Purine/Pyrimidines Flashcards
What is 6-mercaptopurine used for?
Function
Treat some forms of leukemia.
Fx: inhibition of the purine biosynthetic pathway which is needed for formation of nucleotides and thus production of DNA/RNA.
Slows proliferation
A reduced dose must be given to homozygous genetic variants or they will overdose
PRPP Synthetase function
Synthesis of PRPP for purine and pyrimidine nucleotide synthesis
Phosphoribosyl amidotransferase
Regulated/committed enzyme of purine nucleotide synthesis.
Activators: PRPP
Inhibitors: ATP and GTP
Xanthine Oxidase
Enzyme of purine degradation. Forms uric acid and xanthine from hypoxanthine
Inhibitor: Allopurinol
HGPRT
Hypoxanthine Guanine Phosphoribosyl Transferase
Enzyme of Purine salvage pathway.
Deficiency causes: Lesch Nyhan Syndrome-self mutilation, hyperuricemia
Salvage pathway important for brain as it uses less energy
CPS-II
Regulated enzyme of pyrmidine biosynthesis
Inhibited by: UTP
Activated by: PRPP, cytosolic enzymes
UMP Synthase (OPRT and OMP decarboxylase)
Enzyme of pyrmidine biosynthesis
Deficiency causes Orotic aciduria
Ribonucleotide Reductase
Converts ribonucleotides to deoxyribonucleotides.
Inhibitor: Hydroxyurea
Requires Thioredoxin (protein coenzyme), NADPH+, H+
Regulated to ensure equivalent concentrations of dATP, dGTP, dCTP, and dUTP during S phase of cell cycle
Adenosine Deaminase
ADA
Converts adenosine to inosine in purine degradation pathway.
Deficiency results in SCID (T and B cell deficiency)
Purine nucleoside phosphylase (PNP)
Converts purine nucleoside to free purine base in purine degradation pathway.
Deficiency results in T-cell immunodeficiency
How many carbon atoms come from tetrahydrofolate (folic acid) in purine nucleotide denovo synthesis?
2 C
What are the precursors to purine de novo synthesis?
Amino Acids:
1. Glutamine
2. Aspartate
3. Glycine
Formyl Tetrahydrofolate (cofactor)
and CO2
What is the first regulated step?
Purine de novo synthesis
Ribose phosphate to Phosphoriboysl pyrophosphate (PRPP) by
PRPP synthetase
What is the committed step in denovo purine synthesis?
PRPP to Phosphoribosylamine by
Phosphoribosylamidotransferase
What inhibits conversion of IMP to GMP?
Mycophenolic Acid by inhibiting IMP dehydrogenase
Used post transplantation to prevent rejection
How do humans obtain folate (Vit B9)
From our diet
It is essential for DNA synthesis during S phase and critical for rapidly dividing cells
IF deficient: Macrocytic anemia and decreased cell division.
Higher risk of neural tube defects
What is uric acid and why is it important to know?
End product of purine breakdown
Has a low solubility which then can cause deposits (tophi) that can cause gouty arthritis, renal stones…
Blood uric levels are close to saturation limits
Hyperuricemia two causes
- Underexcretion-most common. Due to males/obesity/beer/meat, renal disease, lactic acidosis, inherited disorders (Von Gierke disease, Hereditary Fructose Intolerance)
- Overproduction: Overactive enzyme (PRPP synthetase gene mutation where enzyme actually works better). HGPRT Deficinecy- Lesch Nyhan syndrome-less recycling which causes increase in PRPP. Lastly, chemotherapy patients
Gout
Causes/Treatment
Hyperuricemia: underexcretion leads to deposition of monosodium urate crystals=acute athritic joint pain
Tx: allopurinol inhibits xanthine oxidase. Increased levels of hypoxanthine and xanthine which are more soluble and can be excreted in urine
Adenosine Deaminase Deficiency (ADA)
Autosomal recessive cause of SCID.
If untreated kids die before age 2 d/t overwhelming infection
Purine Nucleoside Phosphorylase Deficiency (PNP)
Autosomal recessive
T-cell deficiency
Therapy: Erythrocyte transfusion Hematopoietic stem cell transplant
When are primidine rings synthesized?
Pyrmidine rings are initially synthesized before attachment to the ribose-5-phosphate (donated by PRPP)
No folic acid is required to make the ring however later in the synthesis thmidine requires one-carbon group donation from methylenetetrahydrofolate (THF)
What is the regulation of Pyrmidine Synthesis?
CPS II domain-activated by PRPP and ATP
Inhibited by: UTP
CPS I is in Urea Cycle
What is the regulated domain of bacterial prymidine nucleotide synthesis?
Aspartate transcarbamoylase
How do you differentiate between orotic aciduria d/t to Urea Cycle defect or prymidine biosynthesis defect?
Check blood ammonia levels
What is the only pyrmidine that needs methylene thetrahydrofolate?
dTMP
