catabolism of purines & gout of purine... · dec. salvage pathway – dec. imp & gmp –...

Catabolism of Purines &

GOUT

1


GOUT

1


GOUT

1


GOUT

1

• Nucleotides of cell undergo continual turnover.

Nucleotides

NucleosidesNucleotidase

2

Nucleoside Phosphorylase

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 catabolism2


• Nucleotides of cell undergo continual turnover.

NucleotidesNucleotidase

2


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 catabolism2


AMP

Nucleotidase2H O

Pi

Adenosine

2H O

Adenosinedeaminase(ADA)

NH4

NN

NH2

R-5-P

N

N

N

N

NH2

3


Ribose

NN

N

NHN

Ribose 1phosphate

O

N

N

Adenosine is notdegraded by PNP, butconverted to inosine &further metabolized NHN 3

IMP

NucleotidaseH2O

Pi

Inosine


NH4

NN

N

N

HN

ON

N

3


Hypoxanthine

Pi Purine nucleoside

phosphorylase (PNP)

NRibose

N

Ribose 1phosphate

O

N

N

NH3

Hypoxanthine

Xanthine

Xanthine OxidaseH2O + O2

H2O2

Guanine deaminase

P

i Ribose 1

phosphate

N

N

N

HN

O

NHN

O

HN

O

O 4

Xanthine

2H O +O

2

H2O2Xanthine Oxidase

URICACID

Guanine deaminase

NH3

HN

NHNH

HN

NH

NH

NH

HN

O

O

O

O 2,6,8 –trioxy purineDr. N. Sivaranjani 4

Xanthine Oxidase

GMP

Nucleotidase

Guanosine

Guanine deaminase

Purine nucleosidephosphorylase

2H O

Pi

P

i Ribose 1

phosphate

HN

HN

HN

O

O

O

4

Xanthine Oxidase

Guanine

Guanine deaminase

H2ONH3

HN

HN

HN

O

O

NH

N

N

HN

O

NH2

2,6,8 –trioxy purineDr. N. Sivaranjani 4

AMP

Adenosine

Purine BasesIMP

Inosine

Adenine nucleotide aredegraded as Hypoxanthine

Hypoxanthine

Xanthine

XMP Xanthosine

Adenine nucleotide aredegraded as Hypoxanthine

Guanine nucleotide aredegraded as Xanthine

URIC ACID

Guanosine

Guanine

GMPPurine Bases

IMP

Inosine

Hypoxanthine

Guanine

Xanthine Guanine nucleotide are

degraded as Xanthine

URIC ACID

Xanthine oxidase

• Found in LIVER & Small intestine

• Metallo flavoprotein

• Contains FAD, Molybdenum and Iron

• This reaction produces H2O2 (reactive oxygen species)

H2O2 H2O + O2Catalase

• Found in LIVER & Small intestine

Hypoxanthine

URICACID

XO

Xanthine

XO

• Contains FAD, Molybdenum and Iron

• This reaction produces H2O2 (reactive oxygen species)

H2O2 H2O + O2

URICACID

• The end product of purine catabolism is uric acid in humans.

• N excreted as uric acid is very little in humans, as humans areureotelic (nitrogen is excreted as urea).

• In birds, amphibians and reptiles are uricotelic – they excrete uricacid as major end product of purine and amino acid catabolism.

• Lower primates and some mammals have the enzyme uricase whichconverts uric acid to allantoin (which is more soluble).













Breakdown of Endogenous purineDiet -300 mg

Purine nucleotidesCatabolized

URIC ACIDBody uric acid pool in Men 1200 mg,Female – 600 mg

Sources and excretion of Uric acid

RenalExcretion


URIC ACIDFemale – 600 mg

2/3

De novo synthesis – 400 mgDiet -300 mg


URIC ACID

Sources and excretion of Uric acid

Gut


URIC ACID

UricolysisCO2 + NH3

Normal serum Uric acid concentration :

• 3 - 7 mg /dl in males , 2 - 5 mg/dl in females

• Uric acid pool –It is on average of 1200 mg

Excretion - 500 to 700 mg /day excreted

• Uric acid is cleared by both glomerular filtration and tubularsecretion.

• Uric acid acts as Natural ANTIOXIDANT



















Hyperuricemia and gout:

• Hyperuricemia –

• increased serum uric acid levels above 7 mg/dl inMen & above 6 mg/dl in women.

