This document discusses purine metabolism and disorders related to purine and uric acid levels. It begins by outlining the catabolic pathway of purine nucleotides to uric acid. It then describes hyperuricemia and gout disease, which results from uric acid crystal deposition due to high uric acid levels. The document outlines the causes of primary gout, which is mainly due to overproduction of uric acid, and secondary gout, which can result from increased nucleic acid turnover or reduced uric acid excretion. Treatment options for gout including diet, medications like allopurinol and colchicine, and other disorders related to purine metabolism like Lesch-Nyhan syndrome are also summarized.

1. UNIT IV :Nucleic acid metabolism and Genetic
information transfer
TOPIC TO BE DISCUSSED UNDER THIS ACC. TO
SYLLABUS:
Biosynthesis of Purine and pyrimidine nucleotides
Catabolism of Purine nucleotides
 Hyperuricemia and Gout disease
Organization of mammalian genome
Structure of DNA and RNA and their functions
DNA replication (semi conservative model)
Transcription or RNA synthesis
Genetic code, Translation or Protein synthesis and inhibitors

2. 1. CATABOLISM OF
PURINE NUCLEOTIDES

3. The end product of Purine metabolism in humans is uric acid. The
sequence of reactions in purine nucleotide degradation is given below:
1. Action of nucleotidase: The nucleotide monophosphates (AMP,IMP and
CMP) are converted to their respective nucleoside forms (adenosine,
inosine and guanosine) by nucleotidases.
2. Removal of amino group.:The amino group, either from AMP or
adenosine,can be removed to produce IMP or inosine, respectively.
3. Action of Phosphorylase: Inosine and guanosine are/
respectively,converted to hypoxanthine and guanine (purine bases) by
purine nucleoside phosphorylase. Adenosine is not degraded by this
enzyme, hence it has to be converted to inosine.
4. Deamination: Guanine undergoes deamination by guanase to form
xanthine.
5. Formation of uric acid: Xanthine oxidase is an important enzyme that
converts hypoxanthine to xanthine, and xanthine to uric acid.
(SEE NEXT SLIDE FOR SAME)
PURINE METABOLISM

4. DEGRADATION OF PURINE NUCLEOTIDES

5.  Hyperuricemia and Gout
 Lesch-Nyhan syndrome
 Hypouricemia
 Imunodeficiency diseases associated with purine metabolism
DISORDERS OF PURINE METABOLISM

6. 2. HYPERURICEMIA
AND GOUT

7.  The normal concentration of uric acid in the serum of
 Males : 3-7 mg/dl.
 In Females, it is slightly lower than in men (2-5 mg/dl).
 The daily excretion of uric acid is about 500-700 mg.
Hyperuricemia refers to “an elevation in the serum uric
acid concentration.”
This is sometimes associated with increased uric acid excretion
(uricosuria).
HYPERURICEMIA AND GOUT

8. GOUT
 It is a metabolic disease associated with overproduction of
uric acid.
 At the physiological pH, uric acid is found in a more soluble form
as sodium urate.
 In severe hyperuricemia, crystals of sodium urate get deposited in
the soft tissues, particularly in the joints.
 Suchdeposits are commonly known astophi
 This causes inflammation in the joints resulting in a
painful gouty arthritis.
 Sodium urate or uric acid may also precipitate in kidneys & ureters
that results in renal damage &stoneformation

11. TYPES OF GOUT
Gout is of two types:
1. Primary Gout :
 Eventually in males
 Common cause of inflammatory arthritis in men >40
years
2. Secondary Gout:
 Due to renal impairment
 Drugs (Diuretics- such as
thiazide, furosemide)

12.  It isdue to overproduction of uric acid.
 Thisismostly related to increased synthesis of purine nucleotides.
 About 1
0 % of casesof primary gout are idiopathic. (-any
disease or condition which arises spontaneously or for which
the cause is unknown.)
 Incidence of primary gout isabout 3 per 1,000.
 Mostly affecting males.
PRIMARY GOUT

13. CAUSES OF PRIMARY GOUT
Among the five enzymes described, the first three are directly involved in
purine synthesis. The remaining two indirectly regulate purine production.

