Purine catabolism

explains the breakdown of purine. source and excretion of purine is explained. hyperuricemia and hypouricemia is discussed. types of Gout, clinical features and treatment is included.

1. Catabolism of Purines &
GOUT
Dr. N. Sivaranjani
Asst. Prof
Dr. N. Sivaranjani 1

2. •Nucleotides of cell undergo continual turnover.
Nucleotides
Nucleosides
Free bases + R-1-P
•Some of bases are reused to form nucleotides by Salvage pathway.
•Others are degraded to products that are excreted.
•Uric acid is end product of purine catabolism
Nucleotidase
Nucleoside Phosphorylase
Dr. N. Sivaranjani 2

3. AMP
IMP
Nucleotidase
Nucleotidase
H
2O
H
2O
Pi
Pi
Adenosine Inosine
H
2O
Adenosine
deaminase
(ADA)
NH
4
Hypoxanthine
Pi
Purine nucleoside
phosphorylase(PNP)
Ribose 1 phosphateRibose
N
N
N
N
NH
2
Ribose
N
N
N
HN
O
NH
N
N
HN
O
R-5-P
N
N
N
N
NH
2
Adenosine is not
degraded by PNP, but
converted to inosine&
further metabolized
Dr. N. Sivaranjani 3

4. Hypoxanthine
Xanthine
Xanthine Oxidase
H
2O + O
2
H
2O
2
H
2O + O
2
H
2O
2
Xanthine Oxidase
URIC ACID
GMP
Nucleotidase
Guanosine
Guanine
Guanine deaminase
H
2ONH
3
Purinenucleoside
phosphorylase
H
2O
Pi
Pi
Ribose 1 phosphate
2,6,8 –trioxypurine
N
N
N
HN
O
NH
N
NH
HN
O
NH
NH
NH
HN
O
O
O
O
NH
N
N
HN
O
NH
2
Dr. N. Sivaranjani 4

5. AMP
Adenosine
Hypoxanthine
Guanosine
Guanine
GMP
Xanthine
URIC ACID
PurineBases
IMP
Inosine
XMP Xanthosine
Adenine nucleotide are
degraded as Hypoxanthine
Guanine nucleotide are
degraded as Xanthine
Dr. N. Sivaranjani 5

6. Xanthineoxidase
•Found in LIVER & Small intestine
•Metalloflavoprotein
•Contains FAD, Molybdenum and Iron
•This reaction produces H
2O
2 (reactive oxygen species)
H
2O
2 H
2O + O
2
Catalase
Hypoxanthine
Xanthine
URIC ACID
XO
XO
Dr. N. Sivaranjani 6

7. •The end product of purinecatabolism is uric acidin humans.
•N excreted as uric acid is very little in humans, as humans are
ureotelic(nitrogen is excreted as urea).
•In birds, amphibians and reptiles are uricotelic–they excrete uric
acid as major end product of purineand amino acid catabolism.
•Lower primates and some mammals have the enzyme uricasewhich
converts uric acid to allantoin(which is more soluble).
Dr. N. Sivaranjani 7

8. Sources and excretion of Uric acid
Gut
Breakdown of Endogenous purine De novo synthesis –400 mg
Diet -
300 mg
Purine nucleotides
URIC ACID
Uricolysis
Renal
Excretion
Catabolized
Body uric acid pool in Men 1200 mg,
Female –600 mg
2/3
CO
2+ NH
3
Dr. N. Sivaranjani 8

9. Normal serum Uric acid concentration :
•3 -7 mg /dlin males , 2 -5 mg/dlin females
•Uric acid pool –It is on average of 1200 mg
Excretion-500 to 700 mg /day excreted
•Uric acid isclearedby both glomerular filtrationand tubular
secretion.
•Uric acid acts as Natural ANTIOXIDANT
Dr. N. Sivaranjani 9

10. Hyperuricemiaand gout:
•Hyperuricemia–
•increased serum uric acid levelsabove 7 mg/dl in
Men & above 6 mg/dl in women.
Causes –Excessive Alcohol consumption, CRF,
inherited metabolic disorders, Malignancies, Pre-eclampsia.
Goutis a metabolic disorder of purine catabolism, resulting in
overproduction of uric acid.
•At physiological pH, uric acid is found in a minimal soluble form as
Monosodium urates–easily pptat lower temperature.
Dr. N. Sivaranjani 10

11. •Types of gout:
Primary gout :
Inherited -90% ,due to an Inborn error of metabolism caused by
defective enzymes of Purine synthesis.
Idiopathic -10 % cases
1)Variant form of PRPP synthetase-not subject to allosteric control.
2)Variant of PRPP glutamylamidotransferase-not sensitive to
feedback control.
3)Glucose 6 phosphatase deficiency -Von Gierke’sdisease
G-6-P enters HMP shunt produces excess R-5-P & PRPP –purine overproduction.
Lactic acidosis in Von Gierke’sdisease –impairs UA excretion.
Dr. N. Sivaranjani 11

12. 4) Deficiency of enzymes of salvage pathway –HGPRTdeficiency
leading toLesch-Nyhansyndrome.
Dec. utilization of purines by salvage pathway –diverts PRPP to purine synthesis
Dec. salvage pathway –dec.IMP & GMP –impairs feedback reg. of denovo
synthesis of purine –leads to overproduction of purines.
5) Elevation of Glutathione reductase
It coverts oxidized Glutathione to reduced form by utilizing NADPH from HMP
shunt.
Abnormal activity of GR -Inc. NADP+ -Inc. HMP shunt –which rises R-5-P and
PRPP synthesis –overproduction of purines.
Dr. N. Sivaranjani 12