Causes – Excessive Alcohol consumption, CRF,inherited metabolic disorders, Malignancies, Pre-eclampsia.

Gout is a metabolic disorder of purine catabolism, resulting inoverproduction of uric acid.

• At physiological pH , uric acid is found in a minimal soluble form asMono sodium urates – easily ppt at lower temperature.



















• Types of gout :

Primary gout :

Inherited - 90% ,due to an Inborn error of metabolism caused bydefective enzymes of Purine synthesis.

Idiopathic - 10 % cases

1) Variant form of PRPP synthetase- not subject to allosteric control.

2) Variant of PRPP glutamyl amidotransferase - not sensitive tofeedback control.

3) Glucose 6 phosphatase deficiency - Von Gierke’s disease G-6-P enters HMP shunt produces excess R-5-P & PRPP – purine overproduction. Lactic acidosis in Von Gierke’s disease – impairs UA excretion.

• Types of gout :

Primary gout :






• Types of gout :

Primary gout :






• Types of gout :

Primary gout :






4) Deficiency of enzymes of salvage pathway –HGPRT deficiencyleading to Lesch-Nyhan syndrome.

Dec. utilization of purines by salvage pathway – diverts PRPP to purine synthesis

Dec. salvage pathway – dec. IMP & GMP – impairs feedback reg. of denovosynthesis 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 andPRPP synthesis – overproduction of purines.




shunt.


4) Deficiency of enzymes of salvage pathway –HGPRT deficiencyleading to Lesch-Nyhan syndrome.




shunt.





shunt.


Glucose 6phosphateNADP+

NADPH

2 GSH

G-S-S-

G

PRPP

Ribose 5phosphate

PRPP synthetase

Glutathionereductase

5-Phosphoribosylamine

Inosine monophosphate

GMP AMP

Hypoxanthine

Xanthine

URICACID

XO XO

Guanine

HGPRTHypoxanthine

HMP shunt

PRPP

Ribose 5phosphate

PRPP synthetase Glutamine

PRPP Glutamylamidotransferase

Glucose

G-6-phosphatase

5-Phosphoribosylamine

Inosine monophosphate

GMP AMP Adenine

Hypoxanthine

APRT

PRPP Glutamylamidotransferase

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.



nucleic acids








nucleic acids








nucleic acids






b) Reduced excretion of uric acid

i) Chronic Renal failure due to reduced GFR.

ii) Increased alcohol consumption leads to lactic acidosis - Lactic aciddecreases tubular excretion of uric acid.

iii) Ketoacidosis – decreases the tubular excretion of uric acid

iv) Thiazide diuretics inhibits tubular secretion of uric acid.
















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

16

• In Gout , serum urate levels exceed solubility limit, leading toformation of MSU crystals and get deposited in joints.

These deposits are called Tophi.inflammation of jointspainful acute gouty arthritis chronic gouty arthritis.

• Other complications like urolithDr.iNa. Sisvariasnjaniand renal damage. 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

16

• In Gout , serum urate levels exceed solubility limit, leading toformation of MSU crystals and get deposited in joints.

These deposits are called Tophi.inflammation of jointspainful acute gouty arthritis chronic gouty arthritis.

• Other complications like urolithDr.iNa. Sisvariasnjaniand renal damage. 16

increased serum uric acid

Deposited in areas where bodytemperature is lower – Tophi

Renal calculi /stoneRenal damage

Gouty arthritis

” redness, swelling, and pain“-hallmarks of a gout attack.

Mono-sodium urate crystalsSevere form – body uric acidpool reach 20,000 -30,000 mg



Gouty arthritis

increased serum uric acid

Deposited in KidneyDeposited in areas where bodytemperature is lower – Tophi


Gouty arthritis

” redness, swelling, and pain“-hallmarks of a gout attack.

Mono-sodium urate crystalsSevere form – body uric acid



Gouty arthritis

Often HISTORY is - patient have few drinks at night , go to sleep symptomless ,but are awakened during early hrs by severe joint pains.

• Hyperuricemia doesn't always cause gout. Over the course of yrs, sharp uratecrystals build up in the synovial fluid of the joints.

Precipitating event - infection, surgery, stress or often heavy ALCOHOL drink.

Often HISTORY is - patient have few drinks at night , go to sleep symptomless ,but are awakened during early hrs by severe joint pains.

