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MSK Summative > Purine Metabolism: Gout and Pseudogout > Flashcards

Purine Metabolism: Gout and Pseudogout Flashcards

1
Q
  • Gout results from?
    • precipitates where?
      • what is classic site?
A
  • Results from:
    • Excess uric acid (purine degredation products)
    • Increase production, decrease excretion, both
      • excess production of consequence of excess consumption (rich food, meats, alcohol)
  • Can precipitate in:
    • areas with space and lower temperature
      • Joint of great toe
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2
Q
  • How are nucleotides processed in the diet?
    • absorbed by?
A
  • In foods as DNA, RNA, nucleotides, derivatives
    • pancreatic enzymes degrade to nucleotides and nucleosides
  • Absorbed by:
    • intestinal epithelium (mostly used there)
    • only 5% reach blood stream

Must be either synthesized or salvaged to maintain all levels in tissue

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3
Q
  • What are the two major sites of synthesis of purines?
  • How is it transported to other tissues?
A
  • Two major purine synthesis:
    • Liver and Brain
  • Transport:
    • export to blood, transported by RBC

NOTE:

  • Body has to make or recycle most of nucleotides it needs
    • unless there is excessive intake
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4
Q
  • What are the 5 sources of materials for purine synthesis?
A
  1. one entire glycine
  2. 2 N from glutamines
  3. 2 C from formyl FH4
  4. N from aspartate
  5. C from CO2
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5
Q
  • What is the first step in purine synthesis?
    • enzyme required
A
  • Ribose -5-P + ATP—-> Glutamine + PRPP
    • ​PRPP synthetase
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6
Q
  • What is the committed step in de novo purine synthesis?
    • rate limiting enzyme?
A
  • Committed step:
    • PRPP——> 5-Phosphoribosyl 1- amine
  • Rate limiting enzyme:
    • Glutamine- phosphoribosylpyrophosphate (PRPP) amidotransferase

All purine nucleotides inhibit this step!

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7
Q

How many ATP are used to make 1 purine?

A

6 ATP

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8
Q

What is the first purine made?

A
  • Inosine monophosphate (IMP)
    • can be modified to AMP or GMP
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9
Q
  • What inhibits de novo purine synthesis?
A
  • PRPP synthetase inhibited by
    • GDP and ADP
  • First specific steps (-) Inhibited by:
    • AMP
    • Inosine monophosphate (IMP)
    • GMP
  • All purine nucleotides inhibit first committed reaction in pathway
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10
Q
  • Salvage pathways of purines can lower need for?
A
  • Recycling lowers need for synthesis
    • free bases can become nucleosides and nucleotides
    • can be converted to other bases by deamination
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11
Q
  • Function of purine nucleoside phosphorylase?
    • lack of this enzyme leads to?
A
  • Function:
    • removes base from GMP or IMP by phosphorolysis
  • Present in most cells, crucial for immune system
  • Deficiency:
    • leads to immunodeficiency, T cells more than B cells
    • child with recurrent infections
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12
Q
  • Function of Adenosine Deaminase?
  • Deficiency causes?
A
  • Function:
    • converts adenosine back to inosine
    • allows bases to be degraded or converted
  • Deficiency causes:
    • Severe Combined Immunodeficiency Disease (SCID)
      • increase dATP causes toxicity in lymphocytes
      • Thymus, B and T cells all affected
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13
Q
  • When rebuilding nucleotides, what enzyme is required to add bases to PRPP?
    • For adenine?
    • For hypoxanthine (I) and guanine?
A
  • Phosphoribosyl transferase adds bases to PRPP
    • Adenine: APRT
    • Hypoxanthine and Guanine: HGPRT
      • HGPRT on X-chrom. mutated in Lesch-Nyahn syndrom
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14
Q
  • Lesch-Nyahn Syndrome is due to deficiency in?
    • Results in?
    • Findings?
    • Inheritance?
A
  • Due to:
    • Defective purine salvage due to absent HGPRT
      • converts hypoxanthine to IMP and guanine to GMP
  • Results in:
    • excess uric acid production and de novo purine synthesis
  • Findings:
    • Hyperuricemia
    • Gout
    • Pissed off (self mutilation)
    • Retardation
    • DysTonia
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15
Q
  • How are purines degraded?
    • what enzyme inhibits this
  • How are they excreted?
A
  • Degraded:
    • Xanthine oxidase (XO) converts hypoxanthine and xanthine to urate
    • Inhibited by:
      • ​allopurinol
  • Excreted:
    • in urine, not very soluble
      • excess amout can precipitate
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16
Q

Precipitation of uric acid results in?

A
  • Uric acid crystals
    • source of pain and inflammation
    • needle shaped and strongly negative birefrigence
  • Crystals penetrate cells
    • inflammatory mediators are released
17
Q
  • In gout, is acute or chronic attacks common?
    • when/where does it happen?
A
  • Acute attacks
    • often overnight in lower extremities
      • hydrostatic pressure during day affects the joint fluid
      • at night water is reabsorbed faster than solutes
18
Q
  • Similarities and differences between gout and pseudogout?
A
  • Similarities:
    • joint pain with crystals in synovial fluid
  • Differences:
    • location: larger joints like knee
    • Calcium pyrophosphate crystals
      • rhomboid with weakly (+) birefringence
19
Q
  • Calcium pyrophosphate deposition disease is due to?
    • age and sex affected?
    • caused by/ associated with?
  • Most affected joint?
A
  • Due to:
    • deposition of calcium phyrophosphate crystals within the joint space
  • Occurs in:
    • patients > 50
    • both sexes
  • Associated with:
    • usually idiopathic
    • can be associated with hemochromatosis, hyperthyroidism, joint trauma
  • Common joint:
    • knee
    • pain and swelling with acute inflammation
20
Q
  • What is gout?
    • What is it due to?
A
  • Deposition of monosodium urate (MSU) crystals in tissues, especially joints
  • due to:
    • hyperuricemia
      • related to overproduction or decreased excretion of uric acid
21
Q

What 3 disorders is secondary gout seen with?

A
  1. Leukemia and myeloproliferative disorders:
    • increased cell turnover leads to hyperuricemia
  2. Lesch-Nyhan syndrome:
    • X-linked deficiency of hypoxanthine-guanine phosphoribosyltransferase (HGPRT)
      • can’t salvage hypoxanthene and guanine—-> increase xanthene—> increase uric acid
  3. Renal Insufficiency:
    • decrease renal excretion of uric acid
22
Q
  • What and where does acute gout present?
  • What can make it worse?
A
  • Presents:
    • very painful arthritis of great toe (podagra)
      • MSU crystals deposit in joint, trigger acute inflammatory reaction
      • activate neutrophils
  • Alcohol or consumption of meat can make it worse
    • alcohol competes with uric acid at kidney for excretion
23
Q

Chronic gout can lead to what two things?

A
  1. Development of tophi
    • white, chalky aggregates of uric acid crystals with fibrosis and giant cell reaction in soft tissue and joints
  2. Renal failure
    • urate crystals may deposit in kidney tubules
24
Q
  • In gout, what does synovial fluid show?
A
  • Needle shaped crystals with (-) birefringence under polarized light
    • when crystals lay flat (low) they are yellow

MSK Summative (8 decks)

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