5'-Deoxy-5'-methylthioadenosine phosphorylase--III. Role of the enzyme in the metabolism and action of 5'-halogenated adenosine analogs.
5'-Deoxy-5'-halogenated adenosines are alternative substrates for 5'-deoxy-5'-methylthioadenosine phosphorylase (MTAPase), an enzyme responsible for the metabolism of 5'-deoxy-5'-methylthioadenosine (MTA), a by-product of polyamine biosynthesis. The relative reactivity of these nucleosides with MTAPase from HL-60 human promyelocytic leukemia cells is MTA greater than 5'-deoxy-5'-fluoroadenosine (5'-FlAdo) greater than 5'-chloro-5'-deoxyadenosine (5'-ClAdo) greter than 5'-bromo-5'-deoxyadenosine (5'-BrAdo) greater than 5'-deoxy-5'-iodoadenosine (5'-IAdo). In MTAPase-containing cells, the adenine released from the 5'-halogenated adenosine was incorporated into adenine nucleotide pools; cleavage by (MTAPase appeared to be the rate-limiting step in this process. 5'-BrAdo and 5'-IAdo were growth inhibitors (EC50 values less than 10 microM) of MTAPase-containing cell lines (HL-60 human promyelocytic leukemia and the L5178Y murine lymphoblastic leukemia) but were much less active (EC50 values greater than 65 microM) against MTAPase-deficient cell lines (the CCRF-CEM human T cell leukemia and the L1210 murine leukemia). The full cytotoxicity of these compounds, therefore, appeared to be related to their phosphorolysis by MTAPase. Indirect evidence suggests that 5-halogenated ribose-1-phosphate derivatives of 5'-BrAdo or 5'-IAdo produced by the MTAPase reaction were the active metabolites of these 5'-halogenated adenosines.
D000227:Adenine Nucleotides / Q000378:metabolism; D000241:Adenosine / Q000031:analogs & derivatives* / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism; D001711:Biotransformation; D002460:Cell Line; D003839:Deoxyadenosines / Q000031:analogs & derivatives / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D007939:Leukemia L1210 / Q000201:enzymology; D007940:Leukemia L5178 / Q000201:enzymology; D007942:Leukemia, Experimental / Q000201:enzymology*; D051379:Mice; D010430:Pentosyltransferases / Q000378:metabolism*; D011683:Purine-Nucleoside Phosphorylase / Q000302:isolation & purification / Q000378:metabolism*
D000227:Adenine Nucleotides; D000970:Antineoplastic Agents; D003839:Deoxyadenosines; D010430:Pentosyltransferases; D011683:Purine-Nucleoside Phosphorylase; C021784:5'-methylthioadenosine phosphorylase; D000241:Adenosine