<table><caption>TABLE 3 Summary of potential chemical scaffolds described as bacterial DNPNB enzymes inhibitors.</caption><thead><tr><th>DNPNB target</th><th>Molecule</th><th>Reported activity</th><th>References</th></tr></thead><tbody><tr><td rowspan="2">3<br>PurN</td><td>13</td><td>Folate analogue; competitive inhibitor for N<sup>10</sup>-formyl FH<sub>4</sub> cofactor; IC<sub>50</sub> = 0.1 µM on <i>Lactobacillus casei</i> PurN</td><td>Thorndike et al. (1990)</td></tr><tr><td>14</td><td>Folate analogue, competitive inhibitor for N<sup>10</sup>-formyl FH<sub>4</sub> cofactor; K<sub>i</sub> = 0.26 µM on <i>E. coli</i> PurN</td><td>Boger et al. (1997a), Boger et al. (1997b)</td></tr><tr><td rowspan="3">6'<br>PurK</td><td>15</td><td>Class I inhibitor; IC<sub>50</sub> = 2.3 µM on <i>E. coli</i> PurK; inhibition due to reaction with AIR and substrate depletion</td><td>Firestine et al. (2009)</td></tr><tr><td>16</td><td>Class II inhibitor (isatin derivative); IC<sub>50</sub> = 10.5 µM on <i>E. coli</i> PurK; inhibition due to AIR:isatin product formation and substrate depletion</td><td>Firestine et al. (2009), Streeter et al. (2019)</td></tr><tr><td>17</td><td>Class III inhibitor competitive for AIR, uncompetitive for ATP; IC<sub>50</sub> = 10 µM on <i>E. coli</i> PurK</td><td>Firestine et al. (2009)</td></tr><tr><td rowspan="3">6<br>PurE</td><td>18</td><td>4-nitro-5-aminoimidazole ribonucleotide (NAIR), competitive inhibitor for CAIR; K<sub>i</sub> = 0.5 µM on <i>E. coli</i> PurE</td><td>Firestine et al. (1994)</td></tr><tr><td>19</td><td>Fragment binder in the active site of <i>B. anthracis</i> PurE; K<sub>D</sub> = 13.5 µM; 49% PurE inhibition at 25 µM</td><td>Lei et al. (2016)</td></tr><tr><td>20</td><td>27% inhibition of <i>B. anthracis</i> PurE at 10 µM; MIC = 0.15, 0.3 and 0.4 µg/mL on <i>B. anthracis</i>, methicillin-susceptible and methicillin-resistant <i>S. aureus</i>, respectively</td><td>Kim et al. (2015a)</td></tr><tr><td>7<br>PurC</td><td>21</td><td>Binding site within the ATP-binding pocket; K<sub>D</sub> = 0.15 µM on <i>M. abscessus</i> PurC; MIC = 50 µM on <i>M. tuberculosis</i></td><td>Charoensutthivarakul et al. (2022)</td></tr><tr><td>12<br>GuaA</td><td>22</td><td>Oxanosine; K<sub>i</sub> = 0.74 mM on <i>E. coli</i> GuaA; bacteriostatic on <i>E. coli</i></td><td>Yagisawa et al. (1982)</td></tr></tbody></table>

IMPDHs (including two bacterial ones, IMPDHba and IMPDHcj, and hIMPDH2) and demonstrated to be a competitive inhibitor for IMP (Yu et al., 2019). Investigating the inhibitory mechanism in more detail led to the conclusion by these same authors that a covalent adduct is formed with the catalytic cysteine of the enzyme.

