Nucleic Acids in Chemistry and Biology

is inhibited by the final product of the pathway. For example, the enzyme ribose phosphate pyrophospho-
kinase (Figure 3.71) is inhibited by AMP, GMP and IMP and this inhibition regulates the production of
PRPP. Similarly, the enzyme amidophosphoribosyl transferase, which is responsible for catalysing the
committed step, is inhibited by a number of purine ribonucleotides including AMP and GMP, which act
synergistically. AMP and GMP also inhibit the conversion of IMP into their own immediate precursors,
adenylosuccinate and XMP. A separate control feature is that GTP is required in the synthesis of AMP,
while ATP is required in the synthesis of GMP.

3.4.1.2 Salvage Pathways. Most organisms use a pathway of nucleotide biosynthesis known as salvage.

This is advantageous since degradation products of nucleic acids can be recycled rather than destroyed,
which is much less wasteful than the energy-demanding reactions of the de novo pathways. In some cancer
cells or virus-infected cells, extra synthetic capacity is required. Here salvage may become the dominant
pathway and hence has become a target for chemotherapeutic inhibitors.
Purine bases, which arise by hydrolytic degradation of nucleotides and nucleic acids, react with PRPP
to give the corresponding purine ribonucleotide and pyrophosphate is eliminated (Figure 3.75). The enzyme,
adenine phosphoribosyl transferase, is specific for the reaction with adenine; whereas, another enzyme,
hypoxanthine-guanine phosphoribosyl transferase (HGPRT), catalyses the formation of IMP and GMP.
A deficiency of HGPRT is responsible for the serious Lesch–Nyhan syndrome, which is often charac-
terised by self-mutilation, mental deficiency and spasticity. Here, elevated concentrations of PRPP give
rise to an increase in de novopurine nucleotide synthesis and degradation to uric acid (Section 3.5).
Another salvage route involves the reaction of a purine (or purine analogue) with ribose 1-phosphate. The
reaction is catalysed by a nucleoside phosphorylase (nucleoside phosphotransferase) and the resultant ribo-
nucleoside is then converted into its corresponding 5-nucleotide by a cellular kinase. Similarly, a deoxynucleo-
sidephosphotransferase produces deoxyribonucleosides from purines and 2-deoxyribose 1-phosphate.

3.4.2 Biosynthesis of Pyrimidine Nucleotides

3.4.2.1 De novo Pathways. Carbamoyl phosphate is an important intermediate in pyrimidine biosyn-

thesis. It is formed from glutamine and bicarbonate in a reaction catalysed by a carbamoyl phosphate
synthetase, and the reaction uses ATP as its energy source (Figure 3.76). The committed step is the subse-
quent formation of N-carbamoyl aspartate from carbamoyl phosphate and aspartate. This step is subject to
feedback inhibition by cytidine triphosphate (CTP), which is the final product of the pathway, while the

Nucleosides and Nucleotides 119

R

CO

HN

R'

ATP ADP

R

CO

N

R'

P

O

O

O NH 3

R

C

O

HN

R'

O

O

O

NH 2

P

R

C

N

R'

Pi NH 2

Figure 3.74 General mechanism for biosynthetic formation of an amidine from an amide

O

O

HO OH

P

O

O

O

O P O P

O O O

O

O

5-phosphoribosyl 1-β-pyrophosphate (PRPP)

Purine

O

O

HO OH

P

O

O

O

purine 5'-ribonucleotide

(AMP, IMP or GMP)

Purine PPi

Figure 3.75 Salvage biosynthesis of purine ribonucleosides