Guanosine-5´-monophosphate reductase (GMPR) catalyzes conversion of GMP to IMP, the hub metabolite for the biosynthesis of all purine nucleotides. This reaction enables mycobacteria and most other organisms to utilize guanine nucleotides in production of adenine nucleotides without the need of de novo synthesis. In our studies of purine metabolism in mycobacteria, we use Mycobacterium smegmatis (Msm) as a model organism. Although GMPR is not essential either for Msm or Mycobacterium tuberculosis (Mtb) under normal conditions, it contributes to the regulation of the purine nucleotide pool by recycling GMP to IMP. In our recently published study1 we show that the enzymatic activity of Msm GMPR is allosterically regulated by ATP and GTP. Whereas ATP inhibits the activity of Msm GMPR, GTP blocks this inhibition, and thus restores the activity of Msm GMPR. Here, we present an explanation of allosteric regulation of Msm GMPR with ATP and GTP at the molecular level. It is based on crystal and cryoEM structures of Msm GMPR with ATP and GTP. Msm GMPR forms tetramers with four-fold axis which further assemble into octamers. The two tetramers in the octamer adopt either compressed or extended conformation1. The changes in the conformation induced by the compression or extension are transferred through various loops to the active site. These changes then can affect the Msm GMPR activity. Our results show that the ligands trap the Msm GMPR octamer in either active or inhibited conformation.
1. Knejzlík Z., Doležal M., Herkommerová K., Clarova K., Klíma M., Dedola M., Zborníková E., Rejman D., Pichová I.: FEBS J. 289, 5571 (2022).
The project National Institute of virology and bacteriology (Programme EXCELES, ID Project No. LX22NPO5103) - Funded by the European Union - Next Generation EU
We acknowledge CF CF CryoEM of CIISB, Instruct-CZ Centre, supported by MEYS CR (LM2018127) and European Regional Development Fund-Project „UP CIISB“ (No.CZ.02.1.01/0.0/0.0/18_046/0015974)