section 27.8

Catabolism of Purine Nucleotides

635

Purine

O H H

D e o xyg u an o sin e

F IG U R E 2 7-21

Reactions catalyzed by adenosine deaminase (ADA) and purine nucleoside phosphorylase (PNP). ADA and PNP

participate in the purine catabolic pathway, and deficiency of either leads to immunodeficiency disease. [Slightly

modified and reproduced, with permission, from N. M. Kredich and M. S. Hershfield, Immunodeficiency diseases

caused by adenosine deaminase and purine nucleoside phosphorylase deficiency. In:

The M etabolic B asis o f Inherited

D isease,

6

th ed., C. S. Scriver, A. L. Beaudet, W. S. Sly, and D. Valle, Eds. New York: McGraw-Hill (1989).]

products to cause toxic effects on the cells of the immune

system.

Patients

with

ADA deficiency

lack both T-

and

B-lymphocyte-mediated functions, namely, cellular and

humoral immunity, respectively, and exhibit a severe

combined immunodeficiency (SCID) disorder. Other ge-

netic defects can cause SCID (Chapter 35), but ADA

deficiency is responsible for about one-third of patients

who have SCID. PNP deficiency is associated only with

T-lymphocyte dysfunction.

The exact mechanisms responsible for immune sys-

tem

dysfunction

are

not

known.

In

ADA-deficient

T lymphocytes, there is a 50- to 100-fold increase in the

concentration of dATP; similarly, PNP-deficient T lym-

phocytes exhibit elevation in dGTP concentration. Both

dATP and dGTP inhibit ribonucleotide reductase, cause

a reduction of other deoxyribonucleotides (e.g., dCTP)

required for DNA synthesis, and inhibit cell division.

S-Adenosylhomocysteine (SAH) also accumulates and

inhibits many methylases required for normal function-

ing of the cell (Chapter 17). Accumulation of SAH re-

sults from the suicide inactivation of SAH hydrolase by

deoxyadenosine. Formation and degradation of SAH are

shown in Figure 27-22. In the hydrolysis of SAH, the sub-

strate undergoes a temporary oxidation by NAD+, which

is

tightly coupled

to the enzyme. This reaction eventually