CTP synthase: the hissing of the cellular serpent

Abstract

CTP biosynthesis is carried out by two pathways: salvage and de novo. CTPsyn catalyzes the latter. The study of CTPsyn activity in mammalian cells began in the 1970s, and various fascinating discoveries were made regarding the role of CTPsyn in cancer and development. However, its ability to fit into a cellular serpent-like structure, termed ‘cytoophidia,’ was only discovered a decade ago by three independent groups of scientists. Although the self-assembly of CTPsyn into a filamentous structure is evolutionarily conserved, the enzyme activity upon this self-assembly varies in different species. CTPsyn is required for cellular development and homeostasis. Changes in the expression of CTPsyn cause developmental changes in Drosophila melanogaster . A high level of CTPsyn activity and formation of cytoophidia are often observed in rapidly proliferating cells such as in stem and cancer cells. Meanwhile, the deficiency of CTPsyn causes severe immunodeficiency leading to immunocompromised diseases caused by bacteria, viruses, and parasites, making CTPsyn an attractive therapeutic target. Here, we provide an overview of the role of CTPsyn in cellular and disease perspectives along with its potential as a drug target.

A model industrial workhorse: Bacillus subtilis strain 168 and its genome after a quarter of a century

“…Evolution has shaped CTP synthase for this specific role, with its expression regulated by reiterative transcription at the promoter of the pyrG gene (Shin et al, 2020 ). A key feature of the enzyme is that, in all organisms where its structure has been explored, it makes filamentous structures, the cytoophidia, with important consequences for the spatial distribution and regulation of enzyme activity (Thangadurai et al, 2022 ). This parallels the CTP‐dependent overall metabolic activity controlling growth homeostasis which must act simultaneously on cytoplasmic, membrane and genome metabolism.…”

Effect on cell survival and cytoophidium assembly of the adRP-10-related IMPDH1 missense mutation Asp226Asn

“…Cytoophidium assembly regulates the enzyme’s activity ( Keppeke et al, 2018 ; Fernandez-Justel et al, 2019 ; Plana-Bonamaiso et al, 2020 ; Burrell et al, 2022 ) and may increase protein half-life by preventing proteasomal degradation ( Chang et al, 2022 ). Other tissues, cells, and organisms have other enzymes beyond IMPDH that also assemble into the cytoophidium, such as CTPS, P5CS, and PRPS, also for enzyme activity regulation ( Hu et al, 2022 ; Thangadurai et al, 2022 ; Zhong et al, 2022 ). In photoreceptor cells, it has been proposed that regulation of IMPDH1 by GDP/GTP allosteric modulation is controlled by phosphorylation in vivo to adjust GTP synthesis to different lighting conditions ( Plana-Bonamaiso et al, 2020 ).…”