Molecular basis for the allosteric activation mechanism of the heterodimeric imidazole glycerol phosphate synthase complex

Imidazole glycerol phosphate synthase (HisFH) is a heterodimeric bienzyme complex operating at a central branch point of metabolism. HisFH is responsible for the HisH-catalyzed hydrolysis of glutamine to glutamate and ammonia, which is then used for a cyclase reaction by HisF. The HisFH complex is allosterically regulated but the underlying mechanism is not well understood. Here, we elucidate the molecular basis of the long range, allosteric activation of HisFH. We establish that the catalytically active HisFH conformation is only formed when the substrates of both HisH and HisF are bound. We show that in this conformation an oxyanion hole in the HisH active site is established, which rationalizes the observed 4500-fold allosteric activation compared to the inactive conformation. In solution, the inactive and active conformations are in a dynamic equilibrium and the HisFH turnover rates correlate with the population of the active conformation, which is in accordance with the ensemble model of allostery. The allosteric regulation of the bienzyme complex imidazole glycerol phosphate synthase (HisFH) remains to be elucidated. Here, the authors provide structural insights into the dynamic allosteric mechanism by which ligand binding to the cyclase and glutaminase active sites of HisFH regulate enzyme activation.

Automated summary

Imidazole glycerol phosphate synthase (HisFH) is a heterodimeric bienzyme complex responsible for catalyzing the hydrolysis of glutamine and cyclase reaction. The catalytically active HisFH conformation is formed only when both substrates of HisH and HisF are bound, leading to allosteric activation. In solution, inactive and active conformations are dynamically balanced, with HisFH turnover rates correlating with the active conformation population.