13. Glucose 6 phosphate
HMP shunt
Ribose 5 phosphate
NADP
+
NADPH
2 GSH
G-S-S-G
PRPP
PRPP synthetase
Glutamine
5-Phosphoribosylamine
Inosine monophosphate
GMP AMP Adenine
Hypoxanthine XanthineURIC ACID
XO XO
Guanine
HGPRT
Hypoxanthine
APRT
PRPP Glutamyl
amidotransferase
Glutathione
reductase
Glucose
G-6-phosphatase
Dr. N. Sivaranjani 13

14. Secondary gout:
•Due to various disease causing increased synthesis or decreased excretion of uric
acid.
a) Overproduction of uric acid –due to enhanced turn over rate of
nucleic acids
i) Increased tissue turn over due to psoriasis.
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.
Dr. N. Sivaranjani 14

15. b) 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 inhibits tubular secretion of uric acid.
Dr. N. Sivaranjani 15

16. Clinical features:
•Due to the low solubility of uric acid.
•More common in Males, post menopausal women.
•Typical gouty arthritis affects first metatarso
phalangeal joint (GREAT TOE) –Classical site
•In Gout , serum uratelevels exceed solubility limit, leading to
formation of MSU crystals and get deposited in joints.
These deposits are called Tophi.
inflammation of joints
painful acute gouty arthritis chronic gouty arthritis.
•Other complications like urolithiasisand renal damage.
Dr. N. Sivaranjani 16

17. increased serum uric acid
Mono-sodium uratecrystals
Deposited in areas where body
temperature is lower–Tophi
Gouty arthritis
Deposited in Kidney
Renal calculi /stone
Renal damage
”redness,swelling,andpain“
-hallmarksofagoutattack.
Severe form –body uric acid
pool reach 20,000 -30,000 mg
Dr. N. Sivaranjani 17

18. Often HISTORY is -patient have few drinks at night , go to sleep symptomless ,
but are awakened during early hrs by severe joint pains.
•Hyperuricemiadoesn'talwayscausegout.Overthecourseofyrs,sharpurate
crystalsbuildupinthesynovialfluidofthe joints.
Precipitatingevent -infection,surgery,stress or often heavy ALCOHOL drink.
Dr. N. Sivaranjani 18

19. Investigations :
•Serum uric acid level -increased
•Microscopic Examination of Synovial
fluid reveals uric acid crystals -rod / needle –shaped crystals.
•Birefringentcrystalsunder polar microscope is
diagnostic.
Dr. N. Sivaranjani 19

20. Treatment of gout :
•Low intake of Purine diet-like red meat,acidy fruits and
vegetables,lentils
•Restrict Alcohol
•Consume plenty of Water
Drugs:
1.Anti-inflammatory drugs -Colchicineis used for treatment of gouty
arthritis. NSAID -indomethacin , ibuprofen. Corticosteroidsalso
useful for acute attacks.
2.Uricosuricdrugs –Probenecid.
Dr. N. Sivaranjani 20

21. N
H
C
C
N
N
C
C
HN
O
N
H
C
C
C
N
N
C
HN
O
N
H
C
C
N
N
C
C
HN
O
Hypoxanthine
Allopurinol Alloxanthine
O
H
XO
3.Xanthine oxidase inhibitors –ALLOPURINOL
drug of choice for treatment of Gout.
It is structural analog of hypoxanthine.
Competitively inhibits XO enzyme.
Suicide inhibition
Hypoxanthine , Xanthine
are more soluble and
excreted in urine.
Dr. N. Sivaranjani 21

22. Pseudogout:
•Serum uric acid level normal.
•Symptoms as seen in gout.
•But it is characterized by deposition ofcalcium –pyrophosphate
crystals in joints.
Dr. N. Sivaranjani 22

23. Lesch-Nyhansyndrome:
•Inherited X-linked recessive disorder, affects only males
•Enzyme defect –hypoxanthine guanine phoshoribosyltransferase(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 disabilitiesoccur.
•Neurological symptoms may be due to dependence
of brainon the salvage pathway.
•Nephrolithiasis –leads to renal failure.
Dr. N. Sivaranjani 23

24. Hypouricemia
Decreased in uric acid level
Xanthinuria
•Xanthineoxidasedeficiency, due to either genetic defect or due to severe
LIVER damage.
•Inc. excretion of xanthine& hypoxanthine
•So decreased uric acid
•Xanthinelithiasisoccur in severe XO def.
Hypoxanthine
Xanthine URIC ACID
XO
XO
Dr. N. Sivaranjani 24

25. Adenosine deaminasedeficiency
•Leads to Both T and B cells are dysfunctional –Severe Combined
Immunodeficiency (SCID )
Adenosine Inosine , dAdenosine dInosine
•Immune dysfunction is due to high levels of deoxyAdenosine
•Deoxyadenosineis converted to dAMP, dADP, dATP.
•dATPallostericallyinhibits Ribonucleotidereductase-decreases
DNA synthesis.
ADA
ADA
Dr. N. Sivaranjani 25

26. Purine-nucleoside phosphorylasedeficeincy
•PNP deficiency
Inosine Hypoxanthine , Guanosine Guanine
uric acid formation is decreased.
•Impaired T-cells function with normal B cells function.
•Here dGTPaccumulates which inhibits Ribonucleotidereductase.
PNP PNP
Dr. N. Sivaranjani 26

27. ADA and PNP deficiency
•both are inherited as autosomalrecessive
•Hypouricemiaseen
•Both associated with symptoms of recurrent and chronic infections
Dr. N. Sivaranjani 27

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