Agmatine: At the Crossroads of the Arginine Pathways

Satriano, Joseph

doi:10.1196/annals.1304.004

Cited by 80 publications

(36 citation statements)

References 85 publications

(156 reference statements)

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“…[14][15][16][17][18][19] The role of L-Arg in the immune system has been suggested by the markedly diminished T-cell responses found in patients with trauma, liver transplantation, and some tumors where L-Arg is reduced by the excess production of arginase 1 in myeloid-derived suppressor cells (MDSCs). 2,3 Both in vitro and animal models have shown that the lack of L-Arg not only blocks T-cell proliferation, but also induces molecular changes including a low expression of CD3 chain and a decreased production of cytokines such IFN␥, but not IL-2.…”

Section: Discussionmentioning

confidence: 99%

l-arginine availability regulates T-lymphocyte cell-cycle progression

Rodríguez

Quiceno

Ochoa

2006

Blood

739

627

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IntroductionL-arginine (L-Arg) is a nonessential amino acid that plays a central role in regulating the immune response. 1 In mammalian cells, L-Arg can be catabolized by 4 enzymatic pathways, namely nitric oxide synthase, arginases I and II, arginine:glycine amidinotransferase, and arginine decarboxylase. L-Arg is profoundly reduced in cancer patients, 2 following liver transplantation, 3 or in severe trauma 4 by an increased production of arginase I. This results in a decreased T-cell proliferation and an impaired T-cell function. This effect can be reversed in trauma by the enteral or parenteral supplementation of We demonstrated that activated T cells cultured in medium without L-Arg or cocultured with myeloidderived suppressor cells (MDSCs) isolated from tumors and producing arginase I have a decreased proliferation, a low expression of T-cell receptor CD3 chain, and an impaired production of cytokines. 2,6,7 However, the mechanisms by which L-Arg starvation blocks T-cell proliferation have not been determined.Signaling through the T-cell receptor, as shown by calcium flux and tyrosine phosphorylation, was not affected for the first 12 hours of culture in the absence of L-Arg and therefore could not completely explain the low proliferation of T cells. 8,9 Furthermore, certain T-cell functions such as up-regulation of IL-2 receptor alpha and production of IL-2 were maintained even in the absence of L-Arg. 8,9 Therefore, we explored whether changes in proteins regulating cell cycle could explain the loss of proliferation in T cells cultured without L-Arg. Cyclin-dependent kinase 4 (cdk4) and cyclin-dependent kinase 6 (cdk6) associate with the D-type cyclins, including cyclin D3, to regulate the progression through early G 1 and into the S phase of cell cycle. This regulation requires inactivation of cyclin D/cdk complex inhibitors and phosphorylation of the Rb protein family. Phosphorylation of Rb by cyclin/cdk complexes induces the subsequent release and nuclear translocation of E2F transcription factors, inducing the expression of genes that promote cell-cycle progression into late G 1 and S phases. 10 The effects of amino acid starvation have been well studied in yeast and some tumor cell lines; however, their role in regulating cell cycle in T cells is unknown. The results shown here demonstrate that L-Arg depletion selectively impairs the expression of cyclin D3 and cdk4, blocking the downstream signaling. GCN2, a kinase involved in amino acid starvation, plays a central role in regulating the cell-cycle arrest induced by L-Arg starvation. These results may provide a new understanding of the impairment of the immune response in various diseases where myeloid-derived suppressor cells, producing high levels of arginase, deplete L-Arg. Materials and methods Cells, cultures, and chemicalsHuman peripheral blood mononuclear cells were obtained from healthy donor buffy coats. T cells were purified using human T-cell enrichment columns (R&D systems, Minneapolis, MN), following the vendor's recommendations. T-ce...

