Nucleic Acids in Chemistry and Biology

deaminase to IMP and adenosine is deaminated to inosine by adenosine deaminase, an enzyme that is
thought to be present in elevated levels in leukaemic cells. Oxidation of hypoxanthine is catalysed by xanthine
oxidase to give xanthine, which is also the deamination product of guanine. Xanthine is further oxidised to uric
acid, which in humans is excreted in the urine. Gout is a painful disease caused by the excessive production
of monosodium urate, which is deposited as crystals in the cartilage of joints. Allopurinolis an analogue of
hypoxanthine that provides an effective treatment of gout by acting as a substrate inhibitor of xanthine oxi-
dase. Since the allopurinol becomes irreversibly bound to the enzyme it is known as a suicide inhibitor.
A variety of deaminases convert cytidine, 2-deoxycytidine and dCMP into the corresponding uracil-
containing derivatives. All of these products can be hydrolysed to uracil, which is then degraded reduc-
tively (Figure 3.83). Thymine is degraded in a way exactly analogous to uracil.

3.6 Polymerisation of Nucleotides

While the complex series of reactions involved in the polymerisation of nucleotides to form DNA and RNA
are described in detail in Chapter 6, we are here primarily concerned with the polymerases as potential tar-
gets for chemotherapy, as they are the enzymes responsible for polymerisation of nucleoside 5-triphosphates
into nucleic acids. In each case there is a requirement for a template strand of nucleic acid and an oligoribo-
or oligodeoxyribo-nucleotide primer.

3.6.1 DNA Polymerases

All cellular polymerases use DNA as a template and polymerise in a 5 → 3 direction (Section 6.6). While poly-
merases are potential targets for cancer chemotherapy (e.g.for intercalators, Section 9.6), much greater scope
is available for anti-viral therapy since many viruses (e.g.herpesvirus (HSV)) encode their own DNA poly-
merases, which often have substrate specificities different from those of the cellular enzymes (Section 3.7.2).
One group of RNA-containing viruses, the retroviruses, replicates via a double-stranded DNA inter-
mediate. Retroviruses are important since many cause cancer and one of them, HIV, is responsible for the dis-
easeAIDS. Its RNA genome is first transcribed into DNA by an RNA-dependent DNA polymerase, also
known as a reverse transcriptase(RT) (Section 6.4.6). In contrast to the cellular polymerases, these RTs

124 Chapter 3

N

H

NH

O

O

N

H

NH

O

O

H

H

H

H

H 2 O

H 3 NCH 2 CH 2 CO 2 H 2 NCONHCH 2 CH 2 CO 2

H 2 O

Pi

ribose

1-α-phosphate

dCMP dUMP

5'-nucleotidase

dC dU

nucleoside

phosphorylase

cytidine uracil

deaminase

deaminase

deaminase

uridine

NADP + H

dihydrouracil

dehydrogenase

dihydrouracil

hydropyrimidine

+NH 3 +CO 2 hydrolase

ß-ureido-

propionase propionateß-ureido-

Pi

2-deoxyribose

1-α-phosphate

NADP

Figure 3.83 Catabolism of pyrimidine nucleotides

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