5'-Deoxy-5'-methylthioadenosine phosphorylase--III. Role of the enzyme in the metabolism and action of 5'-halogenated adenosine analogs

Biochem Pharmacol. 1985 Feb 1;34(3):361-7. doi: 10.1016/0006-2952(85)90044-9.

Abstract

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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenine Nucleotides / metabolism
  • Adenosine / analogs & derivatives*
  • Adenosine / metabolism
  • Animals
  • Antineoplastic Agents / metabolism
  • Biotransformation
  • Cell Line
  • Deoxyadenosines / analogs & derivatives
  • Deoxyadenosines / metabolism
  • Humans
  • Kinetics
  • Leukemia L1210 / enzymology
  • Leukemia L5178 / enzymology
  • Leukemia, Experimental / enzymology*
  • Mice
  • Pentosyltransferases / metabolism*
  • Purine-Nucleoside Phosphorylase / isolation & purification
  • Purine-Nucleoside Phosphorylase / metabolism*

Substances

  • Adenine Nucleotides
  • Antineoplastic Agents
  • Deoxyadenosines
  • Pentosyltransferases
  • Purine-Nucleoside Phosphorylase
  • 5'-methylthioadenosine phosphorylase
  • Adenosine