title: 'Rod and ring' formation from IMP dehydrogenase is regulated through the one-carbon metabolic pathway.
abstract: 'Rods and rings' (RRs) are conserved, non-membrane-bound intracellular polymeric structures composed, in part, of inosine monophosphate dehydrogenase (IMPDH), a key enzyme leading to GMP and GTP biosynthesis. RR formation is induced by IMPDH inhibitors as well as glutamine deprivation. They also form upon treatment of cells with glutamine synthetase inhibitors. We now report that depriving cells of serine and glycine promotes RR formation, and we have traced these effects to dihydrofolate reductase (DHFR) and serine hydroxymethyltransferase-2 (SHMT2), pivotal enzymes in one-carbon metabolism and nucleotide biosynthesis. RR assembly is likewise induced upon DHFR inhibition by methotrexate or aminopterin as well as siRNA-mediated knockdown of DHFR or SHMT2. Because RR assembly occurs when guanine nucleotide biosynthesis is inhibited, and because RRs rapidly disassemble after the addition of guanine nucleotide precursors, RR formation might be an adaptive homeostatic mechanism, allowing IMPDH to sense changes in the one-carbon folate pathway.
authors.affiliation: Department of Oral Biology, University of Florida, 1395 Center Drive, Gainesville, FL 32610-0424, USA.
authors.forename: S John
authors.initials: SJ
authors.lastname: Calise
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Florida, 1200 Newell Drive, Gainesville, FL 32610-0245, USA.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Purich
authors.affiliation: Department of Oral Biology, University of Florida, 1395 Center Drive, Gainesville, FL 32610-0424, USA.
authors.forename: Thuy
authors.initials: T
authors.lastname: Nguyen
authors.affiliation: Department of Oral Biology, University of Florida, 1395 Center Drive, Gainesville, FL 32610-0424, USA.
authors.forename: Dania A
authors.initials: DA
authors.lastname: Saleem
authors.affiliation: Department of Oral Biology, University of Florida, 1395 Center Drive, Gainesville, FL 32610-0424, USA.
authors.forename: Claire
authors.initials: C
authors.lastname: Krueger
authors.affiliation: Department of Oral Biology, University of Florida, 1395 Center Drive, Gainesville, FL 32610-0424, USA.
authors.forename: Joyce D
authors.initials: JD
authors.lastname: Yin
authors.affiliation: Department of Oral Biology, University of Florida, 1395 Center Drive, Gainesville, FL 32610-0424, USA echan@ufl.edu.
authors.forename: Edward K L
authors.identifier: 0000-0003-3938-9503
authors.initials: EK
authors.lastname: Chan
mesh_terms: D000630:Aminopterin / Q000494:pharmacology; D002244:Carbon / Q000378:metabolism*; D003470:Culture Media / Q000494:pharmacology; D055785:Gene Knockdown Techniques; D005998:Glycine / Q000494:pharmacology; D012696:Glycine Hydroxymethyltransferase / Q000378:metabolism; D006151:Guanosine / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D019271:Hypoxanthine / Q000494:pharmacology; D007168:IMP Dehydrogenase / Q000378:metabolism*; D053858:Metabolic Networks and Pathways / Q000187:drug effects; D008727:Methotrexate / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000378:metabolism; D012694:Serine / Q000172:deficiency; D013762:Tetrahydrofolate Dehydrogenase / Q000378:metabolism
chemical_list: D003470:Culture Media; D034741:RNA, Small Interfering; D006151:Guanosine; D019271:Hypoxanthine; D012694:Serine; D002244:Carbon; D007168:IMP Dehydrogenase; D013762:Tetrahydrofolate Dehydrogenase; D012696:Glycine Hydroxymethyltransferase; C520541:SHMT protein, human; D000630:Aminopterin; D005998:Glycine; D008727:Methotrexate
keywords: Allosteric regulation; Cytoophidia; Enzyme inhibition; Enzyme polymerization; Folate metabolism; Intracellular filaments; Nucleotide biosynthesis; One-carbon metabolism