Don’t be intimidated by the word metabolism! Nucleotide metabolism is a very high-yield topic that will come up throughout your career as a physician. Will you be getting into all of the details with your patients? No, of course not. However, when your patient comes to you with a gout flareup, you may prescribe a drug that goes after nucleotide metabolism. You’ll need to understand these mechanisms. The reading is out of Lippincott Illustrated Reviews: Biochemistry, 8e, and a book you’ll see used by me and others quite often. It’s a very level-appropriate book. The link to the chapter is here.
Describe the biosynthesis of purine and pyrimidine bases
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Thymidylate synthase
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Dihydrofolate reductase (DHFR)
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Ribonucleotide reductase
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Adenosine deaminase
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Xanthine oxidase
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PRPP synthetase
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glutamine:phosphoribosylpyrophosphate amidotransferase (GPAT)
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UMP synthase
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Hypoxanthine-guanine phosphoribosyltransferase (HGPRT)
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Adenine phosphoribosyltransferase (APRT)
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Purine salvage pathway
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Pyrimidine and purine de novo synthesis
Describe disease states associated with pyrimidine and purine biosynthesis and degradation
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Gout
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Lesch–Nyhan syndrome
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Orotic Aciduria
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ADA Deficiency—SCID
Describe how inhibitors can interfere with critical steps of nucleotide synthesis and how this can be leveraged for the treatment of different diseases
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5-flourouracil
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Methotrexate
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Allopurinol
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Azathioprine
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6-Mercaptopurine
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Hydroxyurea
Describe the biosynthesis of purine and pyrimidine bases
Osmosis video on Nucleotide Metabolism. This Osmosis video discusses both purine and pyrimidine metabolism at a good level. It also does discuss some of the pharmaceuticals that can be used to disrupt synthesis.
Describe disease states associated with pyrimidine and purine biosynthesis and degradation
There are four disease states that I want you to walk away from this session understanding. There are Osmosis videos for three of these:
Osmosis video on gout.
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- (There’s a cool case study video on gout and pseudogout—you don’t need to go into it for this session, but big picture, this is why metabolism is essential to understand.)
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Osmosis video on Lesch-Nyhan syndrome.
Osmosis video on adenosine deaminase deficiency.
Describe how inhibitors can interfere with critical steps of nucleotide synthesis and how this can be leveraged for the treatment of different diseases
The reading and some of the videos touch on these molecules. All of them would be good to know. The majority of these will show up throughout the curriculum. This is not an entire list of drugs that interfere with nucleotide synthesis, but some of the more common ones.
| Drug | Target | Use |
|---|---|---|
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5-fluorouracil |
Thymidylate synthase
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Cancer
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Methotrexate |
DHFR |
Cancer, psoriasis, rheumatoid arthritis
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Allopurinol |
Xanthine oxidase
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Gout |
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Azathioprine |
Purine synthesis
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Immunosuppressant |
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6-Mercaptopurine
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Purine synthesis
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Autoimmune, cancer, Chron’s disease
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|
Hydroxyurea |
Ribonucleotide reductase
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Cancer |