## 5.4 Future perspectives

Antibiotic resistance remains a main concern of public health, and drugs acting with a novel mode of action are needed. Several possible strategies altering at least one of the regulatory modes of
<table><caption>TABLE 3 Summary of potential chemical scaffolds described as bacterial DNPNB enzymes inhibitors.</caption><thead><tr><th>DNPNB target</th><th>Molecule</th><th>Reported activity</th><th>References</th></tr></thead><tbody><tr><td rowspan="2">3<br>PurN</td><td>13</td><td>Folate analogue; competitive inhibitor for N<sup>10</sup>-formyl FH<sub>4</sub> cofactor; IC<sub>50</sub> = 0.1 µM on <i>Lactobacillus casei</i> PurN</td><td>Thorndike et al. (1990)</td></tr><tr><td>14</td><td>Folate analogue, competitive inhibitor for N<sup>10</sup>-formyl FH<sub>4</sub> cofactor; K<sub>i</sub> = 0.26 µM on <i>E. coli</i> PurN</td><td>Boger et al. (1997a), Boger et al. (1997b)</td></tr><tr><td rowspan="3">6'<br>PurK</td><td>15</td><td>Class I inhibitor; IC<sub>50</sub> = 2.3 µM on <i>E. coli</i> PurK; inhibition due to reaction with AIR and substrate depletion</td><td>Firestine et al. (2009)</td></tr><tr><td>16</td><td>Class II inhibitor (isatin derivative); IC<sub>50</sub> = 10.5 µM on <i>E. coli</i> PurK; inhibition due to AIR:isatin product formation and substrate depletion</td><td>Firestine et al. (2009), Streeter et al. (2019)</td></tr><tr><td>17</td><td>Class III inhibitor competitive for AIR, uncompetitive for ATP; IC<sub>50</sub> = 10 µM on <i>E. coli</i> PurK</td><td>Firestine et al. (2009)</td></tr><tr><td rowspan="3">6<br>PurE</td><td>18</td><td>4-nitro-5-aminoimidazole ribonucleotide (NAIR), competitive inhibitor for CAIR; K<sub>i</sub> = 0.5 µM on <i>E. coli</i> PurE</td><td>Firestine et al. (1994)</td></tr><tr><td>19</td><td>Fragment binder in the active site of <i>B. anthracis</i> PurE; K<sub>D</sub> = 13.5 µM; 49% PurE inhibition at 25 µM</td><td>Lei et al. (2016)</td></tr><tr><td>20</td><td>27% inhibition of <i>B. anthracis</i> PurE at 10 µM; MIC = 0.15, 0.3 and 0.4 µg/mL on <i>B. anthracis</i>, methicillin-susceptible and methicillin-resistant <i>S. aureus</i>, respectively</td><td>Kim et al. (2015a)</td></tr><tr><td>7<br>PurC</td><td>21</td><td>Binding site within the ATP-binding pocket; K<sub>D</sub> = 0.15 µM on <i>M. abscessus</i> PurC; MIC = 50 µM on <i>M. tuberculosis</i></td><td>Charoensutthivarakul et al. (2022)</td></tr><tr><td>12<br>GuaA</td><td>22</td><td>Oxanosine; K<sub>i</sub> = 0.74 mM on <i>E. coli</i> GuaA; bacteriostatic on <i>E. coli</i></td><td>Yagisawa et al. (1982)</td></tr></tbody></table>

IMPDHs (including two bacterial ones, IMPDHba and IMPDHcj, and hIMPDH2) and demonstrated to be a competitive inhibitor for IMP (Yu et al., 2019). Investigating the inhibitory mechanism in more detail led to the conclusion by these same authors that a covalent adduct is formed with the catalytic cysteine of the enzyme.

## 5.4 Future perspectives

Antibiotic resistance remains a main concern of public health, and drugs acting with a novel mode of action are needed. Several possible strategies altering at least one of the regulatory modes of
DNPNB listed in this review could be adopted to develop novel therapeutic agents. IMPDH is still to date the most attractive enzyme among all DNPNB enzymes in human and bacteria from a pharmacological point of view. Only few other bacterial DNPNB enzymes have been exploited as therapeutic targets, although most of them have been shown to play a crucial role in bacterial growth and virulence. Moreover, divergences exist between the bacterial and human DNPNB, therefore it would be possible to develop inhibitors acting only on pathogens, without any impact on humans. Some recent development for screening tools [such as the case of PurE, for example, as reported recently by Sharma et al. (2023)], has the potential to reignite interest in bacterial DNPNB enzymes and facilitate the discovery of novel chemical scaffolds. Nonetheless, despite their attractiveness, it is also worth noting that some possible limitations need to be kept in mind while developing DNPNB modulators. For example, perturbing the nucleotide pool equilibrium can possibly increase the rate of nonspecific incorporation of nucleotides during replication or translation, and therefore raise some serious pharmacodynamic issues (such as induction of mutations in housekeeping genes). Even though this concern is not completely applied to cancer cells, since targeting nucleotide metabolism has been shown to elicit significant therapeutic efficacy in cancer immunotherapies (Wu et al., 2022; Ali and Ben-Sahra, 2023; Mullen and Singh, 2023), this molecular phenomenon in bacteria can lead to the emergence and rise of multidrug-resistant strains.

