BIOCHEMISTRY- DNA, Purines & Pyrimidines, Synthesis and Associated pharmacology Flashcards
Name Purines
Adenine, Guanine
PUR As Gold
Name Pyrimidines
Cytosine, Uracil, Thymine
CUT the Py
What does Leflunomide interfere with?
What does it treat?
Pyrimidine synthesis
Inhibits dihydroorotate dehydrogenase.
Blocks: Carbamoyl phosphate + Aspartate –> orotic acid
Treats: Rheumatoid Arthritis
Why is folate given with 5-FU? Why is folate given with methotrexate and trimethoprim?
5-FU: it increases binding to dUMP to create FU-dUMP (false nucleotide), thus increasing POTENCY
With MTX and TMP, folic acid reduces side effects (e.g. cytopenias, GI upset)
What do Methotrexate, trimethoprim and pyrimethamine inhibit?
What do they treat?
Inhibits pyrimidine synthesis.
Blocks Dihydrofolate reductase that converts DHF –> THF. Ultimately leads to reduction in dTMP.
*Memory aid: METH makes you DIe.
METHotrexate used in autoimmune, cancer
TriMETHoprim used for bacterial infection
PyriMETHamine used for protozoal infection
What does 5-Fluorouracil inhibit?
Inhibits Thymidylate Synthase
Blocks conversion of dUMP to dTMP. Decreases dTMP.
*Memory aid: FU - thy middle ate synthase.
What does hydroxyurea inhibit?
What does it treat?
Inhibits DNA synthesis, BOTH purine and pyrimidine synthesis by inhibiting:
Ribonucleotide reductase which normally catalyzes:
UDP –> dUDP
*Memory Aid: ROXY is so thin her RIBS show.
Treats: cancer, sickle cell anemia (fetal Hb production)
Side effects: cytopenias
What does 6-mercaptopurine (6-MP) and its prodrug azathioprine inhibit?
What does it treat?
Inhibits de novo purine synthesis (PRPP –> IMP)
*Memory aid: has *prine/purine in it
Treats: arthritis, IBD, leukemias
What two genetic diseases can cause an increase in orotic acid (orotic aciduria)?
Try and guess inheritance pattern
What labs distinguish them?
Orotic aciduria
1) Autosomal recessive UMP synthase (UMPS) deficiency (Normally catalyzes: Orotic acid –> UMP).
Labs: No hyperammonemia, + megaloblastic anemia from impaired pyrimidine synthesis.
2) X-linked OTC (ornithine transcarbamylase) deficiency. Usually converts carbamoyl phosphate –> citrulline –> urea cycle. Deficiency causes build up of carbamoyl phosphate which is converted to orotic acid.
Labs: + hyperammonemia, no megaloblastic anemia
What do Mycophenolate and ribavirin inhibit?
What do they treat?
Inhibits de novo purine synthesis by inhibiting the enzyme: inosine monophosphate dehydrogenase (IMPD)
-Blocks conversion of IMP –> GMP.
Treatment:
Mycophenolate: mostly used with organ transplant to prevent rejection.
Ribavirin: used in viral infections (influenza, hepatitis C, hemorrhagic fevers)
From USMLE-Rx Flash Quiz…
Methylation of CpG islands has what effect on transcription?
Represses transcription.
Methylation makes DNA Mute. It will also repress transcription when histones are methylated by making them heterochromatic.
Heterochromatin vs. Euchromatin
Appearance on EM?
HeteroChromatin is Highly Condensed
Euchromatin is lighter on EM
Heterochromatin vs. Euchromatin
Which one is transcriptionally active?
“Eu” = True, Truly Transcribed
Euchromatin - is sterically accessible, not condensed so enzymes can access and transcribe.
Heterochromatin is clumped together, not transcribed, for example extra X chromosomes become Barr bodies.
What 3 amino acids are necessary for purine synthesis?
PUR As Gold - AGG
Aspartate
Glycine
Glutamine
What 2 properties increase the melting temperature of DNA?
1) Increased length of DNA
2) Increased number of Guanine and Cytosine (G-C) bonds (due to 3 Hydrogen bonds whereas A-T has 2 H bonds).
Heterochromatin vs. Euchromatin
Which has more methyl groups and which has more acetyl groups on the histones?
Heterochromatin has more Methyl (Me) groups
Euchromatin has more acetyl (acetyl makes DNA Active)
This condition, causes build up of adenosine which feeds back and inhibits ribonucleotide reductase which can lead to lymphocyte deficiency and SCID (can’t produce nucleotides)
- ADA deficiency (adenosine deaminase).
- Autosomal recessive.
- ADA is required to degrade adenosine and deoxyadenosine.
- Adenosine –>ADA –> inosine
This disorder leads to an accumulation of hypoxanthine and guanine. Findings may include: intellectual disability, self-mutilation, aggression, hyperuricemia (orange “sand” [sodium urate crystals] in diaper), gout, dystonia.
Lesch-Nyhan Syndrome
Absent HGPRT which converts hypoxanthine to IMP and guanine to GMP.
HGPRT: "He's Got Purine Recovery Trouble" Hyperuricemia Gout Pissed off (aggression, self-mutilation) Retardation dysTonia (spasmodic muscle movements)
What is the inheritance pattern of Lesch-Nyhan Syndrome?
What is the treatment?
Inheritance: X-linked recessive
Treatment: allopurinol or febuxostat (2nd line). This inhibits xanthine oxidase that converts hypoxanthine to xanthine and xanthine to uric acid.
What is likely to occur with a mutation replacing the third nucleotide of a degenerate (redundant) code?
Most likely nothing.
Wobble base (3rd nucleotide in degenerate code) are often silent mutations and won’t affect the protein.
Example: Proline can be CCU, CCC, CCA, CCG.
Each amino acid has _________ codon/s.
Each codon codes for ______ amino acid/s.
Each amino acid has multiple codons. (degenerate)
Each codon codes for one amino acid. (unambiguous).
What are the 3 STOP codons?
UGA
UAA
UAG
UGA = U Go Away UAA = U Are Away UAG = U Are Gone
