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Publication Abstract from PubMed

In higher eukaryotes, several ATP-utilizing enzymes known as hexokinases activate glucose in the glycolysis pathway by phosphorylation to glucose-6-phosphate. In contrast to canonical hexokinases which use ATP, ADP-dependent glucokinase (ADPGK) catalyzes non-canonical phosphorylation of glucose to glucose-6-phosphate using ADP as a phosphate donor. Initially discovered in Archaea, the human homolog of ADPGK was described only recently. ADPGK's involvement in modified bioenergetics of activated T cells has been postulated and elevated ADPGK expression has been reported in various cancer tissues. However, the physiological role of ADPGK is still poorly understood and effective ADPGK inhibitors still await discovery. Here we show that 8-bromo substituted adenosine nucleotide inhibits human ADPGK. By solving the crystal structure of archaeal ADPGK in complex with 8-bromoadenosine phosphate (8-Br-AMP) at 1.81 A resolution we identified the mechanism of inhibition. We observed that 8-Br-AMP is a competitive inhibitor of ADPGK and that the bromine substitution induces marked structural changes within the protein's active site by engaging crucial catalytic residues. The results obtained using Jurkat model of activated human T-cells suggest its moderate activity in cellular setting. We propose that our structural insights provide a critical basis for rational development of novel ADPGK inhibitors.

Structural basis for ADP-dependent glucokinase inhibition by 8-bromo-substituted adenosine nucleotide.,Grudnik P, Kaminski MM, Rembacz KP, Kuska K, Madej M, Potempa J, Dawidowski M, Dubin G J Biol Chem. 2018 May 21. pii: RA117.001562. doi: 10.1074/jbc.RA117.001562. PMID:29784881^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.