Fic domain-containing AMPylases (Fic AMPylases) are a family of evolutionarily conserved enzymes present in most metazoans. Fic AMPylases are bi-functional: as monomers, these enzymes catalyze the transfer of AMP at the expense of an ATP molecule to surface-exposed threonine and serine hydroxyl groups (target AMPylation) (Chatterjee and Truttmann, 2021; Perera et al., 2019); upon dimerization and co-factor exchange, the same catalytic site supports AMP removal from modified proteins (target deAMPylation) (Casey et al., 2018; Moehlman et al., 2018; Preissler et al., 2017a; Preissler et al., 2017b; Veyron et al., 2019). Work by many groups suggests that fic AMPylases modify proteins in the endoplasmic reticulum (ER) as well as in the cytoplasm, with a preference for the ER-resident chaperone BiP/Grp78 (Fig. 1A). The activity of fic AMPylases is tightly regulated. Fic AMPylase-mediated hyper-AMPylation, achieved by the over-expression of constitutive AMPylase mutants, is toxic and leads to cell death in human in cellulo models (Sanyal et al., 2015), as well as Saccharomyces cerevisiae (Truttmann et al., 2017), Drosophila melanogaster (Casey et al., 2018) and Caenorhabditis elegans (Truttmann et al., 2018) in vivo models. Hyper-AMPylation-mediated cell death involves caspase-dependent apoptotic signaling (Sanyal et al., 2015). However, a detailed understanding as to why hyper-AMPylation is lethal remains elusive. One major hypothesis in the field is that hyper-AMPylation will deplete cellular ATP pools, leading to starvation-induced apoptosis.