Nucleotide Synthesis De Novo

Abstract

Nucleosides are composed of a heterocyclic ring (defined as the base) that is attached to a ribose. Addition of a phosphate to a nucleoside, at carbon 5 of the ribose, produces a nucleotide. Nucleotides function as ubiquitous building blocks for the synthesis of all nucleic acids, and also function in enzymatic reactions as cofactors and as a source of energy. These central metabolic roles require their continued biosynthesis from readily available precursors, and this process is defined as de novo nucleotide synthesis. The synthesis of purines starts with ribose‐phosphate, to which are attached the individual atoms of the heterocyclic base in a stepwise fashion. Pyrimidine synthesis starts with the stepwise formation of the base, to which is then added the ribose‐phosphate. Bases and nucleosides may also be recycled in salvage pathways.

Key Concepts:

  • Nucleotides form the building blocks for the synthesis of DNA and RNA, which store and transmit genetic information. They also serve as cofactors in many metabolic reactions.

  • All four ribonucleoside triphosphates are important sources of energy for metabolic reactions, though ATP – being more abundant – is the most common cosubstrate in many metabolic reactions.

  • Nucleotides are so essential to metabolism that genetic defects generally are lethal, and for humans only a few gene defects are observed, at a low frequency.

  • Many of the enzymatic reactions in the de novo biosynthesis of nucleotides are combined as two or more reactions catalysed by a single multidomain protein. This has made nucleotide biosynthesis more efficient.

  • For a few of the biosynthetic steps alternate enzymatic strategies have emerged between bacteria and vertebrates, and for such unique bacterial enzymes these present possible targets for drugs as selective antibiotics.

Keywords: nucleotide; biosynthesis; purine; pyrimidine; multifunctional protein

Figure 1.

Overview of the pathways for the biosynthesis of purine and pyrimidine nucleotides (THF, tetrahydrofolate). Ribonucleoside triphosphates are blue; deoxyribonucleoside triphosphates are green. To emphasise that it is not a building block for deoxyribonucleic acid (DNA) synthesis dUTP is red. Both pathways start from a common set of precursor amino acids and other metabolites. Each arrow represents an enzymatic reaction.

Figure 2.

Biosynthesis of the purine ring. (a) Precursors of the ring and numbering of the ring atoms. (b) Numbering of atoms in an imidazole ring.

Figure 3.

Biosynthesis of IMP. Reactions with the same Roman numeral are performed by a single enzyme. A pentagon containing an R (ribose); a circle containing P (phosphate).

Figure 4.

Biosynthesis of AMP and GMP from IMP.

Figure 5.

Biosynthesis of the pyrimidine ring. Precursors of the ring and numbering of the ring atoms.

Figure 6.

Biosynthesis of pyrimidines leading to formation of UMP.

Figure 7.

Biosynthesis of CTP and dTMP. Abbreviation: THF, tetrahydrofolate.

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Further Reading

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Traut, Thomas(Jun 2014) Nucleotide Synthesis De Novo. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0001396.pub3]