IMPDH2's Central Role in Cellular Growth and Diseases: A Potential Therapeutic Target

Abstract

IMPDH2 is a rate-limiting enzyme in guanine nucleotide biosynthesis. It plays diverse roles in various physiological and pathological processes: nucleotide metabolism, inflammation, immune function, ribosomal stress. Structural or regulatory alterations in IMPDH2 are linked to significant health issues, and critical relevance in disease progression. We aim to underscore the potential of IMPDH2 as a promising therapeutic target for clinical applications.

FIGURE 1

The molecular structure of IMPDH2. (A) IMPDH2 has a total 514 aminoacids, and consists of two domains: A catalytic domain (amino acid residues 2–92 and 224–492) forming the core of the active enzyme; and a regulatory Bateman domain (amino acid residues 93–223). Green represents the catalytic domain and yellow represents the bateman domain. (B) 3D rendering of a free standard octamer. Source: Data from https://www.rcsb.org/3d‐view/6UC2,viewed using pymol [2].

FIGURE 2

The biological functions of IMPDH2. (A) Participates in the synthesis of XMP to GTP. (B) Affect the energy supply and thus participate in inflammation signal transduction pathways. (C) Similar immunosuppressive agents that act specifically on IMPDH2, thus participating in the immune response and immunomodulation. (D) By inhibiting cellular IMPDH2, it reduces GTP levels, which in turn reduces nucleostemin (NS) levels, which in turn activates RS and p53 pathway.

FIGURE 3

Energy metabolism and signalling pathways involved in IMPDH2. (A) IMPDH2 is an essential enzyme involved in the de novo synthesis of guanine nucleotides. (B) Accelerate cell cycle transition through activation of the PI3K/AKT/mTOR and PI3K/AKT/FOXO 1 pathways. (C) Involved in NF‐κB signalling pathway, affects inflammatory response. (D) Binds FANCI and participates in the MEK/ERK/MMP pathway thereby affecting proliferation. (E) The Wnt/β‐catenin/IMPDH2 mediated purine metabolism regulating apoptosis.