Intracellular succinylation of 8-chloroadenosine and its effect on fumarate levels.

Abstract

8-Chloroadenosine (8-Cl-Ado) is a ribosyl nucleoside analog currently in phase I testing for the treatment of chronic lymphocytic leukemia (CLL). 8-Cl-Ado activity is dependent on adenosine kinase and requires intracellular accumulation of 8-Cl-Ado as mono-, di-, and tri-phosphates. In the current study with four mantle cell lymphoma cell lines, we report a new major metabolic pathway for 8-Cl-Ado intracellular metabolism, the formation of succinyl-8-chloro-adenosine (S-8-Cl-Ado) and its monophosphate (S-8-Cl-AMP). 8-Cl-AMP levels were highly associated with S-8-Cl-AMP levels and reached a steady-state prior to the secondary metabolites, 8-Cl-ATP and S-8-Cl-Ado. Consistent with fumarate as a required substrate for formation of succinyl-8-Cl-adenylate metabolites, the S-8-Cl-adenylate concentrations in multiple cell lines were associated with fumarate loss. The distribution of metabolites was also altered using the energy metabolism modifiers, metformin and oligomycin. The rates of succinyl-8-Cl-adenylate metabolism were enhanced by increasing the intracellular fumarate concentrations after metformin co-treatment. In addition, the S-8-Cl-AMP concentrations were increased after acute inhibition of ATP synthase by oligomycin. We conclude that 8-Cl-Ado metabolism not only affects intracellular purine metabolism; 8-Cl-Ado conversion to succinyl analogs ties its metabolism to the citric acid cycle by reduction of the fumarate pool.

• Authors: Jennifer B Dennison, Mary L Ayres, Kumar Kaluarachchi, William Plunkett, Varsha Gandhi
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 285 Issue 11 Pg. 8022-30 (Mar 12 2010) ISSN: 1083-351X [Electronic] United States
• PMID: 20064937 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Fumarates
• Hypoglycemic Agents
• Oligomycins
• Purines
• Uncoupling Agents
• 2-Chloroadenosine
• 8-Bromo Cyclic Adenosine Monophosphate
• Metformin
• Succinic Acid
• 8-chloro-cyclic adenosine monophosphate
• 8-chloroadenosine

Topics

• 2-Chloroadenosine (analogs & derivatives, chemistry, pharmacokinetics)
• 8-Bromo Cyclic Adenosine Monophosphate (analogs & derivatives, metabolism)
• Antineoplastic Agents (chemistry, pharmacokinetics)
• Cell Line, Tumor
• Citric Acid Cycle (drug effects)
• Dose-Response Relationship, Drug
• Energy Metabolism (drug effects)
• Fumarates (metabolism)
• Humans
• Hypoglycemic Agents (pharmacology)
• Lymphoma, Mantle-Cell (drug therapy, metabolism, pathology)
• Metformin (pharmacology)
• Oligomycins (pharmacology)
• Purines (metabolism)
• Succinic Acid (chemistry, metabolism)
• Uncoupling Agents (pharmacology)