• Hyperuricemia doesn't always cause gout. Over the course of yrs, sharp uratecrystals build up in the synovial fluid of the joints.

Precipitating event - infection, surgery, stress or often heavy ALCOHOL drink.

Investigations :

• Serum uric acid level -increased

• Microscopic Examination of Synovial

fluid reveals uric acid crystals - rod / needle –shaped crystals.

• Birefringent crystals under polar microscope isdiagnostic.

Investigations :





Investigations :





Investigations :





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 - Colchicine is used for treatment of goutyarthritis. NSAID - indomethacin , ibuprofen. Corticosteroids alsouseful for acute attacks.

2. Uricosuric drugs – Probenecid.

• Low intake of Purine diet- like red meat, acidy fruits andvegetables, lentils


Drugs:





Drugs:





Drugs:



C

HN

O

C

O

3. Xanthine oxidase inhibitors – ALLOPURINOLdrug of choice for treatment of Gout.

It is structural analog of hypoxanthine.

Competitively inhibits XO enzyme.

NH

C

CN

N

C

C

HN

O

C

C

C

C

HN

O

Allopurinol Alloxanthine

O NH

XO

Suicide inhibition

C

HN

NH

C

CC

N

N

C

HN

O

Hypoxanthine

3. Xanthine oxidase inhibitors – ALLOPURINOLdrug of choice for treatment of Gout.

It is structural analog of hypoxanthine.

Competitively inhibits XO enzyme.

C

HN

C

NH

C

CN

C

Alloxanthine

Hypoxanthine , Xanthineare more soluble andexcreted in urine.

Pseudogout :

• Serum uric acid level normal.

• Symptoms as seen in gout.

• But it is characterized by deposition of calcium – pyrophosphatecrystals in joints.

Pseudogout :




Pseudogout :




Pseudogout :




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 , learningdisabilities occur.

• Neurological symptoms may be due to dependenceof brain on the salvage pathway.

• Nephrolithiasis – leads to renal failure.

• Inherited X-linked recessive disorder, affects only males





















HypouricemiaDecreased in uric acid level

Xanthinuria• Xanthine oxidase deficiency, due to either genetic defect or due to severe

LIVER damage.

• Inc. excretion of xanthine & hypoxanthine

• So decreased uric acid

• Xanthine lithiasis occur in severe XO def.

Hypoxanthine

Xanthine

XO

HypouricemiaDecreased in uric acid level

Xanthinuria• Xanthine oxidase deficiency, due to either genetic defect or due to severe

LIVER damage.

• Inc. excretion of xanthine & hypoxanthine

• So decreased uric acid

• Xanthine lithiasis occur in severe XO def.

Xanthine

URICACID

XO

Adenosine deaminase deficiency

• Leads to Both T and B cells are dysfunctional – Severe CombinedImmunodeficiency (SCID )

ADA

Adenosine Inosine , dAdenosine dInosine

• Immune dysfunction is due to high levels of deoxy Adenosine• Deoxyadenosine is converted to dAMP, dADP, dATP.• dATP allosterically inhibits Ribonucleotide reductase - decreases

DNA synthesis.

ADA


Adenosine deaminase deficiency

• Leads to Both T and B cells are dysfunctional – Severe CombinedImmunodeficiency (SCID )

ADA

Adenosine Inosine , dAdenosine dInosineADA

• Immune dysfunction is due to high levels of deoxy Adenosine• Deoxyadenosine is converted to dAMP, dADP, dATP.• dATP allosterically inhibits Ribonucleotide reductase - decreases

DNA synthesis.

ADA


Purine-nucleoside phosphorylase deficeincy

Hypoxanthine , Guanosineuric acid formation is decreased.

• Impaired T-cells function with normal B cells function.

• Here dGTP accumulates which inhibits Ribonucleotide reductase.

• PNP deficiencyPNP

Inosineuric acid formation is decreased.



Purine-nucleoside phosphorylase deficeincy

, Guanosine Guanineuric acid formation is decreased.



PNP

uric acid formation is decreased.



ADA and PNP deficiency

• both are inherited as autosomal recessive

• Hypouricemia seen

• Both associated with symptoms of recurrent and chronic infections













catabolism of purines & gout of purine... · dec. salvage pathway – dec. imp & gmp –...

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