so formed is converted to uridine by cy-
are converted to free bases by pyrimidine nucleoside
catabolism of uracil
thymine proceeds in parallel steps, catalyzed by the same
enzymes (Figure 27-31). The rate-determining step is re-
duction to a 5,6-dihydroderivative by dihydropyrimidine
dehydrogenase. In the second step, dihydropyrimidinase
hydrolyzes cleavage of the dihydropyrimidine rings to
ureido compounds. In the third step, /3-ureidopropionasc
hydrolyzes the /1-ureido compounds to
-alanine or /3-
aminoisobutyrate (BAIB), with release of ammonia and
carbon dioxide. Thus, the major end product of the
catabolism of cytosine and uracil is /
that of thymine is BAIB.
High concentrations of BAIB in urine follow exces-
sive cell turnover or destruction (e.g., owing to leukemias
or radiation therapy). High levels of BAIB excretion has
been observed in some Asian families . Its significance is
not known and the high excretors are otherwise normal.
Degradation of /5-alanine and BAIB or their reutilization
in various biosynthetic pathways is possible.
27.12 Abnormalities of Pyrimidine Metabolism
Hereditary orotic aciduria is a rare autosomal recessive
trait. In this disorder, both orotate phosphoribosyltrans-
ferase and orotidine-5'-phosphate decarboxylase activities
(reactions 5 and
in Figure 27-26) are markedly defi-
cient. Recall that these activities occur on the polypeptide
Orotic aciduria is characterized by failure of normal
growth and by the presence of hypochromic erythro-
cytes and megaloblastic bone marrow, none of which
are improved by the usual hematinic agents (e.g., iron,
pyridoxine, vitamin Bi2, and folate). Leukopenia is also
present. Treatment with uridine (2-4 g/d) results in
marked improvement in the hematological abnormal-
ities, in growth and development, and in decreased
excretion of orotic acid. These patients are pyrimi-
dine auxotrophs and require an exogenous source of
pyrimidine just as all humans need vitamins, essential
amino acids, and essential fatty acids.
Deficiency of folate or vitamin B\i
can cause hema-
tological changes similar to hereditary orotic aciduria.
Folate is directly involved in thymidylic acid synthesis
and indirectly involved in vitamin B
aciduria without the characteristic hematological abnor-
malities occurs in disorders of the urea cycle that lead to ac-
cumulation of carbamoyl phosphate in mitochondria (e.g.,
ornithine transcarbamoylase deficiency; see Chapter 17).
The carbamoyl phosphate exits from the mitochondria
and augments cytosolic pyrimidine biosynthesis. Treat-
ment with allopurinol or
-azauridine also produces orotic
aciduria as a result of inhibition of orotidine-5'phosphatc
decarboxylase by their metabolic products.
Dihydropyrimidine dehydrogenase deficiency
cause unexpected toxic effects to 5-fluorouracil admin-
istration (see page 641).
Supplemental Readings and References
H. H. Balfour, Jr.: Antiviral drugs.
N ew E n g la n d J o u rn a l o f M ed icin e
R. Curto, E. O. Voit, and M. Cascante: Analysis of abnormalities in purine
metabolism leading to gout and to neurological dysfunctions in man.
B io ch em ica l J o u rn a l
B. T. Emmerson: The management of gout.
N ew E n g la n d Jo u rn a l o f
M ed icin e
M. D. Harris, L. B. Siegel, and J. A. Alloway: Gout and hyperuricemia.
A m erica n F am ily P h ysicia n
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S. Haste, E. De Clercq, and J. Balzarini: Role of antimetabolites of purine
and pyrimidine nucleotide metabolism in tumor cell differentiation.
B io -
c h em ica l P h a rm a co lo g y
58, 539 (1999).
W. L. Nyhan and D. F. Wong: New approaches to understanding Lesch-
N ew E n g la n d Jo u rn a l o f M ed ic in e
334, 1602 (1996).
J. R. Pittman and M. H. Brass: Diagnosis and management of gout.
A m erica n
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J. G. Puig, A. D. Michan, M. L. Jimenez, et ah: Clinical spectrum and uric
A rch ives o f In tern a ! M e d icin e
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D. Rush: Periconceptional folate and neural tube defect.
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o f C lin ica l N u tritio n
59(Suppl), 511 S (1994).
A. Saven and L. Piro: Newer purine analogues for the treatment of hairy-cell
N ew E n g la n d Jo u rn a l o f M ed icin e
330, 691 (1994).
V. Serre, G. Hedeel, and X. Liu: Allosteric regulation and substrate chan-
neling in multifunctional pyrimidine biosynthetic complexes: analysis of
isolated domains and yeast-mammalian chemeric proteins.
Jo u rn a l o f
M o le c u la r B io lo g y
281, 363 (1998).