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

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.

• Authors: T M Savarese, S H Chu, M Y Chu, R E Parks Jr
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 34 Issue 3 Pg. 361-7 (Feb 01 1985) ISSN: 0006-2952 [Print] England
• PMID: 3918539 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

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

Topics

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