Purine Metabolism

Question 1

name the amino acids and other molecule that donates N and C

Answer 1

• Glutamine: 2 nitrogens
• Glycine: 2 N + 2 C
• CO2: 1 C
• Aspartate: 1 N
• Tetrahydrofolate: 2 C

Question 2

list the steps in synthesis of IMP

Answer 2

Question 3

describe the conversion of IMP to ATP and GTP

Answer 3

Question 4

describe the regulation of purine biosynthesis

Answer 4

• Regulatory enzymes are PRPP synthetase and phosphoribosylamidotransferase
• ATP and GTP inhibit PRPP synthetase and the phosphoribosylamidotransferase
• PRPP is a feedforward activator of Phosphoribosylamidotransferase
  
  • High levels of PRPP activate this enzyme to increase purine nucleotide synthesis

Question 5

describe the process of folate synthesis and the drugs involved in certain steps

Answer 5

Question 6

describe the conversion of the ribonucleotides to deoxyribonucleotides

Answer 6

Question 7

why is salvaging/recylcing of purines important?

Answer 7

• About 80% of the bases are reused
  
  • uses less energy than denovo synthesis
• salvage pathway is important for the brain

Question 8

list the process of adenine to AMP

Answer 8

Question 9

list the process of hypoxanthine to IMP and guanine to GMP

Answer 9

Question 10

which enzyme deficiency in purine recylcing leads to an X-linked recessive disorder?

Answer 10

• Complete absence of the HGPRT enzyme causes Lesch Nyhan syndrome (X-linked recessive)
• Characterized by hyperuricemia, behavioral disturbances (Self mutilation)

Question 11

why do LHS patients have high uric acid content?

Answer 11

• Purine bases are not reused and therefore there is an increased degradation of purines to form uric acid
• HGPRT inactivity, so therefore high levels of PRPP stimulate the denovo biosynthesis of purine nucleotides

Question 12

describe uric acid

Answer 12

• end product of purine breakdown (adenine, guanine and hypoxanthine)
• Uric acid normally excreted in the urine
• When the blood uric acid levels are high (hyperuricemia), monosodium urate tends to precipitate in the joint
  
  • needle shaped crystal

Question 13

describe the process of the formation of uric acid

Answer 13

Question 14

name the first cause of hyperuricemia

Answer 14

• underexcretion
  
  • cause not defined: males and obesity (risk factors)
  • renal disease
  • lactic acidosis (urate competes with lactate for excretion)
• blood uric acid levels >6.8 mg/dL usually results in precipitation of monosodium urate as crystals in joints and soft tissues - Gout
• underexcretion

Question 15

name the second cause of hyperuricemia

Answer 15

• Overproduction of uric acid
  
  • idiopathic (cause not known)
  • mutants of PRPP synthetase result in elevated levels of PRPP
  • deficiency of HGPRT (LNS) results in less recycling (salvage) of the purine bases and elevated PRPP levels
    
    • increased PRPP stimulates purine biosynthesis
  • patients undergoing chemotherapy

Question 16

describe management of hyperuricemia

Answer 16

• during an acute episode, colchicine and anti-inflammatory agents (NSAID and cortisol) reduce pain and inflammation
• Long-term urate lowering therapy
  
  • Allopurinol: inhibits xanthine oxidase
  • febuxostat: xanthine oxidase inhibitor
• Agents that increase excretion of uric acid (uricosuric agents)
• Decrease intake of meat and alcohol

Question 17

describe SCID

Answer 17

• adenosine deaminase deficiency (SCID)
• deficiency of ADA mainly affects lymphocytes
• ADA deficinecy is one of the causes of severe combined immunodeficiency (SCID)
• Adenosine accumulation results in increased dATP levels that inhibit ribonucleotide reductase
  
  • ​reduced ribonucleotide reductase results in reduced rates of cell division in the lymphocytes
• Decrease in T-cell and B-cell immunity