Nucleic Acids in Chemistry and Biology

reaction catalysed by the enzyme ribose phosphate pyrophosphokinase (Figure 3.71). ATP acts as the
donor of pyrophosphate while ribose 5-phosphate comes primarily from the pentose phosphate pathway.
In contrast to pyrimidine nucleotide biosynthesis, where a preformed heterocycle is incorporated intact
(Section 3.4.2), in purine nucleotide biosynthesis the purine ring is constructed stepwise. The first irreversible
step (the committed step) is displacement of pyrophosphate at C-1 or PRPP by ammonia from glutamine
to give
-D-5-phosphoribosylamine (Figure 3.71). The reaction proceeds with inversion at C-1 to give the
glycosylic bond in the
-configuration. The equilibrium in this reaction is displaced towards the phospho-
ribosylamine by the hydrolysis of the pyrophosphate co-product.
The five carbon and the remaining three nitrogen atoms of the purine skeleton are derived from six dif-
ferent precursor sources and assembled by nine successive steps (Figure 3.72). These steps are

1. reaction of PRPP with glycine to give glycinamide ribonucleotide;


2. formylation of the -amino terminus of the glycine moiety by N^10 -formyltetrahydrofolate to give
   -N-formylglycinamide ribonucleotide;


3. conversion into the corresponding glycinamide with ammonia derived from glutamine;


4. ring closure to give 5-aminoimidazole ribonucleotide;


5. carboxylation of the imidazole C-4 (The carbon atom derived from CO 2 );


6. condensation with aspartate;


7. elimination of fumarate to give 5-aminoimidazole-4-carboxamide ribonucleotide;


8. formylation of the amino imidazole by N^10 -formyltetrahydrofolate; and


9. ring closure condensation to form inosine 5-monophosphate (IMP).

Inosine is a nucleoside rarely found in natural nucleic acids except in the ‘wobble’ position of some tRNAs
(Section 7.2.4). In such cases, the inosine comes from adenosine in the preformed tRNA by displacement
of adenine by hypoxanthine.
Inosine 5-monophosphate is used entirely for the production of the natural purine nucleotides, adenosine
5 -monophosphate (AMP) and guanosine 5-monophosphate (GMP) (Figure 3.73). AMP receives its amino
group at C-6 from aspartate in a reaction that utilises GTP as the phosphate donor. GMP is derived in two
steps from xanthosine 5-monophosphate (XMP) with the final amino group being donated by glutamine,
and ATP is consumed in the process. In both these pathways, a carbonyl group of an amide is replaced by
an amino group to give an amidine. This is a common type of mechanism whereby the amide is phosphor-
ylated by ATP or GTP to its imido-O-phosphoryl ester and then the phosphoryl ester displaced by an amine

Nucleosides and Nucleotides 117

NH 2

O O

HO OH

P

O

O

O

O O

HO

OH

OH

P

O

O

O O O

HO OH

P

O

O

O

O

P

O

P

O O O

O

O

ribose 5-phosphate

ribose phosphate

pyrophosphokinase

5-phosphoribosyl 1-α-pyrophosphate (PRPP)

5-phosphoribosylamine

glutamine

glutamate

amidophosphoribosylamine

transferase

+ PPi

ATP AMP

Figure 3.71 Biosynthesis of 5-phosphoribosylamine