Another approach could involve the development of modulators of protein-protein interactions (PPIs). In comparison with perturbators of enzymatic catalysis in which a molecule binds to the active site, allosteric or PPI modulators can be designed to be more specific to a certain bacterial or mammalian ortholog, since the allosteric and (homo/ hetero)-oligomerization pockets are more evolutionarily divergent than the residues implicated in the binding of substrates and catalysis. Although PPIs have long been considered as challenging targets with small compounds, recent successful development of PPI inhibitors has been documented (Lu et al., 2020). This approach will also benefit from the availability of PPI-focused chemical libraries to increase the hit rate (Zhang et al., 2014; Bosc et al., 2020). With the discovery of the purinosome, and the recent updates supporting the existence of a DNPNB quinary structure in bacteria, several PPIs could be targeted by small molecules to alter protein colocalization and therefore DNPNB. This strategy was already described in the case of the bifunctional human ATIC, for example, with the report of a series of peptides that inhibit ATIC homodimerization (Tavassoli and Benkovic, 2005; Spurr et al., 2012). *In vitro* evaluation of one of the hits showed significant reduction of proliferation of breast cancer cells. In this perspective, it will be interesting to evaluate the effect of these molecules on purinosome formation in cells and DNPNB metabolic flux. Another enzyme of interest could be PurB, not only for its unique essentiality for bacterial growth, but also for its original three-dimensional structure. The resolution of *S. aureus* PurB structure

has revealed that active sites are endowed between dimeric interfaces of the tetramer, and hence alteration of homooligomerization could potentially alter catalytic activity and protein-protein interactions (Fyfe et al., 2010).

Developing antibacterial compounds could be interesting not only for treatment of bacterial infections, but also to potentiate the effect of anticancer drugs. Attractively, it has been shown that the microbiome could be in some cases causative of chemoresistance in gastrointestinal and pulmonary cancers (Halley et al., 2020; Garajová et al., 2021). Developing dual inhibitors targeting human and/or bacterial DNPNB pathway and adding them to mixed therapies could be beneficial for some patients.

## Author contributions

NA: Writing—original draft, Writing—review and editing. AG: Writing—original draft, Writing—review and editing. HM-L: supervision, Writing—original draft, Writing—review and editing.

## Funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported in part by the Centre National de la Recherche Scientifique (CNRS), the Institut National de la Santé Et de la Recherche Médicale (INSERM) and the Institut Pasteur.

## Acknowledgments

NA acknowledges a Ph.D. fellowship from the Médicament, Toxicologie, Chimie et Imageries Ph.D. school (MTCI, ED 563), Université Paris Cité.

## Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

## Publisher's note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

## References

Agarwal, S., Chakravarthi, B. V. S. K., Behring, M., Kim, H.-G., Chandrashekar, D. S., Gupta, N., et al. (2020a). PAICS, a purine nucleotide metabolic enzyme, is involved in tumor growth and the metastasis of colorectal cancer. *Cancers* 12 (4), 772. doi:10.3390/cancers12040772

