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 macrophages release:

PGE2

Tumour necrosis factora (TNFa)

Interleukin-1 (IL-1)

Lysosomal enzymes

The chemicals released by neutrophilsand macrophages cause inflammation

Inflammation produces acute goutyarthritis

This may progress to chronic goutyarthritis

Metatarso-phalangeal joint of big toe is

affected most frequently

Less commonly, other small joints are affected

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

Alcohol decreases urinary excretion ofuric acid

It should be avoided by persons sufferingfrom gout

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