14. 1.PRPPSynthetase:
 In normal circumstances, PRPP synthetase is under
feedback control by purine nucleotides (ADP& GDP).
 A variant forms of PRPP synthetase-which are not
subjected to feedback regulation-leads to the
increased production of purines.
EXPLANATION: CAUSES OF PRIMARY GOUT
CONTINUED

15. 2. PRPP glutamylamidotransferase:
 Thelack of feedback control of this enzyme by purine
nucleotides also leads to their elevated synthesis.
3. Deficiency of enzymes (HGPRT) of salvage pathway:
 HGPRTenzyme of purine salvage pathway & itsdefect causes
Lesch-Nyhan syndrome.
 It is associated with increased synthesis of purine
nucleotides by two-fold mechanism.(Continued….)
EXPLANATION: CAUSES OF PRIMARY GOUT
CONTINUED

16. Decreased
utilization of
purines
(hypoxanthine &
guanine) by
salvage
pathway
Resulting in
accumulation &
diversion of
PRPPfor purine
nucleotides.
Increase
in Uric
acid level
Defect in
salvage
pathway
Leads to
decreased
levels of IMP
and GMP
Impairment
in feedback
regulation
of their
production
Increase
in Uric
acid
level
FIRSTLY
SECONDLY

17. 4.Glucose-6-phosphatase deficiency:
 Thiscondition isknown as von Gierke's disease (glycogen
storage disease, type I)
 When this enzyme isdeficient, glucose-6- phosphate cannot be
converted to glucose.
 More glucose ischannelled into the HMP shunt,resulting in
increased availability of ribose-5-phosphate and PRPP and
ultimately, purine overproduction.
EXPLANATION: CAUSES OF PRIMARY GOUT
CONTINUED

18. 5. Elevation of glutathione reductase :
Increased glutathione reductase
Generates more NADP+ which is utilized by HMP shunt.
increased ribose 5-phosphate and PRPP synthesis.
Increase in production of uric acid
Gout
EXPLANATION: CAUSES OF PRIMARY GOUT
CONTINUED

19. EXPLANATION: CAUSES OF PRIMARY GOUT CONTINUED

20. SECONDARY GOUT
• Due to various disease causing increased synthesis or decreased
excretion of uric acid.
1. Overproduction of uric acid – due to enhanced turn over rate of
nucleic acids
(i) Increased tissue turn over due to psoriasis (skin disease).
(ii) Rapidly growing malignant tissues–CANCER
(Leukemias, polycythemia, lymphomas).
(iii) Increased tissue break down – after treatment
for large tumor masses –radiotherapy &
chemotherapy, trauma and starvation.

21. SECONDARY GOUT
2) Reduced excretion of uric acid
(i) Chronic Renal failure due to reduced GFR.
(ii) Increased alcohol consumption leads to lactic acidosis - Lactic acid
decreases tubular excretion of uric acid.
(iii) Ketoacidosis – decreases the tubular excretion of uric acid.
( iv)Thiazide diuretics (diuretics means which increase urine output)
inhibits tubular secretion of uric acid.
2
1

22. TREATMENT OF GOUT
• Low intake of Purine diet- like red meat, acidy
fruits and vegetables, lentils
• Restrict alcohol
• Consumption of Plenty of water
Drugs
1. Anti-inflammatory drugs - Colchicine is used for treatment of
gouty arthritis. NSAIDs (Non-steroidal antiinflammatory
drugs) - indomethacin , ibuprofen. Corticosteroids also
useful for acute attacks.
2. Uricosuric drugs – Probenecid.
3. Allopurinol (Xanthine oxidase inhibitor): it is the drug of
choice for treatment of primary gout…continued

23. TREATMENT OF GOUT
 Allopurinol is a structural analog of hypoxanthine that competitively
inhibits the enzyme xanthine oxidase.
 Further, allopurinol is oxidized to alloxanthine by xanthine oxidase.
 Alloxanthine, in turn, is a more effective inhibitor of xanthine
oxidase (suicide inhibition)

24. • Serum uric acid level normal.
• Symptoms as seen in gout.
• But it is characterized by deposition of calcium –
pyrophosphate crystals in joints.
PSEUDOGOUT:

25. LESCH-NYHAN SYNDROME
• Inherited X-linked recessive disorder, affects only males
• Enzyme defect – hypoxanthine guanine phoshoribosyl transferase
(HGPRT)
• Characterized by excess production of uric acid leads to GOUT.
• Self mutilation – bite their fingers and lips
• Neurological abnormalities like mental retardation , aggressive
behavior, learning disabilities occur.
• Neurological symptoms may be due to dependence of brain on the
salvagepathway.