Inhibition of ATP synthase by chlorinated adenosine analogue

Lisa S. Chen, Billie J. Nowak, Mary L. Ayres, Nancy L. Krett, Steven T. Rosen, Shuxing Zhang, Varsha Gandhi

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

Abstract

8-Chloroadenosine (8-Cl-Ado) is a ribonucleoside analogue that is currently in clinical trial for chronic lymphocytic leukemia. Based on the decline in cellular ATP pool following 8-Cl-Ado treatment, we hypothesized that 8-Cl-ADP and 8-Cl-ATP may interfere with ATP synthase, a key enzyme in ATP production. Mitochondrial ATP synthase is composed of two major parts; FO intermembrane base and F1 domain, containing α and β subunits. Crystal structures of both α and β subunits that bind to the substrate, ADP, are known in tight binding (αdpβdp) and loose binding (αtpβtp) states. Molecular docking demonstrated that 8-Cl-ADP/8-Cl-ATP occupied similar binding modes as ADP/ATP in the tight and loose binding sites of ATP synthase, respectively, suggesting that the chlorinated nucleotide metabolites may be functional substrates and inhibitors of the enzyme. The computational predictions were consistent with our whole cell biochemical results. Oligomycin, an established pharmacological inhibitor of ATP synthase, decreased both ATP and 8-Cl-ATP formation from exogenous substrates, however, did not affect pyrimidine nucleoside analogue triphosphate accumulation. Synthesis of ATP from ADP was inhibited in cells loaded with 8-Cl-ATP. These biochemical studies are in consent with the computational modeling; in the αtpβtp state 8-Cl-ATP occupies similar binding as ANP, a non-hydrolyzable ATP mimic that is a known inhibitor. Similarly, in the substrate binding site (αdpβdp) 8-Cl-ATP occupies a similar position as ATP mimic ADP-BeF3-. Collectively, our current work suggests that 8-Cl-ADP may serve as a substrate and the 8-Cl-ATP may be an inhibitor of ATP synthase.

Original languageEnglish (US)
Pages (from-to)583-591
Number of pages9
JournalBiochemical Pharmacology
Volume78
Issue number6
DOIs
StatePublished - Sep 15 2009

Keywords

  • 8-Chloroadenosine
  • ATP synthase
  • Cellular bioenergy
  • Chemotherapeutics
  • Molecular modeling
  • Nucleoside analogue

ASJC Scopus subject areas

  • Biochemistry
  • Pharmacology

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