Biophysical and biochemical properties of heterotrimeric phosphofructokinase complexes (360G-Wellcome-106359_Z_14_Z)

Regulation of phosphofructokinase is integral to the control of glycolytic flux and glycolytic biosynthesis.In humans, phosphofructokni ase mutations are associated with neurological dysfunction (Tarui's disease) and control of glycolysis is thought to be important for synaptic development and function. A greater understanding how phosphofructokinase is regulated will provide new insights into controlof glycolysis. Biological modulation of phosphofructokinase activity is achieved by multiple methods,although the precise mechanisms remain poorly characterised.Mammals have three isofomns (M,L, and P) of phosphofructokinase, which are postulated to form heteromeric structures with each other and with other enzymes as glycolytic complexes (metabolons). This project will explore the functional consequences of heteromeric complexes of phosphofructokinase Human phosphofructokinase isoforms will beinvestigated as follows: - Phylogenet c analysis of mammalian phosphofructokinases - Biophysicalanalysis of human phosphofructokinase - Human enzyme kinetics and the effects ofinhibitors and activators - Construction of structure-activity relationships for heteromerlc and homomeric complexes - lsoform localisation within different tissue/cell types in humans and mice