17. Nucleotide synthesis and degradation

Last updated on November 19, 2018 at 17:16

Summary

  • Nucleotides are precursors of RNA, DNA, ATP, GTP, UTP, NAD, FAD, CoA, cAMP, cGMP, among other substances
  • They are phosphorylated nucleosides. Nucleosides are composed of a sugar linked to either a purine or a pyrimidine base.
  • Nucleotides can be synthesized by 2 pathways: the salvage pathway, which recycles old bases, or the de novo pathway, which synthesizes a new base from amino acids
  • The number of nucleotides in the cell is very low (except for ATP), far lower than what is needed for DNA synthesis. This means that by regulating nucleotide synthesis, we effectively regulate DNA synthesis
  • The enzyme xanthine oxidase is involved in degradation of purines, like ATP and GTP

The salvage pathways

In the salvage pathways, PRPP react with recycled bases to yield a nucleotide, for example: adenine + PRPP -> AMP + PPi. The brain is especially dependant on salvage pathways. Problems with salvage pathways causes overexpression of the de novo pathways, which creates bases that are degraded as soon as they are produced. This causes an overproduction of uric acid, which can cause gout or Lesch-Nyhan syndrome.

De novo synthesis of purines

The two classes of bases that can comprise a nucleotide. Note that purines are just pyrimidines with an extra ring.

Purine-derivatives, like adenine, guanine, hypoxanthine and xanthine, are synthesized de novo (from new) from formate, glutamine, glycine, CO2 and aspartate. PRPP is needed for the synthesis. AMP and GMP are purine-based nucleotides, and are both synthesized from IMP. The pathway is regulated by negative feedback.

De novo synthesis of pyrimidines

Pyrimidine-derivatives, like cytosine, thymine and uracil, are synthesized de novo from carbamoyl phosphate and aspartate. Carbamoyl phosphate, a molecule you should recognize from the urea cycle, is synthesized from ammonia and bicarbonate, by carbamoyl phosphate synthase 2. CMP, TMP and UMP are pyrimidine-based nucleotides. TMP is a UMP with a methyl group attached to it. Thymine (TMP) is used in DNA, while uracil (UMP) is used in RNA instead of thymine (you probably already knew that RNA uses U instead of T). The methylation of UMP to yield TMP requires THF, a folic acid derivative. If folic acid is deficient, this reaction will be impaired, and uracil may be incorporated into the DNA, which will break the DNA strand.

Degradation

Purines like ATP and GTP are degraded to uric acid by the enzyme xanthine oxidase. Uric acid is excreted in the urine. Pyrimidines are degraded to ammonia and succinyl-CoA.

What are deoxyribonucleotides and ribonucleotides?

A ribonucleotide (NDP) is a nucleotide that uses ribose as its sugar-component. They make up the RNA. However, the DNA is comprised of deoxyribonucleotides (dNDP), which are ribonucleotides that have been reduced, so they’ve lost an oxygen from the ribose-part.


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16. Synthesis of biologically active molecules from amino acids

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