Upload
ramesh-gupta
View
78
Download
12
Embed Size (px)
Citation preview
Inborn Errors
of
Purine and Pyrimidine Metabolism
R. C. Gupta
Professor and Head
Department of Biochemistry
National Institute of Medical Sciences
Jaipur, India
Inborn errors occur due to mutations ingenes encoding enzymes
Such errors can occur in enzymes involvedin purine and pyrimidine metabolism also
Purine metabolism is affected morecommonly than pyrimidine metabolism
The enzyme defect can affect:
De novo synthesis of purines
Salvage of purines
Catabolism of purines
Disorders of purine metabolism
Important disorders of purine metabolism are:
Primary gout
Lesch-Nyhan syndrome
Adenosine deaminase deficiency
Purine nucleoside phosphorylase deficiency
Primary gout can occur due to X-linked recessive defects in:
Phosphoribosyl pyrophosphate
(PRPP) synthetase
Hypoxanthine guanine
phosphoribosyl transferase (HGPRT)
Primary gout
Mutations in PRPP synthetase gene can result in the synthesis
of an enzyme having:
High Vmax
Low Km
Resistance to allosteric inhibition
The mutant PRPP synthetase becomessuperactive
This increases the synthesis of PRPP
De novo synthesis of purine nucleotides isincreased
In HGPRT deficiency, salvage of hypo-xanthine and guanine is decreased
Decreased salvage relieves the allostericinhibition on de novo synthesis
Decreased use of PRPP in salvage path-way diverts PRPP to de novo synthesis
Increased catabolism results in increased formation of uric acid
Increased synthesis results in increasedcatabolism of purines
Thus, defects in PRPP synthetase and HGPRT increase de novo synthesis of purines
Due to increased formation, serum uric acidlevel is raised (hyperuricaemia)
Urinary excretion of uric acid is alsoincreased (hyperuricosuria)
Hyperuricaemia and hyperuricosuria causevarious signs and symptoms of gout
Uric acid is undissociated at pH below5.8
At pH above 5.8, it is dissociated to formurate
At pH 5.8, uric acid and urate arepresent in equimolar concentrations
Both uric acid and urate are poorlysoluble
But uric acid is even less soluble thanurate
As pH of plasma is above 5.8, uric acid isalways present as urate in plasma
The solubility limit of urate is 7 mg/dl
When the concentration exceeds thesolubility limit, urate gets precipitated
The precipitation occurs mainly in andaround joints
Deposits of urate crystals are known astophi
The needle-shaped tophi in synovial fluidattract neutrophils and macrophages
Neutrophils and macrophages engulf thecrystals
The neutrophils release:
Oxygen-derived free radicals
Leukotriene B4
Chemotactic factors
Lysosomal protease and collagenase
The chemicals released by neutrophilsand macrophages cause inflammation
Inflammation produces acute goutyarthritis
This may progress to chronic goutyarthritis
Acute gouty arthritis is treated with anti-inflammatory drugs and colchicine
The anti-inflammatory drugs reduceinflammation
Colchicine prevents activation of neutro-phils
Hyperuricosuria can lead to precipitationof uric acid in the kidneys
This can lead to formation of uric acidstones
Distal convoluted tubules and collectingducts are the likely sites for such stones
Urine is acidified in distal convolutedtubules and collecting ducts
When urinary pH decreases below 5.8,urate is converted into uric acid
Uric acid gets precipitated due to its lowsolubility
Specific treatment of primary gout and uricacid stones is to lower serum uric acid
Production of uric acid can be decreasedby allopurinol
Allopurinol is a structural analogue ofhypoxanthine
It is a competitive inhibitor of xanthineoxidase
On administration of allopurinol:
Xanthine oxidase is inhibited
Formation of uric acid is decreased
Hypoxanthine and xanthine become the end products of purine catabolism
Hypoxanthine and xanthine are highlysoluble
They are easily excreted in urine
Therefore, chances of stone formationare decreased
Febuxostat is a newer uric acid-loweringdrug
It is a non-competitive inhibitor ofxanthine oxidase
It is used in patients who cannot tolerateallopurinol
Alkalinisation of urine is also helpful inpreventing uric acid stones
It converts uric acid into the more solubleurate
Uricosuric drugs, e.g. probenecid, areused to increase the excretion of uric acid
Secondary (acquired)
gout may occur due to:
Excessive breakdown of cells
Decreased excretion of uric acid
Excessive breakdown of cells occurs in:
Leukaemia
Polycythaemia
Pernicious anaemia
Haemolytic anaemia
Excessive breakdown of cells leads toexcessive catabolism of DNA
Excessive catabolism of purines resultsin excessive formation of uric acid
Excessive production of uric acid causeshyperuricaemia
Uric acid is excreted in urine
Excretion is decreased in renal disorders
This results in accumulation of uric acidin blood and hyperuricaemia
This is an X-linked recessive disorder inwhich HGPRT is completely absent
This results in severe hyperuricaemiaand hyperuricosuria
Gouty arthritis occurs; uric acid stonesare formed in the kidneys
Lesch-Nyhan syndrome
Brain in incapable of de novo synthesis ofpurine nucleotides
It is dependent solely on the salvagepathway for purine nucleotides
Salvage is blocked due to absence ofHGPRT
The neurological features are:
Mental retardation
Spastic paralysis
Aggressive and self-destructive behavior
Severe neurological abnormalitiesoccur in Lesch-Nyhan syndrome
Neurological features of Lesch-Nyhansyndrome are due to deficiency of purinenucleotides in brain
They are not alleviated by allopurinol asthey are not due to an excess of uric acid
ADA deficiency is inherited as an auto-somal recessive defect
ADA deficiency causes severe combinedimmunodeficiency disease (SCID)
Both humoral and cell-mediated immunityare severely impaired in SCID
Adenosine deaminase (ADA) deficiency
SCID can result from a variety of geneticdefects involving a number of enzymes,receptors or signal transducers
About half of the cases of SCID are dueto ADA deficiency
Increased levels of adenosine anddeoxyadenosine are believed to interferewith the formation of lymphocytes
B lymphocytes as well as T lymphocytesare decreased in number, and theirfunctioning is impaired
Purine nucleoside phosphorylase
deficiency
Deficiency of purine nucleoside phospho-rylase is an autosomal recessive defect
It results in increased level of deoxy-guanosine
High deoxyguanosine levels interfere withT lymphocyte differentiation
This causes selective deficiency of Tlymphocytes
T lymphocyte deficiency impairs cell-mediated immunity
Disorders of pyrimidine metabolism are rare
Moreover, they are less severe as compared to disorders of purine
metabolism
Disorders of pyrimidine metabolism
Overproduction of pyrimidines is harm-less as their catabolites are easily
excreted
Deficient production of pyrimidines can cause clinical abnormalities
Important disorders of pyrimidine meta-
bolism are:
Orotic aciduria, type I
Orotic aciduria, type II
The inheritance is autosomal recessive
Orotate phosphoribosyl transferase andOMP decarboxylase are deficient
De novo synthesis of pyrimidines isdecreased
Orotic aciduria, Type I
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
The disease can be easily controlled byoral administration of uridine
All the pyrimidine nucleotides can besynthesized from uridine
The inheritance is autosomal recessive
There is deficiency of OMP decarboxylaseonly
OMP and orotic acid are excreted in urine
Orotic aciduria, Type II
The only clinical abnormality in oroticaciduria, type II is megaloblastic anaemia
This can be easily controlled by oraladministration of uridine