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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?
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?
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?
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?
What are guanosine and inosine?
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?
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?
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.

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