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The functional impact of the C/N-terminal extensions of the mouse retinal IMPDH1 isoforms: a kinetic evaluation

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Abstract

Mutations in the retinal inosine monophosphate dehydrogenase1 (IMPDH1) gene is believed to be one cause of retinitis pigmentosa (RP). The main structural difference between the mutation-susceptible retinal isoforms with canonical one resides in the C- and N-terminal extensions. There are limited studies on the structure and function of terminal peptide extensions of the IMPDH1 retinal isoforms. Using recombinant murine IMPDH1 (mH1), we evaluated the kinetics of the retinal isoforms along with inhibition by some of the purine nucleotides. Molecular modeling tools were also applied to study the probable effect(s) of the terminal peptide tails on the function of the retinal isoforms. Molecular dynamic simulations indicated the possible impact of the end-terminal segments on the enzyme function through interactions with the enzyme’s finger domain, affecting its critical pseudo barrel structure. The higher experimentally-determined Km and Ki values of the retinal mIMPDH1 (546) and mIMPDH1 (603) relative to that of the canonical isoform, mIMPDH1 (514), might clearly be due to these interactions. Furthermore and despite of the canonical isoform, the retinal isoforms of mH1 exhibited no NAD+ substrate inhibition. The resent data would certainly provide the ground for future evaluation of the physiological significance of these variations.

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Acknowledgements

The authors appreciate the joint financial support of this investigation by the Research Council of University of Tehran. We also thank Dr. S. Soheili and Dr. E. Ranaei Pirmardan from the National Institute of Genetic Engineering and Biotechnology (Karaj, Tehran) for their assistance in retina isolation from the mouse eyes.

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Correspondence to Razieh Yazdanparast.

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Andashti, B., Yazdanparast, R., Barzegari, E. et al. The functional impact of the C/N-terminal extensions of the mouse retinal IMPDH1 isoforms: a kinetic evaluation. Mol Cell Biochem 465, 155–164 (2020) doi:10.1007/s11010-019-03675-9

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Keywords

  • Finger domain
  • IMPDH1
  • Molecular modeling
  • Retinal isoforms
  • Retinitis pigmentosa
  • Terminal extension