The first crystal structure of phosphofructokinase from a eukaryote: Trypanosoma brucei

José Martinez-Oyanedel, Iain W McNae, Matthew W Nowicki, Jeffrey W Keillor, Paul A M Michels, Linda A Fothergill-Gilmore, Malcolm D Walkinshaw

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

The crystal structure of the ATP-dependent phosphofructokinase (PFK) from Trypanosoma brucei provides the first detailed description of a eukaryotic PFK, and enables comparisons to be made with the crystal structures of bacterial ATP-dependent and PPi-dependent PFKs. The structure reveals that two insertions (the 17-20 and 329-348 loops) that are characteristic of trypanosomatid PFKs, but absent from bacterial and mammalian ATP-dependent PFKs, are located within and adjacent to the active site, and are in positions to play important roles in the enzyme's mechanism. The 90 residue N-terminal extension forms a novel domain that includes an "embracing arm" across the subunit boundary to the symmetry-related subunit in the tetrameric enzyme. Comparisons with the PPi-dependent PFK from Borrelia burgdorferi show that several features thought to be characteristic of PPi-dependent PFKs are present in the trypanosome ATP-dependent PFK. These two enzymes are generally more similar to each other than to the bacterial or mammalian ATP-dependent PFKs. However, there are critical differences at the active site of PPi-dependent PFKs that are sufficient to prevent the binding of ATP. This crystal structure of a eukaryotic PFK has enabled us to propose a detailed model of human muscle PFK that shows active site and other differences that offer opportunities for structure-based drug discovery for the treatment of sleeping sickness and other diseases caused by the trypanosomatid family of protozoan parasites.
Original languageEnglish
Pages (from-to)1185-98
Number of pages14
JournalJournal of Molecular Biology
Volume366
Issue number4
DOIs
Publication statusPublished - 2007

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