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Suppression of the nucleic acid precursor ribose 5-phosphate by RNA-mediated antiviral immunity.

ABSTRACT: We identify that the antiviral protein kinase PKR alters glycolysis. This response is found to be independent of the kinase’s established control of gene expression that is executed through phosphorylation of the Eukaryotic Translation Initiation Factor 2. Instead, a novel substrate is recognised within the pentose phosphate pathway. The kinase is shown to regulate the activity of an isomerase that produces ribose 5-phosphate, which is an essential precursor for a number of macromolecules, including Coenzyme A, FAD, ATP, and nucleotides.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Ralf Schittenhelm

LAB HEAD: Anthony Sadler

PROVIDER: PXD036779 | Pride | 2024-08-09

REPOSITORIES: Pride

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			Action	DRS
	F1RS20201231_KD_2.raw	Raw
	F1RS20201231_WT_2.raw	Raw
	Results.7z	Other

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Publications

The immune response to RNA suppresses nucleic acid synthesis by limiting ribose 5-phosphate.

Bhattacharjee Pushpak P Wang Die D Anderson Dovile D Buckler Joshua N JN de Geus Eveline E Yan Feng F Polekhina Galina G Schittenhelm Ralf R Creek Darren J DJ Harris Lawrence D LD Sadler Anthony J AJ

The EMBO journal 20240522 13

During infection viruses hijack host cell metabolism to promote their replication. Here, analysis of metabolite alterations in macrophages exposed to poly I:C recognises that the antiviral effector Protein Kinase RNA-activated (PKR) suppresses glucose breakdown within the pentose phosphate pathway (PPP). This pathway runs parallel to central glycolysis and is critical to producing NADPH and pentose precursors for nucleotides. Changes in metabolite levels between wild-type and PKR-ablated macroph ...[more]

PMID: 38778156

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Inhibition of Poly(ADP-Ribose) Polymerase by Nucleic Acid Metabolite 7-Methylguanine.

Project description:The ability of 7-methylguanine, a nucleic acid metabolite, to inhibit poly(ADP-ribose)polymerase-1 (PARP-1) and poly(ADP-ribose)polymerase-2 (PARP-2) has been identified in silico and studied experimentally. The amino group at position 2 and the methyl group at position 7 were shown to be important substituents for the efficient binding of purine derivatives to PARPs. The activity of both tested enzymes, PARP-1 and PARP-2, was suppressed by 7-methylguanine with IC50 values of 150 and 50 μM, respectively. At the PARP inhibitory concentration, 7-methylguanine itself was not cytotoxic, but it was able to accelerate apoptotic death of BRCA1-deficient breast cancer cells induced by cisplatin and doxorubicin, the widely used DNA-damaging chemotherapeutic agents. 7-Methylguanine possesses attractive predictable pharmacokinetics and an adverse-effect profile and may be considered as a new additive to chemotherapeutic treatment.

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Beyond ribose and phosphate: Selected nucleic acid modifications for structure-function investigations and therapeutic applications.

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Global gene expression of Ruegeria pomeroyi DSS-3 during ammonium-limited, ribose phosphate-, methylphosphonate-, or potassium phosphate-excess growth regimes or during potassium phosphate-limited, ammonium-excess regime

Project description:We used the previously designed oligonucleotide microarrays (BM-CM-<rgmann et al., 2007, Environmental Microbiology, 9: 2742-2755) to detect the mRNA transcripts of R. pomeroyi DSS-3 when the cells were cultured under steady-state conditions limited with ammonium (NH4Cl, 0.26 mM) but with an excess of D-ribose-5-phosphate (C5H9Na2O8P*2H2O, 0.5 mM), methylphosphonic acid (CH5PO3, 0.5 mM), or potassium phosphate (KH2PO4, 0.5 mM), or during ammonium excess (NH4Cl, 2.8 mM) but were limited with potassium phosphate (KH2PO4, 9.2 M-NM-<M). A total of 13 microarray hybridizations were performed: three biological replicates each from ribose phosphate, methylphosphonate, or potassium phosphate excess growth regimes, three biological replicates from potassium phosphate limited growth regime, and one technical replicate for the potassium phosphate excess growth regime. Data for the technical replicates were averaged and combined, resulted in a total of 12 samples.

2014-06-02 | E-GEOD-38740 | biostudies-arrayexpress

affy_med_2011_14-Transcriptomic analysis of roots of WT (A17) Medicago truncatula plants and of a hypermycorrhizal mutant (B9) grown on limiting (P/10) or non-limiting phosphate (P2).

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Expression data from mouse embryo

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The immune response to RNA suppresses nucleic acid synthesis by limiting ribose 5-phosphate

Project description:During infection viruses hijack host cell metabolism to promote their replication. Here, analysis of metabolite alterations in macrophages exposed to poly I:C recognises that the antiviral effector Protein Kinase RNA-activated (PKR) suppresses glucose breakdown within the pentose phosphate pathway (PPP). This pathway runs parallel to central glycolysis and is critical to producing NADPH and pentose precursors for nucleotides. Changes in metabolite levels between wild-type and PKR-ablated macrophages show that PKR controls the generation of ribose 5-phosphate, in a manner distinct from its established function in gene expression but dependent on its kinase activity. PKR phosphorylates and inhibits ribose 5-phosphate isomerase (RPIA), preventing interconversion of ribulose- to ribose 5-phosphates. This activity preserves redox control but decreases production of ribose 5-phosphate for nucleotide biosynthesis. Accordingly, the PKR-mediated immune response to RNA suppresses the nucleic acid production. In line, pharmacological targeting of the PPP during infection decreases the replication of the Herpes simplex virus. These results identify an immune response-mediated control of host cell metabolism and suggest targeting the RPIA as a potential innovative antiviral treatment.

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