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Inborn errors of purine and pyrimidine metabolism
1. Inborn Errors
of
Purine and Pyrimidine Metabolism
R. C. Gupta
Professor and Head
Department of Biochemistry
National Institute of Medical Sciences
Jaipur, India
2. Inborn errors occur due to mutations in
genes encoding enzymes
Such errors can occur in enzymes involved
in purine and pyrimidine metabolism also
Purine metabolism is affected more
commonly than pyrimidine metabolism
3. The enzyme defect can affect:
De novo synthesis of purines
Salvage of purines
Catabolism of purines
Disorders of purine metabolism
4. Important disorders of
purine metabolism are:
Primary gout
Lesch-Nyhan syndrome
Adenosine deaminase deficiency
Purine nucleoside phosphorylase
deficiency
5. Primary gout can occur due to X-linked
recessive defects in:
Phosphoribosyl
pyrophosphate
(PRPP) synthetase
Hypoxanthine
guanine
phosphoribosyl
transferase
(HGPRT)
Primary gout
6. Mutations in PRPP synthetase
gene can result in the synthesis
of an enzyme having:
High Vmax
Low Km
Resistance to allosteric inhibition
7. The mutant PRPP synthetase becomes
superactive
This increases the synthesis of PRPP
De novo synthesis of purine nucleotides is
increased
8. In HGPRT deficiency, salvage of hypo-
xanthine and guanine is decreased
Decreased salvage relieves the allosteric
inhibition on de novo synthesis
Decreased use of PRPP in salvage path-
way diverts PRPP to de novo synthesis
9. Increased catabolism results in increased
formation of uric acid
Increased synthesis results in increased
catabolism of purines
Thus, defects in PRPP synthetase and HGPRT
increase de novo synthesis of purines
10. Due to increased formation, serum uric acid
level is raised (hyperuricaemia)
Urinary excretion of uric acid is also
increased (hyperuricosuria)
Hyperuricaemia and hyperuricosuria cause
various signs and symptoms of gout
11.
12.
13. Uric acid is undissociated at pH below
5.8
At pH above 5.8, it is dissociated to form
urate
At pH 5.8, uric acid and urate are
present in equimolar concentrations
14. Both uric acid and urate are poorly
soluble
But uric acid is even less soluble than
urate
As pH of plasma is above 5.8, uric acid is
always present as urate in plasma
15. The solubility limit of urate is 7 mg/dl
When the concentration exceeds the
solubility limit, urate gets precipitated
The precipitation occurs mainly in and
around joints
16. Deposits of urate crystals are known as
tophi
The needle-shaped tophi in synovial fluid
attract neutrophils and macrophages
Neutrophils and macrophages engulf the
crystals
19. The chemicals released by neutrophils
and macrophages cause inflammation
Inflammation produces acute gouty
arthritis
This may progress to chronic gouty
arthritis
22. Acute gouty arthritis is treated with anti-
inflammatory drugs and colchicine
The anti-inflammatory drugs reduce
inflammation
Colchicine prevents activation of neutro-
phils
23. Hyperuricosuria can lead to precipitation
of uric acid in the kidneys
This can lead to formation of uric acid
stones
Distal convoluted tubules and collecting
ducts are the likely sites for such stones
24. Urine is acidified in distal convoluted
tubules and collecting ducts
When urinary pH decreases below 5.8,
urate is converted into uric acid
Uric acid gets precipitated due to its low
solubility
25. Specific treatment of primary gout and uric
acid stones is to lower serum uric acid
Production of uric acid can be decreased
by allopurinol
Allopurinol is a structural analogue of
hypoxanthine
It is a competitive inhibitor of xanthine
oxidase
26.
27. On administration
of allopurinol:
Xanthine oxidase is inhibited
Formation of uric acid is decreased
Hypoxanthine and xanthine become
the end products of purine catabolism
28. Hypoxanthine and xanthine are highly
soluble
They are easily excreted in urine
Therefore, chances of stone formation
are decreased
29. Febuxostat is a newer uric acid-lowering
drug
It is a non-competitive inhibitor of
xanthine oxidase
It is used in patients who cannot tolerate
allopurinol
30. Alkalinisation of urine is also helpful in
preventing uric acid stones
It converts uric acid into the more soluble
urate
Uricosuric drugs, e.g. probenecid, are
used to increase the excretion of uric acid
31. Alcohol decreases urinary excretion of
uric acid
It should be avoided by persons suffering
from gout
34. Excessive breakdown of cells leads to
excessive catabolism of DNA
Excessive catabolism of purines results
in excessive formation of uric acid
Excessive production of uric acid causes
hyperuricaemia
35. Uric acid is excreted in urine
Excretion is decreased in renal disorders
This results in accumulation of uric acid
in blood and hyperuricaemia
36. This is an X-linked recessive disorder in
which HGPRT is completely absent
This results in severe hyperuricaemia
and hyperuricosuria
Gouty arthritis occurs; uric acid stones
are formed in the kidneys
Lesch-Nyhan syndrome
37. Brain in incapable of de novo synthesis of
purine nucleotides
It is dependent solely on the salvage
pathway for purine nucleotides
Salvage is blocked due to absence of
HGPRT
38. The neurological features are:
Mental retardation
Spastic paralysis
Aggressive and self-
destructive behavior
Severe neurological abnormalities
occur in Lesch-Nyhan syndrome
39. Neurological features of Lesch-Nyhan
syndrome are due to deficiency of purine
nucleotides in brain
They are not alleviated by allopurinol as
they are not due to an excess of uric acid
40. ADA deficiency is inherited as an auto-
somal recessive defect
ADA deficiency causes severe combined
immunodeficiency disease (SCID)
Both humoral and cell-mediated immunity
are severely impaired in SCID
Adenosine deaminase (ADA) deficiency
41. SCID can result from a variety of genetic
defects involving a number of enzymes,
receptors or signal transducers
About half of the cases of SCID are due
to ADA deficiency
42. Increased levels of adenosine and
deoxyadenosine are believed to interfere
with the formation of lymphocytes
B lymphocytes as well as T lymphocytes
are decreased in number, and their
functioning is impaired
44. High deoxyguanosine levels interfere with
T lymphocyte differentiation
This causes selective deficiency of T
lymphocytes
T lymphocyte deficiency impairs cell-
mediated immunity
45. Disorders of pyrimidine metabolism are
rare
Moreover, they are less severe as
compared to disorders of purine
metabolism
Disorders of pyrimidine metabolism
46. Overproduction of pyrimidines is harm-
less as their catabolites are easily
excreted
Deficient production of pyrimidines can
cause clinical abnormalities
47. Important disorders of pyrimidine meta-
bolism are:
Orotic aciduria, type I
Orotic aciduria, type II
48. The inheritance is autosomal recessive
Orotate phosphoribosyl transferase and
OMP decarboxylase are deficient
De novo synthesis of pyrimidines is
decreased
Orotic aciduria, Type I
49. There is accumulation of orotic acid
Orotic acid is excreted in urine
The clinical features are:
Retardation of growth
Impairment of immune system
Megaloblastic anaemia
50. The disease can be easily controlled by
oral administration of uridine
All the pyrimidine nucleotides can be
synthesized from uridine
51. The inheritance is autosomal recessive
There is deficiency of OMP decarboxylase
only
OMP and orotic acid are excreted in urine
Orotic aciduria, Type II
52. The only clinical abnormality in orotic
aciduria, type II is megaloblastic anaemia
This can be easily controlled by oral
administration of uridine