon unit is added by folate compounds
- Which organ is the source of most nucleic acids?
- liver
- What happens to DNA from food stuff in the gut?
- The DNA is degraded to nitrogenous bases, then the bases are taken up by the cells of the gut
- What are the 2 possible outcomes for degraded purines?
-
(a) most end up as uric acid
(b) some ends up being put back into nucleic acids - How many ATP and GTP does it take to make a purine?
- 6 ATP and 1 GTP
- In purine synthesis, how many ATP does it take to get from the ribose-5-phosphate to IMP?
- 5 ATP
- Trace the major steps of purine synthesis: (review pathway for exam)
- PPP --> Ribose-5-phosphate --> PRPP (active compound) + glutamine --> (glycine + (2 each) formyl-FH4 + Glutamine + CO2 + Aspartate) -->IMP (branch to AMP or GMP --> conversion of ribo nucleotides to deoxyribo nucleotides
- what is the first commited step in purine synthesis? Which enzyme accomplishes this?
- synthesis of 5-phosphoribosylamine from PRPP + glutamine⬦ b) glutamine phosphoribosyl amidotransferase.
- What is required to convert ribose-5-phosphate into the active form, PRPP? Why is it necessary to active it?
- a) PRPP synthase + ATP⬦ b) it has high transfer potential,which will transfer a NH3 from glutamine (necessary for dividing cells) to the PRPP to make 5-phosphoribosylamine
- Which step in purine synthesis is regulated?
- synthesis of 5-phophoribosylamine (adding the amine to PRPP from glutamine)
- In purine synthesis, what is the first nucleotide formed? What is it eventually converted to?
- IMP⬦ AMP or GMP
- Detail the steps in the conversion of IMP to AMP
- IMP + GTP + Aspartate + adenylosuccinate synthase --> adenylosuccinate + adenlyosuccinate lyase --> AMP
- Again, what is the enzyme that converts IMP to Adenylosuccinate?
- Adenylosuccinate synthase
- Again, what is the enzyme that converts adenylosuccinate to AMP?
- adenylosuccinate Lyase
- In Muscle, does IMP come from R-5-P? and where does AMP in muscle come from?
- No, IMP comes from another source⬦ AMP comes from muscle activity
- What is myoadenylate deaminase deficiency?
- a deficiency in muscle that effects the purine nucleotide cycle
- Where does the nitrogen come from in the conversion of IMP to adenylosuccinate?
- BCAA --> aspartate, where N is contributed to IMP and converted to adenylosuccinate
- Where does the N end up in the rxn from adenylosuccinate to AMP (which also gives off Fumarate)?
- The nitrogen is released as ammonia
- What is the usefulness of this pathway in the muscle?
- 1. The cycle itself allows the for the disposal of nitrogen from BCAA⬦ 2. Two the fumarate product can be used in the TCA cycle to make more NADH, GTP, FADH, which will produce more energy⬦ 3. Ammonia released to balance pH during exercise and avoid an acidotic condition.
- What is the name of the enzyme that catalyses the Adenylosuccinate to AMP reaction?
- adenylosuccinate lyase
- What is the function of AMP deaminase?
- I complete the purine nucleotide cycle in muscle.
- What are the consequences of myoadenylate deaminase deficiency?
- 1. more muscle pain with less exertion⬦2. Lower ammonia:lactate levels
- What is the inheritance of myoadenylate deaminase deficiency?
- autosomal dominant
- Detail the purine nucleotide cycle in muscle.
- what are the 4 methods of purine synthesis regulation?
- 1. GDP and ADP feedback inhibition on the R-5-P to PRPP (PRPP synthetase) rxn⬦ 2. (GMP, AMP, GDP, ADP, GTP, and ATP) all contribute feedback inhibition to the PRPP to 5-Phosphoribosyl-1-amine (glutamine phosphoribosyl amidotransferase) rxn⬦ 3. GMP feedback inhibits the IMP to XMP (IMP dehydrogenase) rxn... 4. AMP feedback inhibits IMP to adenylosuccinate (adenylosuccinate synthetase) rxn.
- What are AMP and GMP?
- nucleotides
- What are guanosine and inosine?
- nucleosides
- Detail all the steps in the degradation of purine nucleotides
- AMP (AMP deaminase)--> IMP; then IMP or GMP ('5 nucleosidease) --> inosine OR guanosine (purine nucleoside phosphorylase) --> hypoxathine & guanine (xanthine oxidase) --> xanthine (xanthine oxidase) --> uric acid
- How else can inosine be derived from?
