Purine Metabolism Flashcards
name the amino acids and other molecule that donates N and C
- Glutamine: 2 nitrogens
- Glycine: 2 N + 2 C
- CO2: 1 C
- Aspartate: 1 N
- Tetrahydrofolate: 2 C
list the steps in synthesis of IMP
describe the conversion of IMP to ATP and GTP
describe the regulation of purine biosynthesis
- 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
describe the process of folate synthesis and the drugs involved in certain steps
describe the conversion of the ribonucleotides to deoxyribonucleotides
why is salvaging/recylcing of purines important?
- About 80% of the bases are reused
- uses less energy than denovo synthesis
- salvage pathway is important for the brain
list the process of adenine to AMP
list the process of hypoxanthine to IMP and guanine to GMP
which enzyme deficiency in purine recylcing leads to an X-linked recessive disorder?
- Complete absence of the HGPRT enzyme causes Lesch Nyhan syndrome (X-linked recessive)
- Characterized by hyperuricemia, behavioral disturbances (Self mutilation)
why do LHS patients have high uric acid content?
- 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
describe uric acid
- 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
describe the process of the formation of uric acid
name the first cause of hyperuricemia
- 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
name the second cause of hyperuricemia
- 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
describe management of hyperuricemia
- 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
describe SCID
- 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