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Section: Discussionmentioning

confidence: 99%

l-arginine availability regulates T-lymphocyte cell-cycle progression

Rodríguez

Quiceno

Ochoa

2006

Blood

739

627

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“…Agmatine is an intermediate in the arginine decarboxylase (ADC) pathway for arginine degradation (180). In P. aeruginosa PAO1, the TFR AguR controls expression of the aguAB operon, involved in agmatine utilization, and is induced by agmatine YijC-O157 SG2156 AB_4089 EFER_3797 ECL_05025 ROD_37821 Kvar_4969 KP1_0117 SBG_3617 STY3747 ESA_03803 PANA_3837 Dd703_3786 Rahaq_4293 plu4738 HDEF_0375 VF_2438 VC0152 PM1345 HI0570 D11S_0300 APL_1480 SO_0198 MAB_1589 0017_02262 0016_02765 SAV2759 SSQG_05532 SSEG_08400 SCAB27351 SSDG_03331 SSOG_03491 SGR2032 SCO5483 SSAG_05048 SSBG_03542 MSMEG_1741 MAB_1424c ro01410 SSMG_01660 PSPTO_4908 PSPA7_5613 DesT PFL_0610 nfa12930 PA1539 PSPA7_3792 A1S_2460 0017_01408 0016_00290 Smlt2833 XCC3880 …”

Section: Tfrs and Amino Acid Metabolismmentioning

confidence: 99%

The TetR Family of Regulators

Cuthbertson

Nodwell

2013

Microbiol Mol Biol Rev

467

512

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SUMMARY The most common prokaryotic signal transduction mechanisms are the one-component systems in which a single polypeptide contains both a sensory domain and a DNA-binding domain. Among the >20 classes of one-component systems, the TetR family of regulators (TFRs) are widely associated with antibiotic resistance and the regulation of genes encoding small-molecule exporters. However, TFRs play a much broader role, controlling genes involved in metabolism, antibiotic production, quorum sensing, and many other aspects of prokaryotic physiology. There are several well-established model systems for understanding these important proteins, and structural studies have begun to unveil the mechanisms by which they bind DNA and recognize small-molecule ligands. The sequences for more than 200,000 TFRs are available in the public databases, and genomics studies are identifying their target genes. Three-dimensional structures have been solved for close to 200 TFRs. Comparison of these structures reveals a common overall architecture of nine conserved α helices. The most important open question concerning TFR biology is the nature and diversity of their ligands and how these relate to the biochemical processes under their control.

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“…Therefore, chlamydiae may encounter an unknown acidic environment prior to endocytosis. Alternatively, this arginine metabolic system could have a function different from pH homeostasis, such as reducing polyamine levels in eukaryotic cells, which inhibits cellular replication and proliferation (38), or inhibiting nitric oxide production.…”

Section: Vol 187 2007mentioning

confidence: 99%

Characterization of an Acid-Dependent Arginine Decarboxylase Enzyme from Chlamydophila pneumoniae

Giles

Graham

2007

J Bacteriol

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Genome sequences from members of the Chlamydiales encode diverged homologs of a pyruvoyl-dependent arginine decarboxylase enzyme that nonpathogenic euryarchaea use in polyamine biosynthesis. The Chlamydiales lack subsequent genes required for polyamine biosynthesis and probably obtain polyamines from their host cells. To identify the function of this protein, the CPn1032 homolog from the respiratory pathogen Chlamydophila pneumoniae was heterologously expressed and purified. This protein self-cleaved to form a reactive pyruvoyl group, and the subunits assembled into a thermostable (␣␤) 3 complex. The mature enzyme specifically catalyzed the decarboxylation of L-arginine, with an unusually low pH optimum of 3.4. The CPn1032 gene complemented a mutation in the Escherichia coli adiA gene, which encodes a pyridoxal 5-phosphate-dependent arginine decarboxylase, restoring arginine-dependent acid resistance. Acting together with a putative arginine-agmatine antiporter, the CPn1032 homologs may have evolved convergently to form an arginine-dependent acid resistance system. These genes are the first evidence that obligately intracellular chlamydiae may encounter acidic conditions. Alternatively, this system could reduce the host cell arginine concentration and produce inhibitors of nitric oxide synthase.

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Agmatine: At the Crossroads of the Arginine Pathways

Cited by 80 publications

References 85 publications

l-arginine availability regulates T-lymphocyte cell-cycle progression

l-arginine availability regulates T-lymphocyte cell-cycle progression

The TetR Family of Regulators

Characterization of an Acid-Dependent Arginine Decarboxylase Enzyme from Chlamydophila pneumoniae

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