Purine and Pyrimidine Synthesis Flashcards
Which of the following is not a reactant in purine synthesis?
Tyrosine
The reactants involved in purine synthesis are:
Ribose-5-phosphate
Aspartate
Glycine
Glutamine
N-Formyl-tetrahydrofolate (formate carrier)
To convert IMP to AMP, which energy source is hydrolyzed?
GTP
The conversion of IMP to AMP is driven by GTP hydrolysis.
Mnemonic: The letters “AIG” must all be present in any conversion between AMP, IMP, and GMP:
IMP → AMP - The G is missing, and thus the energy source is GTP
IMP → GMP - The A is missing, and thus the energy source is ATP
Which of the following would not inhibit the activity of PRPP amidotransferase?
PRPP
GMP, AMP, and IMP produced by the purine synthesis pathway will inhibit the pathway as part of negative feedback. One of the main targets of the negative feedback would be PRPP amidotransferase.
PRPP is a substrate in the reaction catalyzed by PRPP amidotransferase; it does not inhibit the enzyme’s activity.
Key Takeaway:
PRPP amidotransferase converts PRPP + glutamine to IMP.
IMP, AMP, and GMP will inhibit additional purine synthesis, as part of negative feedback.
Which of the following enzymes catalyzes the conversion of IMP to GMP?
IMP dehydrogenase catalyzes the conversion of IMP to GMP.
The first step in nucleotide breakdown is losing a ________ to become a ________.
phosphate group; nucleoside
The first step in nucleotide breakdown is the conversion of nucleotides to nucleosides (e.g., AMP to adenosine), which involves the loss of the phosphate group.
The second step in nucleotide breakdown is the conversion of nucleosides to nitrogenous bases (e.g., adenosine to adenine), which involves the loss of the pentose sugar.
Key Takeaway:
Nucleotides (e.g., AMP) are composed of the nitrogenous base, a pentose sugar (deoxyribose or ribose), and a phosphate group.
Nucleotide breakdown first involves the loss of the phosphate group, then the loss of the pentose sugar (i.e., AMP → adenosine → adenine).
Which of the following enzymes is most directly responsible for producing uric acid?
Xanthine oxidase
As part of the final step of purine catabolism, xanthine oxidase converts hypoxanthine into xanthine then into uric acid. Important drugs that inhibit xanthine oxidase are allopurinol and febuxostat, which can be used to treat gout (caused by the precipitation of uric acid crystals in joints).
Mnemonic: Xanthine oxidase acts as an eXit in the purine synthesis pathway.
Which of the following cannot be directly converted into xanthine?
Adenine
Adenine cannot be directly converted to xanthine. To become xanthine, adenosine uses adenosine deaminase to convert to inosine instead of adenine. Inosine can then become hypoxanthine, then xanthine.
Which of the following enzymes will convert guanine to GMP?
HGPRT
HGPRT (hypoxanthine-guanine phosphoribosyltransferase) converts guanine to GMP, and hypoxanthine to IMP.
Mnemonic: HGPRT and APRT add phosphates to move in the opposite direction of the purine metabolism pathway. This can be remembered with PRT = Purine Rescue Team.
Which of the following is true of Lesch-Nyhan syndrome?
Inherited in an x-linked reccessive pattern
HGPRT converts hypoxanthine to IMP, and guanine to GMP, thereby reducing the amount of purine breakdown products (e.g., xanthine and uric acid).
Lesch-Nyhan syndrome is an X-linked recessive disorder caused by HGPRT deficiency. This deficiency can lead to hyperuricemia and potentially gout.
Mnemonic: Signs/symptoms of HGPRT deficiency can be remembered with HGPRT: Hyperuricemia, Gout, Pissed off (aggression, self-mutilation), Random muscle contractions, and Thinking (neurological impairment).
Key Takeaway:
Lesch-Nyhan syndrome is an X-linked recessive disorder characterized by HGPRT deficiency.
Symptoms of Lesch-Nyhan syndrome include hyperuricemia, gout, self-mutilating behaviors, dystonia, and neurological impairment.
Which of the following deficiencies causes SCID?
adenosine deaminase deficiency
SCID is a very rare and serious autosomal recessive cause of life-threatening immunodeficiency. The underlying etiology is adenosine deaminase deficiency.
Gout can result from uric acid __________ due to xanthine oxidase _________ in the purine pathway.
excess; activity
Gout results from the buildup of uric acid crystals in the joints.
Xanthine oxidase converts hypoxanthine, a purine derivative, into uric acid. When there is increased dietary intake of purines, or impaired purine salvage from uric acid (i.e., Lesch-Nyhan syndrome), there is hyperuricemia which increases the risk of gout.
Hyperuricemia and gout can be treated with a xanthine oxidase inhibitor (e.g., allopurinol), which will decrease uric acid production.
Key Takeaway:
Xanthine oxidase converts hypoxanthine into uric acid.
Excessive levels of uric acid can lead to gout.
________ and ________ are treatment options for gout.
Allopurinol and febuxostat
Allopurinol and febuxostat are both xanthine oxidase inhibitors that are used to treat hyperuricemia and gout.
6-mercaptopurine and azathioprine are both PRPP amidotransferase inhibitors; they impair purine synthesis and therefore DNA production, and are effective in the treatment of specific types of leukemia and autoimmune disease.
Key Takeaway:
Xanthine oxidase inhibitors (allopurinol, febuxostat) treat gout by reducing uric acid production.
