View
13
Download
0
Category
Preview:
Citation preview
Nucleotide Metabolism II
• Biosynthesis of deoxynucleotides
• Salvage Pathway• Catabolism: Purines• Catabolism:
Pyrimidines
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
Ribonucleotide reductase reaction
• removes 2' OH to H • Thioredoxin and
NADPH
Thymidylate synthesis
• UDP ------> dUMP• dUMP --------> dTMP• required THF • methylates uracil
Regulation
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
Cancer Drugs
• fluorouracil-- suicide inhibitor of Thy synthase
• aminopterin• Methotrexate --
inhibits DHF reductase
Salvage Pathway
• extra-hepatic tissues • free purines• APRT • HGPRT • Uracil• Salvage via Purine
Nucleoside phosphorylase
Lesch-Nyhan syndrome
• Lack of HGPRT • x- linked • elevates PRPP • Increase de novo
purine biosynthesis • overproduction of
urate
Catabolism: Purines
• Dietary purines: mostly degraded • Purines produce urate• excreted in urine in mammals
Degradation of uric acid
Problems
• Urate soluble 7 mg/dLat 37C
• cooler extremities, crstallizes
• synovial fluid • Gout
Treatment
• Allopurinol • inhibit xanthine oxidase• Chelates Mo 4+ • suicide inhibitor • deplete PRPP • secrete hypoxanthine/Xanthine, more soluble
Catabolism: Pyrimidines
• No problems • produce B-alanine,
NH3, and CO2
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
Nucleotide Catabolism: disorders
• PNP deficiency • T lymphocytes • elevated dGTP• inhibit ribonucleotide
reductase • inhibit synthesis of
other deoxynucleotides
• no cell division
Recommended