Transcript Lecture 4- Purine degradation-Gout.ppt

THIRD EDITION
Purine
degradation
&
Gout
HUMAN PHYSIOLOGY
(Musculoskeletal
Block)
AN INTEGRATED APPROACH
Dee Unglaub Silverthorn, Ph.D.
1 Lecture
Dr. Sumbul Fatma
•Purine degradation pathway
•Fate of uric acid in humans
•Gout and hyperuricemia:
•Biochemistry
•Types
•Treatment
PowerPoint® Lecture Slide Presentation by
Dr. Howard D. Booth, Professor of Biology, Eastern Michigan University
Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings
Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings
Purine degradation pathway
 The major source of dietary nucleic acids (purines and
pyrimidines) is meat
 Purine and pyrimidine bases are absorbed by the
intestine
 The ingested bases are mostly degraded into different
products by degradation pathways
 These products are then excreted by the body
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Dietary
DNA / RNA
Nucleotides
Pancreatic
nucleases
Nucleotidases
Nucleosides
Nucleosidases
Uric acid
Free purine bases + Ribose
Purine
Degradation
pathway
Purine degradation pathway
 Adenosine and guanosine (purines) are finally
degraded to uric acid by:
 Purine degradation pathway
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CATABOLISM OF
PURINES
Purine nucleoside phosphorylase
AMP
AMP
Deaminase
NTDase
Adenosine
IMP
XMP
NTDase
ADA
Inosine
PNP
Hypoxanthine
Xanthine
Oxidase
GMP
NTDase
NTDase
Xanthosine
Guanosine
PNP
Xanthine
PNP
GDA
Xanthine Oxidase
Uric acid
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Guanine
Fate of uric acid in humans
 In humans, primates, birds and reptiles the final
product of purine degradation is uric acid
 Uric acid is excreted in the urine
 Some animals convert uric acid to other products:
 Allantoin
 Allantoic acid
 Urea
 Ammonia
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Fate of uric acid
Uric AcidPrimates, Birds, Reptiles and insects
Urate Oxidase
Allantoin Other mammals
Allantoinase
Allantoic acid Teleost Fish
Allantoicase
UreaCartilagenous fish and Amphibia
Urease
Ammonia Marine invertebrates
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Fate of uric acid in humans
 Uric acid is less soluble in water
 Reptiles, insects and birds excrete uric acid as a paste of
crystals To save water
 Humans excrete uric acid in urine
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Fate of uric acid in humans
 Humans do not have enzymes to further degrade uric
acid
 Excessive production of uric acid causes deposition of
uric acid crystals in the joints leading to:
 Gout
 Hyperuricemia
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Gout
Once fashionable to associate gout with intelligence
 people with gout:
 Isaac Newton
 Benjamin Frankin
 Martin Luther
 Charles Darwin
 Samuel Johnson
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Disease of the riches
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Gout
 Gout is a disease due to high levels of uric acid in body
fluids
 7.0 mg/dL and above
 Uric acid accumulates because of:
 Overproduction or
 Underexcretion
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Gout
 prevails mainly in adult males
 rarely encountered in premenopausal women
 Sodium urate/uric acid may also precipitate in the kidneys and
ureters as stones, resulting in renal damage and urinary tract
obstruction
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Gout
 Painful arthritic joint inflammation due to deposits of
insoluble sodium urate crystals (especially big toe)
 Affects 3 per 1000 persons
 Sodium urate crystals accumulate in kidneys, ureter,
joints leading to chronic gouty arthritis
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Voet Biochemistry 3e
© 2004 John Wiley & Sons, Inc.
Sodium urate crystals in urine
Gout
 Inaccurately associated with overeating and drinking
 Alcohol used to be contaminated with lead during
manufacture and storage
 Lead decreases excretion of uric acid from kidneys
causing hyperuricemia and gout
 Excessive meat comsumption increases uric acid
production in some individuals
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Gout
 Two main causes
 Overproduction of uric acid
 Underexcretion of uric acid
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Hyperuricemia- soft tissues
 Nodular masses of
monosodium urate crystals
(tophi) may be deposited in
the soft tissues, resulting in
chronic tophaceous gout
 Hyperuricemia is typically
asymptomatic and does not
lead to gout, but gout is
preceded by hyperuricemia
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Overproduction of uric acid
 Primary hyperuricemia is, for the most part, idiopathic (having
no known cause)
 Lesch-Nyhan syndrome also causes hyperuricemia through PRPP
accumulation
 Secondary hyperuricemia is typically the consequence of
increased availability of purines, for example, in patients with
myeloproliferative disorders or who are undergoing chemotherapy
and so have a high rate of cell turnover
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Underexcretion of uric acid
 Underexcretion can be
 Primary- due to as-yet-unidentified inherent
excretory defects
 secondary to known disease processes that affect
how the kidney handles urate, for example lactic
acidosis, and to environmental factors such as the
use of drugs, for example, thiazide diuretics, or
exposure to lead
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Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings
Diagnostic features
 usually affect joints in the lower
extremities (95%)
 onset is fast and sudden
 pain is usually severe; joint may be
swollen, red and hot
 attack may be accompanied by fever,
leukocytosis and an elevated ESR
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Diagnosis
 The definitive diagnosis of
gout requires aspiration and
examination of synovial fluid
from an affected joint (or
material from a tophus) using
polarized light microscopy to
confirm the presence of
needle-shaped monosodium
urate crystals
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Monosodium urate crystals
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Nonpharmacological Approaches
 Avoid purine rich foods:
 red meat and organ meat (liver, kidneys)
 shellfish, anchovies, mackerel, herring
 meat extracts and gravies
 peas and beans, asparagus, lentils
 alcoholic beverages
 Weight loss
 Control alcohol
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Treatment of gout- Acute attacks
 Acute attacks of gout are treated with anti-inflammatory
agents. Colchicine, steroidal drugs such as prednisone, and
nonsteroidal drugs such as indomethacin are used
 Colchicine depolymerizes microtubules, thus decreasing the
movement of neutrophils into the affected area.
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Treatment - Long term
 Involves lowering the uric acid level below the saturation
point, thereby preventing the deposition of urate crystals
 Uricosuric agents- probenecid or sulfinpyrazone, that increase
renal excretion of uric acid
 Allopurinol, an inhibitor of uric acid synthesis
 Allopurinol is converted in the body to oxypurinol, which
inhibits xanthine oxidase, resulting in an accumulation of
hypoxanthine and xanthine—compounds more soluble than
uric acid and, therefore, less likely to initiate an inflammatory
response
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References
 Lippincott 4th Edition
 Voet & Voet
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