634
chapter 27
Nucleotide Metabolism
T A B L E 2 7 -2
Examples o f Missense Mutations That Alter Human Hypoxanthine-Guanine Phosphoribsoyl-Transferase (HPRT)
and Cause Lesch-Nyhan Syndrome (LN) or Gout
Mutant HPRT
Nucleotide change
Amino acid change
Clinical presentation
Kinston
G—>A
D194N
LN
Urangan
G—>A
G16S
Gout
Mashad
A—>T
D20V
Gout
Montreal
T ^ C
M57T
LN
Toowong
G->A
G58R
Gout
London
C ^ T
S110L
Gout
Ann Arbor
T—>G
I132M
Gout
Tokyo
G—>A
G140D
LN
Brisbane
C-VT
T168I
Gout
neurological manifestations is not understood. The most
significant abnormality identified in neurotransmitter sys-
tems is in the dopaminergic pathway (Chapter 32). There
is no known treatment for the central nervous system dys-
function. Allopurinol has been used in the management of
the hyperuricemia.
Adenine Phosphoribosyltransferase
(APRT) Deficiency
APRT isolated from erythrocytes is a dimer with each
subunit having a molecular weight of 19,481: the gene is
located on chromosome 16. This autosomal recessive trait
results in inability to salvage adenine, which accumulates
and is oxidized to
2
,
8
-dihydroxyadenine by xanthine oxi-
dase (Figure 27-20). The main clinical abnormality is the
excretion of
2
,
8
-dihydroxyadenine as insoluble material
(gravel) in the urine. These stones can be confused with
those of urate on routine analysis. Thus, appropriate chem-
ical analyses are required, particularly in the pediatric age
group, to identify APRT-deficient individuals. The neuro-
logical disorders characteristic of HPRT deficiency are not
found in APRT deficiency, indicating that APRT may not
play a significant role in the overall regulation of purine
metabolism in humans. APRT deficiency is treated with a
low-purine diet and allopurinol.
Adenosine Deaminase (ADA) Deficiency and
Purine Nucleoside Phosphorylase (PNP) Deficiency
ADA deficiency and PNP deficiency are two autosomal
recessive traits that cause immune system dysfunction.
The reactions catalyzed by ADA and PNP are shown in
Figure 27-21. Both enzymes function in conversion of
adenosine and deoxyadenosine to hypoxanthine. PNP is
also involved in conversion of guanosine and deoxyguano-
sine to guanine. In ADA or PNP deficiency, the appro-
priate substrates accumulate along with other alternative
8
-H ydroxyadenine
Xanthine
oxid ase
2,8-D ihydroxyadenine
F IG U R E 2 7 -2 0
Metabolic pathways for the conversion of adenine. Adenine is normally
salvaged by conversion to AMP by adenine phosphoribosyltransferase
(APRT). In the absence of APRT, adenine is oxidized to the highly
insoluble product
2
,
8
-dihydroxyadenine by xanthine oxidase.
