Purine Synthesis

Purine Synthesis

De Novo Synthesis
1. liver
  1. most active
2. requires
  1. aa
    1. aspartate, glycine, glutamine
  2. CO2
  3. NH3
  4. ribose-5-phosphate
    1. ring assembled
      1. PRPP
        activated form of ribose
        1 ATP
        5-phosphoribosyl-1-amine
        amdio-phosphoribosyltransferase
        committed step
        need glutamine
        hypoxanthine
        attached to ribose-P
        inosinate (IMP)
        precursor
        AMP
        use 1 GTP
        GMP
        use 1 ATP
        3 ATP
  5. THF derivatives
    1. N10-formyl-THF
Salvage Pathway
1. recycle free purine bases
2. adenine + PRPP --> adenylate PPi
  1. APRT
3. hypoxanthine --> IMP + PPi
  1. HGPRT
4. guanine + PRPP --> GMP + PPi
  1. HGPRT
5. conserve ATP
  1. recycle nucleoside bases
    1. nucleotide monophosphates
      1. limits De-Novo
  2. catalyzed by
    1. APRT
    2. HGPRT
      1. deficiency
        severe
        Lesch-Nyhan syndrome
        partial
        gout
  3. brain
Purine Metabolism
1. regulation
  1. PRPP synthetase
    1. (-) ADP, GDP
  2. PRPP aminotransferase
    1. (-) A & G nucleotides
      1. mono, di, tri
    2. (-) IMP
    3. (+) PPRP
  3. IMP dehydrogenase
    1. (-) GMP
      1. ATP substrate
        excess ATP = increase GMP
  4. Adenylosuccinate synthetase
    1. (-) AMP
      1. GTP substrate
        excess GTP = increase AMP
Disorders
1. phosphoribosylpyrophosphate synthetase superactivity
  1. X-linked
    1. recessive
  2. purine overproduction
    1. excess purine degraded
      1. hyperuricemmia
      2. gout
      3. neurologic developmental abnormalities
  3. diagnosis
    1. enzyme studies
      1. RBCs, skin fibroblasts
  4. treatment
    1. allopurinol
    2. low-purine diet
2. adenylosuccinase deficiency
  1. autosomal
    1. recessive
  2. effects
    1. mental retardation
    2. autistic behavior
    3. seizures
  3. diagnosis
    1. ID elevations in CSF/urine
      1. succinylaminoimidazole carboxaminde riboside
      2. succinyladenosine
  4. treatment
    1. none effective
3. adenosine deaminase deficiency
  1. function
    1. convert adenosine/deoxyadenosine to inosine/deoxyinosinee
      1. more breakdown
        excretion
  2. accumulation of adenosine
    1. converted to dATP
      1. inhibits ribonucleotide reductase
        DNA replication compromised
        no other dNTPs synthesized
  3. immune cells susceptible
  4. SCID
    1. destroy B/T lymphocytes
      1. need to proliferate dramatically
        affected by inability of DNA synthesis
4. xanthine oxidase deficiency
  1. function
    1. catalyze uric acid production
      1. from xanthine/hypoxanthine
  2. build up of xanthine
    1. precipitate in urine
      1. stones, hematuria, urinary colic, UTI
  3. diagnosis
    1. low plasma uric acid
    2. high plasma hypoxanthine/xanthine
    3. liver/intestinal biopsy rare
  4. treatment
    1. high fluid intakte
      1. minimize stone formation
    2. allopurinol
5. Lesch-Nyhan Syndrome
  1. function loss HGPRT
  2. X-linked
  3. symptoms
    1. severe gout
      1. high [uric acid/sodium urate]
        defect in reg
        nucleotide metabolism
      2. treatment
        colchicine
        inflammation
        allopurinol
        inhibit xanthine oxidase
        diet
        low purine
      3. pain
        crystals
        inflammation
    2. malfunction of nervous system
      1. no treatment
  4. death before 20 yo
6. adenine pohsphoribosyltransferase deficiency
  1. autosomal
    1. recessive
  2. inability to salvage adenine
    1. purine synthesis
    2. accumulated adenine
      1. oxidized
        2,8-dihydroxyadenine
        precipitates
        renal colic, infections, renal failure
  3. diagnosis
    1. elevated levels (urine)
      1. 2,8-dihydroxyadenine
      2. 8-hydroxadenine
      3. adenine
    2. normal
      1. serum uric acid
Catabolism
1. source
  1. breakdown
    1. RNA
    2. DNA
    3. nucleases
    4. phosphomonoesterase
2. product
  1. uric acid
    1. xanthine oxidase
      1. abundant in liver/intestine
        salvage pathway
Purine Nucleotide Cycle
1. increase muscle activity
  1. increase TCA cycle
    1. generate NADH
      1. more ATP
  2. muscle lacks anaplerotic enzymes
    1. replenish TCA cycle
      1. fumarate
        purine nucleotide cycle
Synthesis Inhibitors
1. inhibit proliferation
  1. leukocytes
2. azathioprine
  1. immunosuppresant
    1. organ transplant
    2. autoimmune
      1. rheumatoid arthritis
    3. inflammatory bowel disease
      1. Crohn's
      2. ulceerative colitis
Purine Analogs
1. acycloguanines
  1. treats
    1. HSV-1 HSV-2
    2. shingles
    3. chicken pox

Next up

Description

Resource summary

Similar

	Created by hardinbc about 11 years ago