Purine Metabolism Flashcards
Hypoxathine
Base found in inosine monophosphate, and intermediate in purine synthesis and degradation
Xanthine
Found in xanthosine MP, an intermediate in purine synthesis
Nucleoside
Nitrogenous base+pentose sugar
Nucleotide
Nucleoside+phosphate groups
In humans, where are the enzymes necessary for de novo purine synthesis found?
The cytoplasm
De novo Purine Synthesis
Adding carbon and nitrogen to a preformed ribose-5-phosphate
Where do you get the ribose for purine synthesis?
The HMP pathway gives you the ribose-5-phosphate
What amino acids donate the nitrogens for purine synthesis?
Glycine, glutamine, and aspartate.
What donates the carbon needed for purine synthesis?
Tetrahydrofolate (THF)
PRPP
5-phosphoribosyl-1-pyrophosphate. Involved in the synthesis of purines, pyrimidines, and their degradation.
What is the rate limiting/committed step for de novo purine synthesis?
PRPP being helping to create 5’-phosphoribosylamine.
What controls the first step in de novo purine synthesis?
Concentrations of glutamine and PRPP
What is the first nucleotide made in de novo purine synthesis?
IMP
Why do sulfa drugs not interfere with human purine synthesis?
Humans can’t synthesize folic acid. (Sulfa drugs affect the synthesis of folic acid in bacteria). They are competitive inhibitors.
How does methotrexate work?
Inhibit the synthesis of THF, which slows DNA replication (not enough purines available). Helps treat cancer. Competitively inhibits the enzyme dihydrofolate reductase. It is a structural analog of folic acid.
Trimethoprim
Inhibits THF synthesis via dihydrofolate reductase in prokaryotes only
Megablastic Anemias
First sign of a folate deficiency. Hemoglobin levels are low and bone marrow shows abnormally high number of megaloblastic cells.
Sulfonamides
PABA analogues that inhibit the synthesis of folate in bacteria.
What do you need to synthesize AMP from IMP?
GTP and adenylosuccinate synthetase
What do you need to convert IMP to GMP?
ATP and GMP synthetase
Mycophenolic Acid
Inhibits inosine monophosphate dehydrogenase. Anti-rejection drug as it stops B and T cells from proliferating.
Purine salvage: What two enzymes are involved?
HGPRT and APRT
Lesch-Nyhan Syndrome and the salvage pathway
LN is caused by a deficiency of HGPRT, meaning it can’t salvage hypoxanthine or guanine, leading to an increase of uric acid.
What was HGPRT do?
Converts hypoxanthine to IMP and guanine to GMP
What does APRT do?
Convert adenine to AMP
what is characteristic of Lesch-Nyhan in babies?
Orange crystals in diaper due to excess uric acid.
What are purines degraded to?
Uric acid
What happens to ribose and deoxyribose during purine degradation?
They are absorbed into the intestinal mucosa and returned to the circulation
ADA and SCIDS
Adenosine deaminase deficiency. Without ADA you cannot turn adenosine into inosine, leading to a buildup of dATP which stops DNA synthesis in T and B cells.
PNP Deficiency
Purine nucleoside phosphorylase deficiency causes impairment of T-cell function. Decrease uric acid production and increase in purine production.
Colchicine
Microtubule inhibitor that inhibits migration of white cells to joins where uric acid crystals are phagocytized.
Allopurinol
Treatment of gout. Non-competitive inhibitor of xanthine oxidase. Causes excretion of hypoxanthine and xanthine instead of urate.
Where do you get the carbons for pyrimidine synthesis?
Aspartic acid
Where do you get the nitrogen for pyrimidine synthesis?
Glutamine
What is the rate limiting step for pyrimidine synthesis?
Synthesis of carbamoyl phosphate from glutamine and CO2 CPS II
Carbamoyl Phosphate Synthetase II
CPS II. Involved in pyrimidine synthesis. Used glutamine as the source of nitrogen. Occurs in the cytoplasm of all nucleated cells. Inhibited by UDP and UTP.
Orotic Aciduria
Causes abnormal growth, megaloblastic anemia, and excretion of large amounts of orotic acid in urine. Caused by a deficiency in orotate phosphoribosyltransferase and OMP.
Synthesis of CTP from UTP
UMP–>UDP–>UTP (by kinases)—>CTP by CTP synthase
Ribonuelctoide Diphosphate Reductase
Enzyme that catalyzes the reaction of ribonuelceotides to deoxyribonucleotides
What inhibits ribonuelceotide Diphosphate reductase?
dATP and hydroxyurea
Synthesis of thymidine MP
Thymidylate synthase uses THF to produce dTMP from dUMP
5-Fluorouracil
Uracil analog. Anti-cancer drug that blocks dTMP production.
