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Cleghorn WM, Burrell AL, Giarmarco MM, et al. A highly conserved zebrafish IMPDH retinal isoform produces the majority of guanine and forms dynamic protein filaments in photoreceptor cells. J Biol Chem. 2021;298(1):101441doi: 10.1016/j.jbc.2021.101441.
Cleghorn, W. M., Burrell, A. L., Giarmarco, M. M., Brock, D. C., Wang, Y., Chambers, Z. S., Du, J., Kollman, J. M., & Brockerhoff, S. E. (2021). A highly conserved zebrafish IMPDH retinal isoform produces the majority of guanine and forms dynamic protein filaments in photoreceptor cells. The Journal of biological chemistry, 298(1), 101441. https://doi.org/10.1016/j.jbc.2021.101441
Cleghorn, Whitney M, et al. "A highly conserved zebrafish IMPDH retinal isoform produces the majority of guanine and forms dynamic protein filaments in photoreceptor cells." The Journal of biological chemistry vol. 298,1 (2021): 101441. doi: https://doi.org/10.1016/j.jbc.2021.101441
Cleghorn WM, Burrell AL, Giarmarco MM, Brock DC, Wang Y, Chambers ZS, Du J, Kollman JM, Brockerhoff SE. A highly conserved zebrafish IMPDH retinal isoform produces the majority of guanine and forms dynamic protein filaments in photoreceptor cells. J Biol Chem. 2021 Nov 20;298(1):101441. doi: 10.1016/j.jbc.2021.101441. Epub 2021 Nov 20. PMID: 34813793; PMCID: PMC8688572.
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J Biol Chem. 2021 Nov 20;298(1):101441. doi: 10.1016/j.jbc.2021.101441. Epub 2021 Nov 20.

A highly conserved zebrafish IMPDH retinal isoform produces the majority of guanine and forms dynamic protein filaments in photoreceptor cells.

The Journal of biological chemistry

Whitney M Cleghorn, Anika L Burrell, Michelle M Giarmarco, Daniel C Brock, Yekai Wang, Zachary S Chambers, Jianhai Du, Justin M Kollman, Susan E Brockerhoff

Affiliations

  1. Department of Biochemistry, University of Washington, Seattle, Washington, USA; Department of Ophthalmology, University of Washington, Seattle, Washington, USA.
  2. Department of Biochemistry, University of Washington, Seattle, Washington, USA.
  3. Department of Ophthalmology, University of Washington, Seattle, Washington, USA.
  4. Department of Ophthalmology and Visual Sciences, West Virginia University, Morgantown, West Virginia, USA; Department of Biochemistry, West Virginia University, Morgantown, West Virginia, USA.
  5. Department of Biochemistry, University of Washington, Seattle, Washington, USA; Department of Ophthalmology, University of Washington, Seattle, Washington, USA. Electronic address: [email protected].

PMID: 34813793 PMCID: PMC8688572 DOI: 10.1016/j.jbc.2021.101441

Abstract

Inosine monophosphate dehydrogenase (IMPDH) is a key regulatory enzyme in the de novo synthesis of the purine base guanine. Dominant mutations in human IMPDH1 cause photoreceptor degeneration for reasons that are unknown. Here, we sought to provide some foundational information on Impdh1a in the zebrafish retina. We found that in zebrafish, gene subfunctionalization due to ancestral duplication resulted in a predominant retinal variant expressed exclusively in rod and cone photoreceptors. This variant is structurally and functionally similar to the human IMPDH1 retinal variant and shares a reduced sensitivity to GTP-mediated inhibition. We also demonstrated that Impdh1a forms prominent protein filaments in vitro and in vivo in both rod and cone photoreceptor cell bodies, synapses, and to a lesser degree, in outer segments. These filaments changed length and cellular distribution throughout the day consistent with diurnal changes in both mRNA and protein levels. The loss of Impdh1a resulted in a substantial reduction of guanine levels, although cellular morphology and cGMP levels remained normal. Our findings demonstrate a significant role for IMPDH1 in photoreceptor guanine production and provide fundamental new information on the details of this protein in the zebrafish retina.

Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

Keywords: IMPDH; Zebrafish; inosine monophosphate dehydrogenase; metabolic filaments; photoreceptor metabolism; photoreceptors; purine metabolism

Conflict of interest statement

Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article.

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