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Synthesis of Nucleotides

©2000 Timothy Paustian, University of Wisconsin-Madison

Nucleotides are some of the largest monomers that have to be made by the cell and understandably their synthesis involves many steps and large amounts of energy. The entire process is complex and a full treatment is not attempted here. Instead we give an overview of the process so that the student appreciates the substrates involved and the amount of effort a cell has to go through to make nucleic acids.

Biosynthesis of nucleotides is under tight regulatory control in the cell. Organisms need to make just the right amount of each base; if too much is made, energy is wasted, if too little, DNA replication and cellular metabolism come to a halt. Also, the cell is sensitive to the presence of any premade nucleotides in its environment and will down regulate their de novo synthesis pathways in favor of using what is already present in the surroundings. Bacteria are capable of interconverting purines (adenine and guanine) and interconverting pyrimidines (thymidine, cytidine and uracil). If a growth medium provides a purine and a pyrimidine, many microbes are capable of synthesizing the other needed nucleotides from them.

All nucleotides contain a ribose sugar and phosphate that form the backbone of DNA and RNA. These are synthesized from ribose 5-phosphate, a central metabolite of the pentose phosphate pathway. In this single step reaction, two of the phosphates of ATP are transferred to ribose 5-phosphate to form 5-phospho-a-D-ribosyl 1-pyrophosphate (PRPP). This intermediate is required for the biosynthesis of purines, pyrimidines, NAD, histidine and tryptophan. It plays a critical role in anabolism.

PRPPsyn picture

Figure 1 - Synthesis of PRPP.

Synthesis of Purines

Purine synthesis starts by the addition of an ammonia from glutamine to PRPP. In six more step the five membered ring of purines in synthesized with a net cost of five ATP. Glycine, tetrahydorfolate (a one carbon carrier that donates a methyl group), glutamine, and bicarbonate (HCO3-) all donate parts of the five membered ring, the final product being 5'-phosphoribosyl-5-aminoimidazole-4-carbonate (CAIR).

CAIRsyn picture

Figure 2 - Synthesis of CAIR from PRPP. There is an alternative step for the addition of formate to the growing nucleotide that uses tetrahydrofolate and does not require ATP.

In the next series of reactions the 6 membered ring of purine is added to CAIR creating Inosine 5'-monophosphate (IMP). This costs an additional ATP with the members of the ring coming from aspartate and tetrahydrofolate. IMP is a purine - compare it to adenosine or guanine and you will see they are very similar.

IMPsyn picture

Figure 3 - Synthesis of IMP.

Synthesis or guanine or adenine involves the addition of an amino group in the appropriate place. To form guanine monophosphate (GMP), IMP is first oxidized to xanthosine monophosphate. This adds a ketone group (see figure) that is attacked by the ammonia on glutamine in the next reaction yielding GMP. The cost to the cell is one ATP. In the synthesis of adenosine monophosphate (AMP), IMP first combines with aspartate and in a second reaction the combination is split into fumarate and AMP. The cost to the cell is one GTP. It is interesting to note that synthesis of ATP from IMP requires GTP as an energy source and not ATP.

AMPsyn picture

Figure 4 - Synthesis of AMP from IMP. Note the use of GTP instead of ATP to catalyze the first step in the reaction.

GMPsyn picture

Figure 5 - Synthesis of GMP from IMP. Note the extra energy that is required in the form of pyrophosphate to drive the reaction.

Synthesis of Pyrimidines

Pyrimidine synthesis is simpler due to the single ring of these nucleotides. The synthesis of pyrimidines begins by combining glutamine, 2 ATP and bicarbonate to form glutamate, 2 ADP and carbamoylphosphate. Aspartate next reacts with carbamoylphosphate forming carbamoylasparate. In the critical third step, carbamoylasparate is cyclized to form the recognizable 6 membered ring of pyrimidines. Later in the pathway, PRPP is combined with the six membered ring to form orotidine 5'-phosphate. Removal of CO2 results in the formation of Uradine monophosphate (UMP). Two kinase reactions (addition of phosphate) finally form UTP. An addition of an amino group to UTP results in the formation of CTP. The synthesis of UTP uses 4 ATP (not counting the formation of PRPP) and making CTP adds an extra ATP to the cost.

PyrimidineSyn picture

Figure 6 - Synthesis of UTP, TTP and CTP.

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