TBL 2 - Purine and Pyrimidine

Adenine Structure

• NH2 on position 6

Guanine Structure

• NH2 on position 2

Cytosine Structure

• NH2 on position 4

• Under deamination, it becomes uracil

Uracil Structure

• Carbonyl group on position 4

• Under methylation, it becomes thymine

Thymine Structure

• Carbonyl group on position 4

• Methyl group on positon 5

What small molecules are used to make purine?

Asp

Glu

CO2

Gly

THF

What small molecules are used to make pyrimidine?

Asp

Glu

CO2

Lesch-Nyhan Syndrome (which enzyme?)

HGPRT

Lesch-Nyhan Syndrome (findings)

High uric acid

Gout attacks

Neurological impairments

Hypotonia

Self-mutilation (like biting tongue and headbanging)

Severe Combined Immunodeficiency (which enzyme?)

Adenosine deaminase

Severe Combined Immunodeficiency (Lab findings)

High dATP (which inhibits ribonucleotide reductase)

Low dNTP

Low IgG (B lymphocyte dysfunction)

T lymphocyte dysfunction

Susceptible to infections

Cladribine

• For hairy cell leukemia

• Resists ADA deamination > Elevated ladribine in cancerous

Allopurinol

• Xanthine oxidase inhibitor

• For chronic gout (only) and Lesch-Nyhan Syndrome

• Leads to

  • Lower uric acid

  • Higher hypoxanthine (which is the substrate for Lesch-Nyhan)

Febuxostat

• Xanthine oxidase inhibitor

• For chronic gout (only) and Lesch-Nyhan Syndrome

• Leads to

  • Lower uric acid

  • Higher hypoxanthine (which is the substrate for Lesch-Nyhan)

UMP Synthase Deficiency (findings)

• Orotic aciduria

• Multisegmented neutrophils

• B-12 and folate-resistant megaloblast

Ornithine Transcarbamylase Deficiency (findings)

High carbamoyl phosphate

High orotic acid

Hyperammonemia

Encepalopathy

Hydroxyurea

• Inhibits ribonucleotide reductase (UDP > dUDP)

• Anti-neoplastic effects

• Good for sickle cell (increase in NO, cGMP, and thus, HbF)

6-Mercaptopurine

Immunosuppressive

• Reduces nucleotide synthesis

• Reduced lymphocyte proliferation

Azathioprine

Immunosuppressive (as a pro-drug)

• Reduces nucleotide synthesis

• Reduced lymphocyte proliferation

Mycophenolate

Immunosuppressive

• Inhibits IMP dehydrogenase (IMP > GMP) reversibly

• Blocked purine synthesis

Ribavirin

Antiviral

• Inhibits IMP dehydrogenase (IMP > GMP)

• Blocked purine synthesis

Methotrexate

Immunosuppressive

• Inhibits dihydrofolate reductase (DHF > THF)

• Low dTMP

Trimethoprim

Antibiotic

• Inhibits dihydrofolate reductase (DHF > THF)

• Low dTMP

Pyrimethane

Antihelminthic (parasitic worms)

• Inhibits dihydrofolate reductase (DHF > THF)

Leflunomide

• Inhibits dihidryoorotate dehydrogenase (dihydroorotate > orotic acid)

Capecitabine

Pro-drug

• adds fluoride to UMP, UDP, etc

• Inhibits thymidylate synthase

5-fluorouracil (5-FU)

• adds fluoride to UMP, UDP, etc

• Inhibits thymidylate synthase