Agarwal, S., Chakravarthi, B. V. S. K., Kim, H.-G., Gupta, N., Hale, K., Balasubramanya, S. A. H., et al. (2020b). PAICS, a *de novo* purine biosynthetic enzyme, is overexpressed in pancreatic cancer and is involved in its progression. *Transl. Oncol.* 13 (7), 100776. doi:10.1016/j.tranon.2020.100776
DNPNB listed in this review could be adopted to develop novel therapeutic agents. IMPDH is still to date the most attractive enzyme among all DNPNB enzymes in human and bacteria from a pharmacological point of view. Only few other bacterial DNPNB enzymes have been exploited as therapeutic targets, although most of them have been shown to play a crucial role in bacterial growth and virulence. Moreover, divergences exist between the bacterial and human DNPNB, therefore it would be possible to develop inhibitors acting only on pathogens, without any impact on humans. Some recent development for screening tools [such as the case of PurE, for example, as reported recently by Sharma et al. (2023)], has the potential to reignite interest in bacterial DNPNB enzymes and facilitate the discovery of novel chemical scaffolds. Nonetheless, despite their attractiveness, it is also worth noting that some possible limitations need to be kept in mind while developing DNPNB modulators. For example, perturbing the nucleotide pool equilibrium can possibly increase the rate of nonspecific incorporation of nucleotides during replication or translation, and therefore raise some serious pharmacodynamic issues (such as induction of mutations in housekeeping genes). Even though this concern is not completely applied to cancer cells, since targeting nucleotide metabolism has been shown to elicit significant therapeutic efficacy in cancer immunotherapies (Wu et al., 2022; Ali and Ben-Sahra, 2023; Mullen and Singh, 2023), this molecular phenomenon in bacteria can lead to the emergence and rise of multidrug-resistant strains.

Another approach could involve the development of modulators of protein-protein interactions (PPIs). In comparison with perturbators of enzymatic catalysis in which a molecule binds to the active site, allosteric or PPI modulators can be designed to be more specific to a certain bacterial or mammalian ortholog, since the allosteric and (homo/ hetero)-oligomerization pockets are more evolutionarily divergent than the residues implicated in the binding of substrates and catalysis. Although PPIs have long been considered as challenging targets with small compounds, recent successful development of PPI inhibitors has been documented (Lu et al., 2020). This approach will also benefit from the availability of PPI-focused chemical libraries to increase the hit rate (Zhang et al., 2014; Bosc et al., 2020). With the discovery of the purinosome, and the recent updates supporting the existence of a DNPNB quinary structure in bacteria, several PPIs could be targeted by small molecules to alter protein colocalization and therefore DNPNB. This strategy was already described in the case of the bifunctional human ATIC, for example, with the report of a series of peptides that inhibit ATIC homodimerization (Tavassoli and Benkovic, 2005; Spurr et al., 2012). *In vitro* evaluation of one of the hits showed significant reduction of proliferation of breast cancer cells. In this perspective, it will be interesting to evaluate the effect of these molecules on purinosome formation in cells and DNPNB metabolic flux. Another enzyme of interest could be PurB, not only for its unique essentiality for bacterial growth, but also for its original three-dimensional structure. The resolution of *S. aureus* PurB structure

has revealed that active sites are endowed between dimeric interfaces of the tetramer, and hence alteration of homooligomerization could potentially alter catalytic activity and protein-protein interactions (Fyfe et al., 2010).

Developing antibacterial compounds could be interesting not only for treatment of bacterial infections, but also to potentiate the effect of anticancer drugs. Attractively, it has been shown that the microbiome could be in some cases causative of chemoresistance in gastrointestinal and pulmonary cancers (Halley et al., 2020; Garajová et al., 2021). Developing dual inhibitors targeting human and/or bacterial DNPNB pathway and adding them to mixed therapies could be beneficial for some patients.

## Author contributions

NA: Writing—original draft, Writing—review and editing. AG: Writing—original draft, Writing—review and editing. HM-L: supervision, Writing—original draft, Writing—review and editing.

## Funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported in part by the Centre National de la Recherche Scientifique (CNRS), the Institut National de la Santé Et de la Recherche Médicale (INSERM) and the Institut Pasteur.

## Acknowledgments

NA acknowledges a Ph.D. fellowship from the Médicament, Toxicologie, Chimie et Imageries Ph.D. school (MTCI, ED 563), Université Paris Cité.

## Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

## Publisher's note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

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Liao, L. X., Song, X. M., Wang, L. C., Lv, H. N., Chen, J. F., Liu, D., et al. (2017). Highly selective inhibition of IMPDH2 provides the basis of antineuroinflammation therapy. *Proc. Natl. Acad. Sci. U. S. A.* 112 (24), E5986–E5994. doi:10.1073/pnas.1706778114

Liberati, N. T., Urbach, J. M., Miyata, S., Lee, D. G., Drenkard, E., Wu, G., et al. (2006). An ordered, nonredundant library of *Pseudomonas aeruginosa* strain PA14 transposon insertion mutants. *Proc. Natl. Acad. Sci. U. S. A.* 103 (8), 2833–2838. doi:10.1073/pnas.0511100103

Link, J. O., and Straub, K. (1996). Trapping of an IMP Dehydrogenase–Substrate covalent intermediate by mycophenolic acid. *J. Am. Chem. Soc.* 118 (8), 2091–2092. doi:10.1021/ja9534056

Lins, M., Corrêa, G. G., Amorim, L., Franco, R. A. L., Ribeiro, N. V., Jesus, V. N., et al. (2022). Characterization of five purine riboswitches in cellular and cell-free expression systems. *Curr. Microbiol.* 79 (7), 207. doi:10.1007/s00284-022-02902-9

Liu, C., Knudsen, G. M., Pedley, A. M., He, J., Johnson, J. L., Yaron, T. M., et al. (2019). Mapping post-translational modifications of *de novo* purine biosynthetic enzymes: implications for pathway regulation. *J. Proteome Res.* 18 (5), 2078–2087. doi:10.1021/acs.jproteome.8b00969

Liu, X., Kimmey, J. M., Matarazzo, L., de Bakker, V., Van Maele, L., Sirard, J.-C., et al. (2021). Exploration of bacterial bottlenecks and *Streptococcus pneumoniae* pathogenesis by CRISPRi-seq. *Cell Host Microbe* 29 (1), 107–120.e6. doi:10.1016/j.chom.2020.10.001

Liu, Y.-C., Li, F., Handler, J., Huang, C. R. L., Xiang, Y., Neretti, N., et al. (2008). Global regulation of nucleotide biosynthetic genes by c-myc. *PLoS ONE* 3 (7), e2722. doi:10.1371/journal.pone.0002722

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Macpherson, I. S., Kirubakaran, S., Gorla, S. K., Riera, T. V., D’Aquino, J. A., Zhang, M., et al. (2010). The structural basis of *Cryptosporidium*-specific IMP dehydrogenase inhibitor selectivity. *J. Am. Chem. Soc.* 132 (4), 1230–1231. doi:10.1021/ja909947a

Magasanik, B., Moyed, H. S., and Gehring, L. B. (1957). Enzymes essential for the biosynthesis of nucleic acid guanine; inosine 5'-phosphate dehydrogenase of *Aerobacter aerogenes*. *J. Biol. Chem.* 226 (1), 339–350. doi:10.1016/s0021-9258(18)64835-5

Makowska-Grzyska, M., Kim, Y., Wu, R., Wilton, R., Gollapalli, D. R., Wang, X. K., et al. (2012). *Bacillus anthracis* inosine 5'-monophosphate dehydrogenase in action: the first bacterial series of structures of phosphate ion-substrate-and product-bound complexes. *Biochemistry* 51 (31), 6148–6163. doi:10.1021/bi300511w

Mandal, M., Boese, B., Barrick, J. E., Winkler, W. C., and Breaker, R. R. (2003). Riboswitches control fundamental biochemical pathways in *Bacillus subtilis* and other bacteria. *Cell* 113 (5), 577–586. doi:10.1016/s0092-8674(03)00391-x

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Marie, S., Heron, B., Bitoun, P., Timmerman, T., Van den Berghe, G., and Vincent, M.-F. (2004). AICA-Ribosiduria: a novel, neurologically devastating inborn error of purine biosynthesis caused by mutation of ATIC. *Am. J. Hum. Genet.* 74 (6), 1276–1281. doi:10.1086/421475

Marolewski, A., Smith, J. M., and Benkovic, S. J. (1994). Cloning and characterization of a new purine biosynthetic enzyme: a non-folate glycinamide ribonucleotide transformase from *E. coli*. *Biochemistry* 33 (9), 2531–2537. doi:10.1021/bi00175a023

