Disorders in Purine Metabolism

Rondang R. Soegianto

2013
1. Synthetic Defects of Purine Metabolism

Ability to synthesize purine de novo crucial

to survival of fertilized ovum

Genetic defect  nonviable conception

Disturbed ATP production 

nonviable conception
2. PRPP synthetase superactivity

PRPP - First step in purine de novo biosynthesis

- Regulated allosterically
Harper’s Review Fig 26-11 p365
PRPP synthetase encoded on X- chromosome

Mutations on gene may cause:

- Disruption of normal regulation process
- Superactivity
- Salvage pathway overburdened
- Increased uric acid production
3. Glucose-6-phosphatase Deficiency
(Von Gierke’s Disease)
- Improper PO4 release to produce free
glucose
Only free gluc can pass biological membrane
Important in liver to maintain blood glucose
(prevents hypoglycemia)
- In VGD Gluc-6-P proceeds thru glycolysis
 increased production of lactic acid
Also, increased catab of ATP for
glycolytic intermediates
Resulting in:

- Deficit of inorganic phosphates

- Increased catab of adenine nucleotides
causing hyperuricemia
- Elevation of uric acid levels  competition
lactate and urate at renal tubules for excretion
- May result is nephrolithiasis
4. High Fructose Diet (Drinks)
F  F-1-P Enz: Fructokinase
F is not an insulin secretagogue
Regulation of F metab independent of Gluc
Metabolism

High F intake can deplete ATP

Lack of phosphate to produce ATP causes catab
of adenine nucleotides  elevation of uric
acid in blood and urine  hyperuricemia
5. Salvage Defects

HGPRT Deficiency (Lesch Nyhan Syndrome)

HGPRT transfers phosphoribosyl group of

PRPP to either guanine or hypoxanthine to
form nucleotide
Biochem & Disease Fig 16-3 p285
LNS X-linked
Complete deficiency of HGPRT
Severe neurologic disease
Self mutilation
Urate nephrolithiasis
HGPRT = key to recycle purine bases
HGPRT complete deficiency  all purine
nucleotides catab proceeds to hypox and
guanine  xanthine  uric acid by
xanth oxidase
Allopurinol = competitive inhibitor of
xanthine oxidase
No positive effect in LNS
 Purine Catabolism
Harper’s Review Fig 26-1 p358
At plasma ph, uric acid  Na-urate (salt)
At normal urine pH  urate (acid form)

Uric acid solubility diminishes with

Decreasing pH and temperature.

Accumulation of uric ac in interstitial fluid

 tophus(i) = synovial deposition of uric
acid
crystals  inflammation
In hyperuricemia only 20% develop gout
Depends on degree of hyperuricemia and age
Gender relationship after puberty
Predilection in males
Correct diagnosis:
- Serum uric acid level
- Identify uric acid crystals in an aspirate
of affected joint
Neutrophil phagocytoses urate crystals
 oxygen radicals formation 
further inflammatory reaction
Purine catabolic defects

Adenosine deaminase deficiency

May cause immune deficiency both T and

B cells

Normally, adenosine deaminase activity

highest in lymphoid tissue
Purine Nucleoside Phosphorylase
Deficiency
Catalyzes phosphorolytic degradation of
nucleoside inosine and guanosine
(and deoxy compounds)
Release of ribose-1-P or deoxyribose-1-P
Absence of enzyme  accumulation of
nucleosides  effects T cells (B cells
spared)
Clinical manifestation of purine catabolic
defects: Recurrent infections . . .
Biochem & Disease Fig 16-4 p286
References:

Harper’s Illustrated Biochemistry 27th ed. 2006

Harper’s Review of Biochemistry 20th ed. 1985

Master Medicine. Medical Biochemistry 2nd ed. 2005

Biochemistry and Disease 1996