title: IMPDH2 Is an Intracellular Target of the Cyclophilin A and Sanglifehrin A Complex.
abstract: Natural products have demonstrated utility in the clinic and can also act as probes to understand complex cellular pathways. Sanglifehrin A (SFA) is a mixed polyketide and non-ribosomal peptide synthase natural product with sub-nano-molar affinity for its receptor cyclophilin A (PPIA). It has been shown to behave in vitro as an immune suppressant. Here, we identify inosine-5'-monophosphate dehydrogenase 2 (IMPDH2) as an intracellular target of the PPIA-SFA binary complex. The formation of this ternary complex does not inhibit the enzymatic activity of IMPDH2. Rather, ternary complex formation modulates cell growth through interaction with the cystathionine-β-synthase (CBS) domain of IMPDH2. We further demonstrate that the SFA complex is highly isoform selective for IMPDH2 (versus IMPDH1). This work reveals a role for the CBS domains of IMPDH2 in cellular proliferation, suggesting a more complex role than previously suspected for IMPDH2 in T cell activation and proliferation.
authors.affiliation: Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA; Warp Drive Bio, Cambridge, MA 02139, USA.
authors.forename: Khian Hong
authors.initials: KH
authors.lastname: Pua
authors.affiliation: Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA; Warp Drive Bio, Cambridge, MA 02139, USA.
authors.forename: Dylan T
authors.initials: DT
authors.lastname: Stiles
authors.affiliation: Warp Drive Bio, Cambridge, MA 02139, USA; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Mathew E
authors.initials: ME
authors.lastname: Sowa
authors.affiliation: Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA; Warp Drive Bio, Cambridge, MA 02139, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA. Electronic address: gregory_verdine@harvard.edu.
authors.forename: Gregory L
authors.initials: GL
authors.lastname: Verdine
mesh_terms: D049109:Cell Proliferation; D021984:Cyclophilin A / Q000378:metabolism*; D006801:Humans; D007168:IMP Dehydrogenase / Q000737:chemistry / Q000378:metabolism*; D019169:Jurkat Cells; D020014:K562 Cells; D007783:Lactones / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D000072417:Protein Domains; D013141:Spiro Compounds / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D007783:Lactones; D013141:Spiro Compounds; C121329:sanglifehrin A; D007168:IMP Dehydrogenase; C501687:IMPDH2 protein, human; D021984:Cyclophilin A
keywords: cyclophilin A; cystathionine-β-synthase domains; inosine-5′-monophosphate dehydrogenase; protein-protein interactions; sanglifehrin A