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Glossary

<table><tr><td>ADP</td><td>adenosine 5'-diphosphate</td><td>IMPDHsc</td><td>Streptomyces coelicolor IMPDH</td></tr><tr><td>AdS</td><td>adenylosuccinate</td><td>IMPDHtb</td><td>Trypanosoma brucei IMPDH</td></tr><tr><td>ADSL</td><td>Ads lyase</td><td>MIC</td><td>minimum inhibitory concentration</td></tr><tr><td>ADSS</td><td>Ads synthase</td><td>MPA</td><td>mycophenolic acid</td></tr><tr><td>AICAR<br>(or ZMP)</td><td>5-aminoimidazole-4-carboxamide ribonucleotide</td><td>MPM</td><td>mycophenolate mofetil</td></tr><tr><td>AIR</td><td>5-aminoimidazole ribonucleotide</td><td>MTHFD2</td><td>methylenetetrahydrofolate dehydrogenase 2</td></tr><tr><td>AMP</td><td>adenosine 5'-monophosphate</td><td>MTHFS</td><td>methenyltetrahydrofolate synthetase</td></tr><tr><td>AMPK</td><td>AMP-activated protein kinase</td><td>mTORC1</td><td>mammalian target of rapamycin complex 1</td></tr><tr><td>ATIC</td><td>bifunctional AICAR formyltransferase domain (AICART)/IMP cyclohydrolase domain (IMPC)</td><td>NAD+/NADH</td><td>nicotinamide adenine dinucleotide</td></tr><tr><td>ATP</td><td>adenosine 5'-triphosphate</td><td>NAIR</td><td>4-nitro-5-aminoimidazole ribonucleotide</td></tr><tr><td>CAIR</td><td>5-phosphoribosyl-4-carboxy-5-aminoimidazole</td><td>NCAIR</td><td>N<sup>5</sup>-carboxyamino-imidazole ribonucleotide</td></tr><tr><td>CBS</td><td>cystathionine-β-synthase</td><td>NMR</td><td>nuclear magnetic resonance</td></tr><tr><td>CK2</td><td>casein kinase 2</td><td>Nwd1</td><td>NACHT and WD repeat domain containing protein 1</td></tr><tr><td>DNPNB</td><td>de novo purine nucleotide biosynthesis</td><td>OFP</td><td>orange fluorescent protein</td></tr><tr><td>FAICAR</td><td>5-formamidoimidazole-4-carboxamide ribonucleotide</td><td>PAICS</td><td>bifunctional phosphoribosyl aminoimidazole carboxylase (CAIRS) and phosphoribosyl-aminoimidazole-succinocarboxamide synthase (SAICARS)</td></tr><tr><td>FGAM</td><td>5'-phosphoribosyl-N-formyl glycineamidine</td><td>PDK1</td><td>3-phosphoinositide-dependent kinase-1</td></tr><tr><td>FGAMS</td><td>FGAM synthase</td><td>PI-2P</td><td>phosphatidylinositol (4,5)-bisphosphate</td></tr><tr><td>FGAR</td><td>5'-phosphoribosyl-N-formylglycinamide</td><td>PI-3P</td><td>phosphatidylinositol (3,4,5)-trisphosphate</td></tr><tr><td>FH<sub>4</sub></td><td>5,6,7,8-tetrahydrofolic acid</td><td>PI3K</td><td>phosphatidylinositol 3-kinase</td></tr><tr><td>GAR</td><td>5'-phosphoribosylglycinamide</td><td>PKB (or Akt)</td><td>protein kinase B</td></tr><tr><td>GDP</td><td>guanosine 5'-diphosphate</td><td>PKC</td><td>protein kinase C</td></tr><tr><td>GFP</td><td>green fluorescent protein</td><td>PPAT</td><td>PRPP amidotransferase</td></tr><tr><td>GMP</td><td>guanosine 5'-monophosphate</td><td>ppGp</td><td>guanosine-3'-monophosphate-5'-diphosphate</td></tr><tr><td>GMPR</td><td>guanosine 5'-monophosphate reductase</td><td>ppGpp</td><td>guanosine-3',5'-tetraphosphate</td></tr><tr><td>GMPS</td><td>GMP synthase</td><td>pppGpp</td><td>guanosine-3'-diphosphate-5'-triphosphate</td></tr><tr><td>GPCRs</td><td>G protein-coupled receptors</td><td>PPI</td><td>protein-protein interaction</td></tr><tr><td>GTP</td><td>guanosine 5'-triphosphate</td><td>PRA</td><td>5-phosphoribosyl-1-amine</td></tr><tr><td>hIMPDH1</td><td>type 1 human IMPDH</td><td>PRPP</td><td>5-phosphoribosyl-1-pyrophosphate</td></tr><tr><td>hIMPDH2</td><td>type 2 human IMPDH</td><td>PTMs</td><td>post-translational modifications</td></tr><tr><td>Hsp</td><td>heat-shock protein</td><td>R<sub>5</sub>P</td><td>ribose 5-phosphate</td></tr><tr><td>HTS</td><td>high-throughput screening</td><td>S6K</td><td>p70 ribosomal S6 kinase</td></tr><tr><td>IMP</td><td>inosine 5'-monophosphate</td><td>SAICAR</td><td>5-Amino-4-imidazole-N-succinocarboxamide ribonucleotide</td></tr><tr><td>IMPDH</td><td>IMP dehydrogenase</td><td>SAXS</td><td>small-angle X-ray scattering</td></tr><tr><td>IMPDHag</td><td>Ashbya gossypii IMPDH</td><td>TEADs</td><td>TEA domain transcription factors</td></tr><tr><td>IMPDHbs</td><td>Bacillus subtilis IMPDH</td><td>TIM</td><td>triose-phosphate isomerase</td></tr><tr><td>IMPDHcj</td><td>Campylobacter jejuni IMPDH</td><td>TrifGART</td><td>Trifunctional GAR synthetase (GARS), GAR formyltransferase (GART), AIR synthetase (AIRS) domains</td></tr><tr><td>IMPDHec</td><td>Escherichia coli IMPDH</td><td>UTR</td><td>untranslated region</td></tr><tr><td>IMPDHpa</td><td>Pseudomonas aeruginosa IMPDH</td><td>VGLL3</td><td>vestigial-like family member 3</td></tr><tr><td></td><td></td><td>XMP</td><td>xanthosine 5'-monophosphate</td></tr></table>
Glossary

