IMP/GTP balance modulates cytoophidium assembly and IMPDH activity

Abstract

BackgroundInosine monophosphate dehydrogenase (IMPDH), the rate-limiting enzyme in de novo GTP biosynthesis, plays an important role in cell metabolism and proliferation. It has been demonstrated that IMPDH can aggregate into a macrostructure, termed the cytoophidium, in mammalian cells under a variety of conditions. However, the regulation and function of the cytoophidium are still elusive.ResultsIn this study, we report that spontaneous filamentation of IMPDH is correlated with rapid cell proliferation. Intracellular IMP accumulation promoted cytoophidium assembly, whereas elevated GTP level triggered disassociation of aggregates. By using IMPDH2 CBS domain mutant cell models, which are unable to form the cytoophidium, we have determined that the cytoophidium is of the utmost importance for maintaining the GTP pool and normal cell proliferation in the condition that higher IMPDH activity is required.ConclusionsTogether, our results suggest a novel mechanism whereby cytoophidium assembly upregulates IMPDH activity and mediates guanine nucleotide homeostasis.Electronic supplementary materialThe online version of this article (10.1186/s13008-018-0038-0) contains supplementary material, which is available to authorized users.

De-novo purine biosynthesis is a major driver of chemoresistance in glioblastoma

“…The dwell time was 3 ms per SRM transition, and the total cycle time was 1. 55 For all extractions, the remaining pellets were resuspended in 8 M Urea /10 mM Tris, pH 8, heated at 60°C degrees for 30 min with shaking, centrifuged, and protein concentration in the supernatant was quantified using Bradford kit. Peak areas of metabolites detected by mass spectrometry were normalized to the median and then normalized to protein concentrations.…”

Anfractuous assemblies of IMP dehydrogenase and CTP synthase: new twists on regulation?

“…Again, two isoforms, IMPDH1 and IMPDH2, have been identified. Similarly, human IMPDH2 filaments can form bound to activators (IMP and NAD + ) [17] and are dismantled by GTP in vivo [18]. Because rapidly proliferating cells require CTP and GTP, both allosterically controlled enzymes are targets for the development of anticancer, antiviral, and immunosuppressive chemotherapies.…”

“…They share 84% amino acid sequence identity and function as octamers. CTPS1/IMPDH2 assemblies are induced by inhibitors of these enzymes, but whether the assembly follows inhibitor binding or depletion of CTP and GTP pools has not been fully explored [6,[16][17][18][19][20]. In this issue of The FEBS Journal, Liu, Sung, and co-workers [14] explore the morphology and dynamics of CTPS1/IMPDH2-containing assemblies in live human cells.…”

“…Factors governing the assembly of these structures are unclear, but fluctuations in intracellular NTP levels appear to be involved. Similarly, human IMPDH2 filaments can form bound to activators (IMP and NAD + ) [17] and are dismantled by GTP in vivo [18]. Similarly, human IMPDH2 filaments can form bound to activators (IMP and NAD + ) [17] and are dismantled by GTP in vivo [18].…”

“…Human CTPS filaments form bound to substrates (UTP and ATP) and disassemble with the abundance of the product (CTP) [16]. CTPS1/IMPDH2 assemblies are induced by inhibitors of these enzymes, but whether the assembly follows inhibitor binding or depletion of CTP and GTP pools has not been fully explored [6,[16][17][18][19][20]. CTPS1/IMPDH2 assemblies are induced by inhibitors of these enzymes, but whether the assembly follows inhibitor binding or depletion of CTP and GTP pools has not been fully explored [6,[16][17][18][19][20].…”