NUCLEOTIDE BIOSYNTHESIS (POINT OF COMMONALITY AND DIFFERENCE)

Nucleotide Biosynthesis

Points of Commonality and Difference






  Learning the pathways of nucleotide synthesis can be a daunting task. You have both purines and pyrimidines to deal with. How best to go about learning these steps is the lesson of this tutorial. The first thing to take note of is that both the purines and the pyrimidines have many points in common in their pathways. Knowing what these are allows you to absorb the information from a comparative perspective as opposed to two separate pathways. Having one to match with the other is the key to making points stick.

Lets start by looking at the basic ring systems of purine and pyrimidines. The first thing we note is the size.  The pyrimidine ring is smaller and has two fewer nitrogens, and one less carbon. That doesn’t help, except to inform us that a purine ring requires more C and N donors. Next we look at the composition. Lets start with the chemical formulas. Again, we see the major factor is twice the number of N’s; C and H are about the same. Again, we consider that N addition is going to be a factor.  Finally, we turn to the biochemistry. We see the a purine ring is synthesized from 3 amino acids, two formyl-THFs, and one CO2. The pyrimidine requires two amino acids and CO2. Thus, purine assembly relies on multiple amino acids,  whereas pyrimidines require only two and both use CO2.  The purine ring needs twice as many glutamines and depends on 2 formyl-THFs. Now we understand where the extra N’s and C’s are coming from.




We now know roughly the factors that take part in the biosynthesis of purine and pyrimidine rings.  To help us learn the pathway.  Let’s ask what is the first, last and mid-point compound for each. For purines, the first is 5-phosphoribosylamine and the last is 5’-IMP. For pyrimidines, its carbamoyl aspartate and the last is 5’-UMP. Thus, the last compound of each has ribose attached, but only purines have ribose in the first. The mid-point compound, for  purines is 5-aminoimidazole ribotide; for pyrimidines its orotate. Note that no sugar has been attached to a pyrimidine even by the mid point of the pathway. This means that PRPP addition is immediate with purines and near the end with pyrimidines. We now can appreciate that there will be major differences at the start and PRPP is a key player.

What about the amino acids and CO2? Since glutamine and aspartate, are required for both, where do they appear in each ring? As we search for glutamine, we notice that both use glutamine as a N donor. Similarly, CO2 is a carbon donor for both. But, with aspartate there is something entirely different. A purine uses aspartate as a N donor, but a pyrimidine in corporates the whole amino acid into the ring. This means that 3 of a pyrimidines ring C’s and one N come from aspartate.  But, aspartate has 4 C’s. The a–COOH group of aspartate is not present in the final product.  Therefore, there must be a pathway step that removes the –COOH group from the ring. As you study the results below, note that there are 4 C and one N in the purine ring that have not been assigned. Connect this fact with the fact that glycine and formyl-THF have not been mentioned.


We now know the source of all C’s and N’s in a pyrimidine ring.  The purine is still unfinished, however, because there are two formyl-THFs and one glycine that have not been located.  Recall formyl groups are used to close the small and large rings of purines. Thus, don’t look for formyl carbons at fusion points that join the rings. There can only be two likely candidates in the structure below that represent the two formyl groups. The part that stays unmarked must be glycine. With a little imagination you should be able to see this molecule. Now all C’s and N’s in a purine ring have been accounted for.







Test Your Understanding of Purine and Pyrimidine Biosynthesis
1.What compounds contribute the most ring atoms of a purine?  A pyrimidine?
Ans:  Glycine for a purine (3), glutamine and formyl-THF (2 each) are close seconds.  Aspartate for a pyrimidine. 
2.  What compounds are common in both pathways?
Ans:  There are 4.  Aspartate, glutamine and CO2 are most obvious.  The fourth is PRPP.
3.  What is the link between carbamoyl-PO4 and glutamine in the synthesis of a pyrimidine?
Ans:  Glutamine provides the NH3 group to synthesize carbamoyl-PO4.  A special enzyme,
carbamoyl-PO4 synthetase II is required.
4.  Can you think of another amino acid that could be involved indirectly in the synthesis of a purine ring?
Ans:  A likely candidate would be serine, which by forming N5,N10-methylene THF, provides the carbon for the formation of N10-formyl-THF.  

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