<table><tr><td>ADP</td><td>adenosine 5'-diphosphate</td><td>IMPDHsc</td><td>Streptomyces coelicolor IMPDH</td></tr><tr><td>AdS</td><td>adenylosuccinate</td><td>IMPDHtb</td><td>Trypanosoma brucei IMPDH</td></tr><tr><td>ADSL</td><td>Ads lyase</td><td>MIC</td><td>minimum inhibitory concentration</td></tr><tr><td>ADSS</td><td>Ads synthase</td><td>MPA</td><td>mycophenolic acid</td></tr><tr><td>AICAR (or ZMP)</td><td>5-aminoimidazole-4-carboxamide ribonucleotide</td><td>MPM</td><td>mycophenolate mofetil</td></tr><tr><td>AIR</td><td>5-aminoimidazole ribonucleotide</td><td>MTHFD2</td><td>methylenetetrahydrofolate dehydrogenase 2</td></tr><tr><td>AMP</td><td>adenosine 5'-monophosphate</td><td>MTHFS</td><td>methenyltetrahydrofolate synthetase</td></tr><tr><td>AMPK</td><td>AMP-activated protein kinase</td><td>mTORC1</td><td>mammalian target of rapamycin complex 1</td></tr><tr><td>ATIC</td><td>bifunctional AICAR formyltransferase domain (AICART)/IMP cyclohydrolase domain (IMPC)</td><td>NAD+/NADH</td><td>nicotinamide adenine dinucleotide</td></tr><tr><td>ATP</td><td>adenosine 5'-triphosphate</td><td>NAIR</td><td>4-nitro-5-aminoimidazole ribonucleotide</td></tr><tr><td>CAIR</td><td>5-phosphoribosyl-4-carboxy-5-aminoimidazole</td><td>NCAIR</td><td>N<sup>5</sup>-carboxyamino-imidazole ribonucleotide</td></tr><tr><td>CBS</td><td>cystathionine-β-synthase</td><td>NMR</td><td>nuclear magnetic resonance</td></tr><tr><td>CK2</td><td>casein kinase 2</td><td>Nwdl</td><td>NACHT and WD repeat domain containing protein 1</td></tr><tr><td>DNPNB</td><td>de novo purine nucleotide biosynthesis</td><td>OFP</td><td>orange fluorescent protein</td></tr><tr><td>FAICAR</td><td>5-formamidoimidazole-4-carboxamide ribonucleotide</td><td>PAICS</td><td>bifunctional phosphoribosyl aminoimidazole carboxylase (CAIRS) and phosphoribosyl-aminoimidazole-succinocarboxamide synthase (SAICARS)</td></tr><tr><td>FGAM</td><td>5'-phosphoribosyl-N-formyl glycineamidine</td><td>PDK1</td><td>3-phosphoinositide-dependent kinase-1</td></tr><tr><td>FGAMS</td><td>FGAM synthase</td><td>PI-2P</td><td>phosphatidylinositol (4,5)-bisphosphate</td></tr><tr><td>FGAR</td><td>5'-phosphoribosyl-N-formylglycinamide</td><td>PI-3P</td><td>phosphatidylinositol (3,4,5)-trisphosphate</td></tr><tr><td>FH<sub>4</sub></td><td>5,6,7,8-tetrahydrofolic acid</td><td>PI3K</td><td>phosphatidylinositol 3-kinase</td></tr><tr><td>GAR</td><td>5'-phosphoribosylglycinamide</td><td>PKB (or Akt)</td><td>protein kinase B</td></tr><tr><td>GDP</td><td>guanosine 5'-diphosphate</td><td>PKC</td><td>protein kinase C</td></tr><tr><td>GFP</td><td>green fluorescent protein</td><td>PPAT</td><td>PRPP amidotransferase</td></tr><tr><td>GMP</td><td>guanosine 5'-monophosphate</td><td>ppGp</td><td>guanosine-3'-monophosphate-5'-diphosphate</td></tr><tr><td>GMPR</td><td>guanosine 5'-monophosphate reductase</td><td>ppGpp</td><td>guanosine-3',5'-tetraphosphate</td></tr><tr><td>GMPS</td><td>GMP synthase</td><td>pppGpp</td><td>guanosine-3'-diphosphate-5'-triphosphate</td></tr><tr><td>GPCRs</td><td>G protein-coupled receptors</td><td>PPI</td><td>protein-protein interaction</td></tr><tr><td>GTP</td><td>guanosine 5'-triphosphate</td><td>PRA</td><td>5-phosphoribosyl-1-amine</td></tr><tr><td>hIMPDH1</td><td>type 1 human IMPDH</td><td>PRPP</td><td>5-phosphoribosyl-1-pyrophosphate</td></tr><tr><td>hIMPDH2</td><td>type 2 human IMPDH</td><td>PTMs</td><td>post-translational modifications</td></tr><tr><td>Hsp</td><td>heat-shock protein</td><td>R<sub>5</sub>P</td><td>ribose 5-phosphate</td></tr><tr><td>HTS</td><td>high-throughput screening</td><td>S6K</td><td>p70 ribosomal S6 kinase</td></tr><tr><td>IMP</td><td>inosine 5'-monophosphate</td><td>SAICAR</td><td>5-Amino-4-imidazole-N-succinocarboxamide ribonucleotide</td></tr><tr><td>IMPDH</td><td>IMP dehydrogenase</td><td>SAXS</td><td>small-angle X-ray scattering</td></tr><tr><td>IMPDHag</td><td>Ashbya gossypii IMPDH</td><td>TEADs</td><td>TEA domain transcription factors</td></tr><tr><td>IMPDHbs</td><td>Bacillus subtilis IMPDH</td><td>TIM</td><td>triose-phosphate isomerase</td></tr><tr><td>IMPDHcj</td><td>Campylobacter jejuni IMPDH</td><td>TrifGART</td><td>Trifunctional GAR synthetase (GARS), GAR formyltransferase (GART), AIR synthetase (AIRS) domains</td></tr><tr><td>IMPDHec</td><td>Escherichia coli IMPDH</td><td>UTR</td><td>untranslated region</td></tr><tr><td>IMPDHpa</td><td>Pseudomonas aeruginosa IMPDH</td><td>VGLL3</td><td>vestigial-like family member 3</td></tr><tr><td></td><td></td><td>XMP</td><td>xanthosine 5'-monophosphate</td></tr></table>