DLA 30/Lectures 39-40 Purine and pyrimidine Flashcards
(29 cards)
6-mercaptopurine
Uses
Mechanism
Uses:
- Chemotherapy
- Treats leukemia
Mechanism:
-Inhibits purine biosynthesis = prevents nucelotide formation for DNA/RNA = slows proliferation
Thiopurine (mercaptopurine) S-methltransferae Polymorphism
Cause:
-Homozygous for genetic variants = Low TPMT activity
Result:
- higher risk of myelosuppression when treated w/ standard doses of thiopurine
- Need reduced dose of 6-mercatopurine (Normal dose = overdose)
Ribonucleotide
-Building blocks on RNA
1) Base
2) Ribose
4) Phosphate
Deoxyribonucleotide
-Building blocks on DNA
1) Base
2) Deoxyribose
3) Phosphate
What do inhibitor of purine and pyrimidine biosynthesis do?
- Anticancer agents
- Antimicrobial agents
Purine nucleotide metabolism
DNA:
1) Amino acid –> purine nucleotide –> ATP and GTP –> dATP and dGTP –> DNA (During replication)
RNA:
1) Amino acid –> purine nucleotide –> ATP and GTP –> RNA (Transcription)
2) RNA –> Adenine, hypoxanthine and guanine –> uric acid
Purine Nucleotide denovo synthesis
-Forms purine nucleotides from amino acids (DNA metabolism)
- Adenine and guanine synthesized
- N10-Formyl-tetrahydrofolate donate C or N = purine ring (Derived from folic acid)
- Needs ATP
- Ribose derived from PPP
-Ribose phosphate –> (ATP PRPP synthase) –> phosphoribosyl pyrophosphate (PRPP) –> (Glutamine & Phosphotibosylamidotransferase) –> Phosphoribosylamine
- First two enzymes = regulation enzymes of the pathway
- PRPP = feedforward activator
Conversion of IMP to AMP and GMP
AMP:
IMP –> (GTP) –> monophosphate (AMP) –> (Kinase) –> Diphosphate (ADP) –> (Kinase) –> Triphosphate (ATP)
GMP:
IMP –> (ATP) –> monophophate (GMP) –> (Kinase) –> Diphosphate (GDP) –> (Kinase) –> Triphosphate (GTP)
- Mycophenolic acids INHIBITS conversion of IMP –> GMP (Enzyme = IMP dehydrogenase)
- ADP and GDP used for ribonucleotide reductase to form (dADP and DGDP)
Inhibitors of Bacterial Purine Nucleotide Synthesis
PABA analogs:
1) Suldonamides –> antibacterial agent
2) Trimethoprim –> inhibits Bacterial dihydrofolate reductase
-Decreases tetrahydrofolate = reduced availability for purine nucleotide synthesis
Inhibitors of Eukaryotic Purine Nucleotide Synthesis
Folate Analog:
1) Methotrexate –> Anti cancer
- Inhibits dihydrofolate reductase = reduced tetrahydrofolate = reduced availability for purine nucleotide synthesis = slows cell division
Side effects:
-Anemia, Gi disturbance, Scaly skin, hair loss, immune deficients
Folate Deficiency and effects
-Need to obtain it from diet for DNA synthesis and S phase of cell cycle (Cell divison)
- Macrocytic Anemia = Folate Deficiency (decreases cell division)
- Neural tube defects = Folate Deficiency (pregnant women)
Conversion of the Ribonucleotides to deoxyribonucleotides
Process, Needs, and inhibitors
Process:
-Ribonucelotide reductase converts purine and pyrimdine ribonucleotides –> deoxyribonucleotides
(very active just before S-Phase of cell cycle)
Requires:
-Needs NADPH+ and H+
Inhibitors:
- High levels of dATP (SCIDS)
- Hydroxyurea (Anti cancer agent)
Salvage/Recycling pathway of purines
- Free purine bases –> purine nucleotides
- Uses less energy than denovo synthesis pathway
- Enzymes = HGPRT and APRT
- Good for Brain
Adenine Phosphoribosyl transferase (APRT)
Adenine –> Adeniosine monophosphate (AMP)
Enzyme: Adenine Phosphoribosyl transferase (APRT)
PRPP donates ribose-phosphate to form AMP
Lesch-Nyan Syndrome
Cause/symptoms
Cause:
-Absence of Hypoxanthine Guanine Phosphoribosyl Transferase (HGPRT) = purines not reused (salvage pathways inhibited) = increased degradation/Uric acid
“Hes Got Problems Repressed Thriving”
“Hes got purine recycle that!”
