NADPH FAD SH SH SHSH、/ND SHSH NADP fade Thioredoxin reductase Thioredoxin Ribonucleotide reductase Figure An electron-transfer pathway for nucleoside diphosphate(NDP reduction. NADPH provides the reducing equivalents for this process through the intermediacy of thioredoxin reductase, thioredoxin, and ribonucleotide reductase
Hydroxyurea HD2N一C-NHOH Specifically inhibits ribonucleotide reductase Inhibits dna synthesis without affecting rNa synthesis or other nucleotide pools Cleared from the body rapidly so not used extensively in the clinic
Hydroxyurea • Specifically inhibits ribonucleotide reductase • Inhibits DNA synthesis without affecting RNA synthesis or other nucleotide pools • Cleared from the body rapidly so not used extensively in the clinic H2 N C O NHOH
FdUMP dUMP dTMP thymidylate synthase N5, NT0-Methylene-THF DHF NAdPH +hi Glycine dihydrofolate NH.-CHo-co0 reductase serine Methotrexate THF hydroxymethyl Aminopterin transferase Trimethoprim NH3-CH-Coo NADP CHOH Serine Regeneration of N, N-methylenetetrahydrofolate. The DhF product of the thymidylate synthase reaction is converted back to N, N-methylene THF by the sequential actions of (1)dihydrofolate reductase and (2)serine hydroxy- methyltransferase. The sites of action of some inhibitors are indicated by red octagons. Thymidylate synthase is inhibited by FdUMP, whereas dihydrofolate reductase is inhibited by the antifolates methotrexate, aminopterin, and trimetho prim(see Box 22-1)
H2N CH N O—P O一H2CO CHoN 一 CNCHCH2CH2COO HH H H R=H Aminopterin OH H R=CH, Methotrexate(amethopterin) 5-Fluorodeoxyuridylate(FdUMP) OCH 3 HoN OCH CH OCH NH Trimethe