Induction of IMPDH-Based Cytoophidia by a Probable IMP-Dependent ARL13B–IMPDH Interaction

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Najva Alijani¹, Razieh Yazdanparast^1,a*

¹Institute of Biochemistry and Biophysics, University of Tehran, Tehran, 13145-1384, Iran

^* To whom correspondence should be addressed.

Received: August 26, 2024; Revised: October 22, 2024; Accepted: November 18, 2024

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Inosine Monophosphate Dehydrogenase (IMPDH) catalyzes rate-limiting step of the reaction converting inosine monophosphate (IMP) to guanine nucleotides. IMPDH is up-regulated in the healthy proliferating cells and also in tumor cells to meet their elevated demand for guanine nucleotides. An exclusive regulatory mechanism for this enzyme is filamentation, through which IMPDH can resist allosteric inhibition by the end product, GTP. It has been proven that intracellular IMP, which rises during the proliferative state, potentially promotes IMPDH filamentation. On the other hand, interaction of IMPDH with ADP-ribosylation factor-like protein 13B (ARL13B) directs guanine biosynthesis toward the de novo pathway. However, ARL13B is not localized in the IMPDH-based cytoophidia, super structures composed of bundled IMPDH filaments and other proteins. Here, we hypothesized that ARL13B could increase availability of the de novo-produced IMP for IMPDH by interacting with the IMP-free IMPDH and microtubules adjacent to the purinosome. Following IMP-binding, IMPDH would be released from ARL13B and preferentially associated with its cytoophidia. Considering clinical side effects of catalytic inhibitors of IMPDH and their ability to induce IMPDH cytoophidia, we suggest that combination of proper doses of IMPDH catalytic inhibitors and inhibitors of the de novo IMP biosynthesis could be more effective in controlling cell proliferation.

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KEY WORDS: ARL13B–IMPDH interaction, IMP, cytoophidia, purine biosynthesis

DOI: 10.1134/S0006297924120162

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