Nucleotide Metabolism II - WOU Homepagewou.edu/~guralnl/gural/451Nucleotide Metabolism...
Transcript of Nucleotide Metabolism II - WOU Homepagewou.edu/~guralnl/gural/451Nucleotide Metabolism...
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Nucleotide Metabolism II
• Biosynthesis of deoxynucleotides
• Salvage Pathway• Catabolism: Purines• Catabolism:
Pyrimidines
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Biosynthesis of deoxynucleotides
• Uses diphosphates (ribo) • Ribonucleotide
reducatase• 2 sub-units • R1- reduces, active and
two allosteric sites • R2- tyrosine radical
carries electrons • removes 2' OH to H
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Ribonucleotide reductase reaction
• removes 2' OH to H • Thioredoxin and
NADPH
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Thymidylate synthesis
• UDP ------> dUMP• dUMP --------> dTMP• required THF • methylates uracil
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Regulation
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THF• Mammals cannot conjugate rings or synthesize PABA.• So must get in diet.• Sulfonamides effective in bacteria due to competitive
inhibition of the incorporation of PABA
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Cancer Drugs
• fluorouracil-- suicide inhibitor of Thy synthase
• aminopterin• Methotrexate --
inhibits DHF reductase
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Salvage Pathway
• extra-hepatic tissues • free purines• APRT • HGPRT • Uracil• Salvage via Purine
Nucleoside phosphorylase
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Lesch-Nyhan syndrome
• Lack of HGPRT • x- linked • elevates PRPP • Increase de novo
purine biosynthesis • overproduction of
urate
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Catabolism: Purines
• Dietary purines: mostly degraded • Purines produce urate• excreted in urine in mammals
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Degradation of uric acid
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Problems
• Urate soluble 7 mg/dLat 37C
• cooler extremities, crstallizes
• synovial fluid • Gout
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Treatment
• Allopurinol • inhibit xanthine oxidase• Chelates Mo 4+ • suicide inhibitor • deplete PRPP • secrete hypoxanthine/Xanthine, more soluble
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Catabolism: Pyrimidines
• No problems • produce B-alanine,
NH3, and CO2
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Nucleotide Catabolism: disorders
• SCID • ADA deficiency • Both B/T lymphocytes
affected • elevated dATP 50-100x • inhibit ribonucleotide
reductase • inhibit synthesis of other
deoxynucleotides• pyrimidine starvation • no cell division
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Nucleotide Catabolism: disorders
• PNP deficiency • T lymphocytes • elevated dGTP• inhibit ribonucleotide
reductase • inhibit synthesis of
other deoxynucleotides
• no cell division