- adenosine (adenosine deaminase) --> inosine
- With respect to the degradation of purine nucleotides, which enzymes are associated with immuno deficiencies?
- a) purine nucleoside phosphorylase, which converts guanosine and inosine into guanine and hypoxanthine⬦ and b) adenosine deaminase, which convert adenosine into inosine.
- Which are more soluble, nucleosides or uric acid?
- nucleosides
- With respect to the degradation of purine nucleotides, what is the fate of GMP and IMP?
- degraded to uric acid
- Which enzyme reutilizes the free bases Guanine and Hypoxanthine?
- HRPRT
- What are guanine and hypoxanthine?
- free bases
- What is a side effect of treating leukemias with chemotherapy?
- acute tumor cell lysis syndrome: purinase is massive --> massive acidosis --> renal failure due to uric acid --> also, hypercalemia due to more K+⬦ thus ionic imbalance⬦ patient dies
- How do you profilactically treat acute tumor cell lysis?
- administer HCO3 + allopurinol
- What are the key points of pyrimidine synthesis?
- 1. Carbamoyl phosphate synthesis II (made is in the cytosol) is used here instead of CPSI found in the urea cycle⬦ 2. CPSII is regulated by UTP feedback inhibition⬦ 3. Guanine is the source of nitrogen⬦ .4 UMP is the first NT made⬦ 5. Pyrimidine bases are made first then ribose... 6. ribo must changed to deoxyribo for DNA... 6. synthesis of dTMP uses 5,10-methylene-FH4.
- How can a deficiency in the urea cycle, the ornithine transcarbamolase (OTC) cause carbamoyl phosphate levels to rise in the cytosol and affect pyrimidine synthesis.
- Carbamoyl phosphate leaks out into the cytosol
- Besides B12 deficiency, what else can cause megaloblastic anemia?
- hereditary orotic aciduria
- What is seen in hereditary orotic aciduria? And what is the cause of it?
- ineffective hematopoesis, megaloblastic anemia, and immune cell deficiency⬦ b) it is caused by a deficiency in the enzyme that produces UMPs from orotate.
- Can you treat hereditary orotic aciduria with B12?
- No⬦ it's in a different pathway⬦ this is before the dUMP is made
- What is needed of the ribose NT in order for it to become deoxy?
- It must have two phosphates
- Which enzyme removes the 2° -OH from the ribose? What cofactor is needed and what is special about? Where does the reducing power of the cofactor come from?
- a. ribonucleotide reductase⬦ b) thioredoxin (has a disulfied bond)⬦ c) NADPH
- What is the enzyme that drives the conversion of dUMP to dTMP? What is the cycle of rxns necessary to convert dUMP to dTMP?
- thymidylate synthase⬦ b) methylene-FH4 -> FH2 (NADPH + FH2 reductase) -> FH4 [serine w/ serine hydroxymethyl transferase -> glycine contributes 1-C unit] --> methylene-FH4
- How are 5-fuorouracil and methotrexate effective in fighting cancer?
- 5-fluorouracil inhibits the rxn of dUMP -> dTMP⬦ b) methotrexate inhibits FH2-reductase, which converts FH2 -> FH4
- What type of drug is 5-fluorouracil? And when is it active?
- a. prodrug, which requires bioactivation⬦ b. upon conversion to 5-F UTP (RNA metabolism) and conversion to 5-F dUMP
- Does methotrexate require bioactivation? What is significant about the structure of methotrexate?
- No⬦ it is similar to FH4
- What 4 things are hypothesized mechanisms for resistance to methotrexate?
- In general these are all due to a high mutation rate: 1. DHFR mutations have low MTX affinity (decreased binding)⬦ 2. Amplification of DHFR so inhibition by MTX is not as efficient⬦ 3. Decrease polyglutamates⬦ 4. Decreased transport of MTX into the cell
- How does 6-mercaptopuine work? What activates it?
- produces analogs of IMP and feedback inhibition of of purine synthesis⬦ b) HGPRT converts into monophospates⬦ analogs of IMP
- How is 6-mercaptopurine mitigated by the body?
- TPMT (w/SAM) convert 6MP to an inactive form.
- How would a deficient TPMT be detrimental to patients taking 6MP?
- they would convert more 6MP to the active cytotoxic form and it could be life threatening
- What is another way the body mitigates the amount of activated 6MP?
- xanthine oxidase converts 6MP to thiouric acid, which is excreted.
- How could you increase the effectiveness of 6MP?
- give allopurinol and more 6MP will be activated.