Symptoms:
- “Self mutilation” (Biting of lips/fingers)
- Hyperuricemia
- Developmental delay
- “Failure to thrive”
- Orange colored crystals
- Uric acid levels elevated
Hyperuricemia and Gout
Cause
Symptoms
Diagnosis
Advised
Cause:
- Purine degradation
- Uric acid = end product of purine (all products that are degraded)
- Hyperuricemia = monosodium urate = gout
Symptoms:
- Pain/warmth in joints
- Big toe
- Renal stones
Diagnosis:
-Needle shaped monosodium urate crystals
Advised:
- Reduce beer and meat intake bc it increases uric acid
- Allopurinol (prevents uric acid formation)
Formation of Uric acid
Pathway
AMP –> Adenosine –> (Adenosine deaminase) –> Inosine –> (Purine nucleoside phosphorylase PNP) –> Purine base hypoxanthine –> xanthine –> (xanthine oxidase) –> uric acid
GMP –> (5’nucleotidase) –> Guanosine –> (Purine nucleoside phosphorylase PNP) –> Guanine –> (Gaunase) –> Xanthine –> (Xanthine oxidase) –> Uric acid
*Allopurinol inhibits xanthine oxidase = prevents uric acid formation
2 Causes of Hyperuricemia
Uric acid levels = saturated
1) Overproduction of uric acid = gout
- Increase levels of PRPP
- Deficiency of HGPRT = less recycling of purines (Lesch)
2) Loss of excretion of uric acid = gout
- Renal disease
- Higher risk in men
- Lactic acidosis
SCID (AR)
Cause/symptoms/treatment
Cause:
-Adenosine deaminase deficiency
-Adenosine accumulation = increased dATP levels = inhibit ribonucleotide reductase = reduced rates of cell
division in the lymphocytes
Symptoms:
- immunoglobulins = low (decrease in immunity)
- pneumonia
- Improper T and B cell functioning = severe infections
Treatment:
- enzyme/bone marrow replacement
- Gene therapy
Purine nucleoside phosphorylase (PNP) deficiency
- Purine degradation can’t occur
- Effects T-cell lymphocytes
- Repeated Infections
Pyrimidine metabolism
Pathway
Amino acid –> (Pyrimidine nucleotide denovo synthesis) –> Pyrimidine nucleotides UTP, CTP –> dUMP –> (Methylene tetrahydrofolate) –> dTMP and dCTP –> DNA replication
• The synthesis of thymidine requires one-carbon
groups as methylene tetrahydrofolate (THF)
• Donors of C and N atoms for the pyrimidine
ring are Aspartate, Glutamine and CO2
Pyrimidine biosynthesis and regulation
CPS-II (carbamoyl phosphate synthetase-II)
- Regulates
- Inhibited by UTP (by feedback inhibition)
- activated by ATP and PRPP
OPRT and OMP decarboxylase = UMP synthase
Formation of CTP and CDP
UTP –> (CTP synthetase) –> CTP –> CDP
-CDP and UDP used to form deoxyribonucleotides (DNA) by ribonucleotide reductast
Synthesis of thymidine (dTMP) and Inhibitors
dUMP –> (thymidylate synthase) –> Thymidine
-dTMP NEEDS methylene tetrahydrofolate (THF) (one
carbon donor) which converts to dihydrofolate