Which of the following enzymes metabolizes Azathioprine and 6-mercaptopurine?
xanthine oxidase
Both azathioprine and 6-mercaptopurine (6-MP) are PRPP amidotransferase inhibitors activated by HGPRT. Thus, azathioprine and 6-MP may have reduced drug effects among patients with HGPRT deficiency (i.e., Lesch-Nyhan syndrome).
Azathioprine and 6-MP are both metabolized by xanthine oxidase (XO); they are thus contraindicated with XO inhibitors as concurrent use would result in excessive drug activity and potential toxicity.
Key Takeaway:
Azathioprine and 6-mercaptopurine are both metabolized by xanthine oxidase.
Concurrent use of azathioprine or 6-mercaptopurine with a xanthine oxidase inhibitor (e.g., allopurinol) is contraindicated.
Which of the following enzymes do Mycophenolate mofetil and ribavirin inhibit?
IMP dehydrogenase
Mycophenolate mofetil is an immunosuppressant and ribavirin is an antiviral that treats hepatitis C. Both drugs are IMP dehydrogenase inhibitors.
CPS I works in the ________, while CPS II works in the ________.
Mitochondria; cytosol
Carbamoyl phosphate synthetase II (CPS II) is an enzyme involved in the pyrimidine synthesis pathway; it works in the cytosol. Carbamoyl phosphate synthetase I (CPS I) is not involved in the pyrimidine synthesis pathway; rather, it is a part of the urea cycle and operates in the mitochondria.
Mnemonic: CPS II works in the cy-TWO-sol.
Which of the following is not a reactant of pyrimidine synthesis?
Threonine
The main reactants involved in pyrimidine synthesis are:
Ribose-5-phosphate
Aspartate
Glutamine
Which of the following is not a pyrimidine base?
Adenine
Pyrimidines include:
Uracil
Cytosine
Thymine
Mnemonic: The purines and pyrimidines can be remembered with the phrases “Pure AG (silver)” and “CUTie Py”: purine = AG, CUT = pyrimidine.
Which enzymes catalyzes the conversion of UDP to dUDP?
ribonucleotide reductase
Which enzyme in the pyrimidine synthesis pathway requires the modified form of tetrahydrofolate (THF) as a cofactor?
Thymidylate synthase
Thymidylate synthase catalyzes the conversion of dUMP to dTMP. To accomplish this, the cofactor 5,10-methylenetetrahydrofolate is required.
Which of the following is the least likely symptom of orotic aciduria?
Orotic aciduria is a disease that typically presents in infancy due to UMP synthase deficiency. Typical symptoms include a lack of oral intake resulting in failure to thrive, orange crystals (orotic acid) in diapers, and megaloblastic anemia (due to impaired DNA replication).
A coma would be extremely uncommon as a presenting symptom.
Key Takeaway:
Symptoms of orotic aciduria: failure to thrive, megaloblastic anemia, and orange crystals in diaper.
Which of the following is not a dihydrofolate reductase inhibitor?
Leucovorin
Pyrimethamine, methotrexate, and trimethoprim are all dihydrofolate reductase (DHF reductase) inhibitors.
Leucovorin is a folic acid metabolite administered to bypass the dihydrofolate reductase step. It is often used to decrease methotrexate and pyrimethamine toxicity.
Mnemonic: Inhibitors of DHF reductase can be remembered with the phrase “don’t METH (mess) with the DHF inhibitors”: pyriMETHamine, METHotrexate, triMETHoprim.
Key Takeaway:
Dihydrofolate reductase inhibitors include methotrexate (immunosuppressant, chemotherapy), trimethoprim (antibiotic), and pyrimethamine (antiprotozoal).
Which of the following is a dihydrofolate reductase inhibitor typically used as an antibiotic?
Trimethoprim
Trimethoprim binds to and inhibits dihydrofolate reductase in bacteria only, making it an effective antibiotic.
Which of the following drugs will directly inhibit thymidylate synthase?
5-fluorouracil (5-FU) and capecitabine (a pro-drug of 5-FU)
5-fluorouracil (5-FU) and capecitabine (a pro-drug of 5-FU) are thymidylate synthase inhibitors. This will inhibit synthesis of dTMP, which is required for DNA replication. As a result, 5-FU and capecitabine are effective chemotherapeutic agents.
Key Takeaway:
5-fluorouracil (5-FU) and capecitabine are chemotherapeutic agents that inhibit thymidylate synthase (and therefore DNA replication).
Which of the following is a ribonucleotide reductase inhibitor?
Hydroxyurea
Hydroxyurea is a ribonucleotide reductase inhibitor used to treat sickle cell anemia and as an immunosuppressant.
Hydroxyurea increases fetal hemoglobin (HbF) production, decreasing reliance on adult hemoglobin (which possesses the defective beta chain in sickle cell anemia).
A 2-year-old boy comes to the office because of developmental delay. His mother states that he has yet to learn to walk and has a 10-word vocabulary. He appears aggressive and agitated. He is constantly biting his lips. A basic metabolic panel shows no abnormalities, and a 24 hour urinalysis shows elevated levels of uric acid. Which of the following is the most likely etiology of this patient’s condition?
Hypoxanthine-guanine phosphoribosyltransferase deficiency
Lesch-Nyhan syndrome is due to the absence of hypoxanthine guanine phosphoribosyltransferase, leading to increased uric acid levels from increased purine synthesis and breakdown.
A mnemonic for Lesch-Nyhan syndrome is HGPRT:
Hyperuricemia
Gout
Pissed off (aggression, self-mutilation)
Retardation (mental retardation)
Tone (abnormal muscle tone)
