BIOCHEMISTRY- DNA, Purines & Pyrimidines, Synthesis and Associated pharmacology

Question 1

Name Purines

Answer 1

Adenine, Guanine

PUR As Gold

Question 2

Name Pyrimidines

Answer 2

Cytosine, Uracil, Thymine

CUT the Py

Question 3

What does Leflunomide interfere with?

What does it treat?

Answer 3

Pyrimidine synthesis

Inhibits dihydroorotate dehydrogenase.
Blocks: Carbamoyl phosphate + Aspartate –> orotic acid

Treats: Rheumatoid Arthritis

Question 4

Why is folate given with 5-FU? Why is folate given with methotrexate and trimethoprim?

Answer 4

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)

Question 5

What do Methotrexate, trimethoprim and pyrimethamine inhibit?

What do they treat?

Answer 5

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

Question 6

What does 5-Fluorouracil inhibit?

Answer 6

Inhibits Thymidylate Synthase
Blocks conversion of dUMP to dTMP. Decreases dTMP.

*Memory aid: FU - thy middle ate synthase.

Question 7

What does hydroxyurea inhibit?

What does it treat?

Answer 7

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

Question 8

What does 6-mercaptopurine (6-MP) and its prodrug azathioprine inhibit?

What does it treat?

Answer 8

Inhibits de novo purine synthesis (PRPP –> IMP)

*Memory aid: has *prine/purine in it

Treats: arthritis, IBD, leukemias

Question 9

What two genetic diseases can cause an increase in orotic acid (orotic aciduria)?

Try and guess inheritance pattern

What labs distinguish them?

Answer 9

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

Question 10

What do Mycophenolate and ribavirin inhibit?

What do they treat?

Answer 10

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)

Question 11

From USMLE-Rx Flash Quiz…

Methylation of CpG islands has what effect on transcription?

Answer 11

Represses transcription.

Methylation makes DNA Mute. It will also repress transcription when histones are methylated by making them heterochromatic.

Question 12

Heterochromatin vs. Euchromatin

Appearance on EM?

Answer 12

HeteroChromatin is Highly Condensed

Euchromatin is lighter on EM

Question 13

Heterochromatin vs. Euchromatin

Which one is transcriptionally active?

Answer 13

“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.

Question 14

What 3 amino acids are necessary for purine synthesis?

Answer 14

PUR As Gold - AGG
Aspartate
Glycine
Glutamine

Question 15

What 2 properties increase the melting temperature of DNA?

Answer 15

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).

Question 16

Heterochromatin vs. Euchromatin

Which has more methyl groups and which has more acetyl groups on the histones?

Answer 16

Heterochromatin has more Methyl (Me) groups

Euchromatin has more acetyl (acetyl makes DNA Active)

Question 17

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)

Answer 17

• ADA deficiency (adenosine deaminase).
• Autosomal recessive.
• ADA is required to degrade adenosine and deoxyadenosine.
• Adenosine –>ADA –> inosine

Question 18

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.

Answer 18

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)

Question 19

What is the inheritance pattern of Lesch-Nyhan Syndrome?

What is the treatment?

Answer 19

Inheritance: X-linked recessive

Treatment: allopurinol or febuxostat (2nd line). This inhibits xanthine oxidase that converts hypoxanthine to xanthine and xanthine to uric acid.

Question 20

What is likely to occur with a mutation replacing the third nucleotide of a degenerate (redundant) code?

Answer 20

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.

Question 21

Each amino acid has _________ codon/s.

Each codon codes for ______ amino acid/s.

Answer 21

Each amino acid has multiple codons. (degenerate)

Each codon codes for one amino acid. (unambiguous).

Question 22

What are the 3 STOP codons?

Answer 22

UGA
UAA
UAG

UGA = U Go Away
UAA = U Are Away
UAG = U Are Gone