A mammalian arginine/lysine transporter uses multiple promoters.

Finley, Kim D.; Kakuda, Donald K.; Barrieux, A; Kleeman, Jeanine; Huynh, Paul; MacLeod, Carol L.

doi:10.1073/pnas.92.20.9378

Cited by 45 publications

(32 citation statements)

References 35 publications

(32 reference statements)

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“…The increased MCAT2B protein levels detected in AS1-infected macrophages suggests that MCAT2B has other roles in L-arginine metabolism in the macrophage. This notion is supported by the presence of the five distinct promoter regions in the 5Ј-untranslated region of the MCAT2B gene; the most distal promoter being responsible for L-arginine transport by LPS-IFN-␥-activated macrophages (8). The other four promoter regions of MCAT2B remain uncharacterized with respect to their activity.…”

mentioning

confidence: 62%

Modulation of J774.1 Macrophage l- Arginine Metabolism by Intracellular Mycobacterium bovis BCG

Peteroy-Kelly¹,

Venketaraman²,

Talaue³

et al. 2003

Infect Immun

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Using a Mycobacterium bovis BCG mutant (AS1) lacking a Bacillus subtilis L-arginine transporter homolog, we demonstrate here that the interaction between intracellular mycobacteria and the macrophage with respect to L-arginine transport and metabolism is quite complex. Intracellular AS1 stimulates macrophage L-arginine transport and accumulates 2.5-fold more 3 H label derived from L-arginine than does the wild type. These studies suggest that the accumulation of 3 H label reflects the acquisition of metabolites of L-arginine produced by the macrophage.L-Arginine can be used as a source of carbon, nitrogen, or both by a variety of microorganisms. The existence of several different L-arginine uptake systems and catabolic pathways in these microorganisms illustrates the importance of this amino acid. In Escherichia coli and Salmonella spp., the major Larginine permease consists of three separate periplasmic binding proteins with different specificities for L-arginine, L-lysine, and L-ornithine (3,4,12,21). Pseudomonads also have multiple systems for L-arginine transport. The first system consists of the genes in the aot operon, encoding transport proteins with specificities for L-arginine and L-ornithine (19). The second system in pseudomonads, encoded by the arcD gene, is an L-arginine/L-ornithine antiporter (26). Finally, Bacillus subtilis has two L-arginine transporters, encoded by the rocC and rocE genes (9, 18). There are at least four L-arginine catabolic pathways identified in microorganisms. The first pathway, the arginine deiminase pathway, converts L-arginine to L-ornithine, ATP, bicarbonate, and ammonia. The arginine decarboxylase pathway converts L-arginine into GABA. L-Arginine is converted to glutamate and succinate by the arginine succinyl transferase pathway. Finally, the arginase pathway is responsible for the conversion of L-arginine to glutamate.Until recently, there have been few studies of L-arginine metabolism in mycobacteria. Previous studies from our laboratory have demonstrated that Mycobacterium bovis BCG is unable to utilize L-arginine as a sole carbon and/or nitrogen source in vitro (22). Despite these findings, scrutiny of the published M. tuberculosis genome reveals the presence of homologs of enzymes in the arginine deiminase (Rv1001), arginine decarboxylase (Rv2531c), and arginase (Rv2321c, Rv2322c, and Rv1187) pathways (7). Using the Sanger database (7), we also identified two open reading frames with homology to the B. subtilis RocE L-arginine transporter (annotated as Rv0522 and Rv2320c). The presence of multiple L-arginine transporters and catabolic pathways in mycobacteria suggests that L-arginine does indeed play an important role in mycobacterial metabolism.Little is known about the metabolic requirements of mycobacteria residing within the macrophage. Several studies have demonstrated that intracellular mycobacteria are able to acquire and metabolize nutrients from within the mycobacterial phagosome (1, 10, 16). The aim of these studies was to characterize intracellular L-arg...

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confidence: 62%

Modulation of J774.1 Macrophage l- Arginine Metabolism by Intracellular Mycobacterium bovis BCG

Peteroy-Kelly¹,

Venketaraman²,

Talaue³

et al. 2003

Infect Immun

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“…The 5Ј untranslated region of MCAT2B contains five distinct promoter regions. The most distal promoter (approximately 18 kb upstream from the first coding exon) is the promoter responsive to macrophage activation by LPS-IFN-␥ stimulation (12). Using Xenopus oocytes, Kakuda et al (17) were able to demonstrate that MCAT2B was solely responsible for the increased uptake of L-arginine detected upon LPS-IFN-␥ stimulation of the macrophage.…”

mentioning

confidence: 88%

Effects ofMycobacterium bovisBCG Infection on Regulation ofl-Arginine Uptake and Synthesis of Reactive Nitrogen Intermediates in J774.1 Murine Macrophages

2001

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“…2B). Because exon 1A is noncoding (25), any initiating methionine in the Cat2 Ϫ/Ϫ transcripts must lie within or downstream of exon 3. Inspection of the exon 3 DNA sequence disclosed that the first long open reading frame is located ϩ466 into the Cat2 coding sequence, constituting a loss of 24% of the CAT2 protein if the transcript were translated.…”

Section: Production and Characterization Of The Cat2 Knockoutmentioning

confidence: 99%

Sustained Nitric Oxide Production in Macrophages Requires the Arginine Transporter CAT2

Nicholson¹,

Manner²,

Kleeman

et al. 2001

Journal of Biological Chemistry

200

187

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The aberrant production of nitric oxide (NO) contributes to the pathogenesis of diseases as diverse as cancer and arthritis. Sustained NO production via the inducible enzyme, nitric-oxide synthase 2 (NOS2), requires extracellular arginine uptake. Three closely related cationic amino acid transporter genes (Cat1-3) encode the transporters that mediate most arginine uptake in mammalian cells. Because CAT2 is induced coordinately with NOS2 in numerous cell types, we investigated a possible role for CAT2-mediated arginine transport in regulating NO production. The complexity of arginine transport systems and their biochemically similar transport properties called for a genetic approach to determine the role of CAT2. CAT2-deficient mice were generated and found to be healthy and fertile in contrast to Cat1 animals. Analysis of cytokine-activated macrophages from Cat2؊/؊ mice revealed a 92% reduction in NO production and a 95% reduction in L-Arg uptake. The reduction in NO production was not due to differences in NOS2 protein expression, NOS2 activity, or intracellular L-arginine content. In conclusion, our results show that sustained abundant NO synthesis by macrophages requires arginine transport via the CAT2 transporter.The production and release of nitric oxide (NO) 1 are involved in numerous cellular processes. Overproduction of NO by inflammatory cells is implicated in the pathogenesis of diseases as diverse as cancer, endotoxic shock, atherosclerosis, and arthritis (1-7). NO is synthesized from arginine by three related enzymes. Two of these enzymes, the Ca 2ϩ -dependent neuronal nitric-oxide synthase and endothelial NOS, generate small amounts of NO over short periods of time (7). The Ca 2ϩ -independent inducible NOS (NOS2) produces large amounts of NO over sustained periods of time (1, 2). Activated macrophages produce copious quantities of NO via NOS2 over extended periods of time that contribute to tissue injury (2). Extracellular L-arginine is not required for endothelial NO synthasemediated NO production in human endothelial cells (8). In contrast, extracellular arginine is required for sustained NO production via NOS2 in macrophages (8,9). In addition, increased arginine transport is known to accompany NO production via NOS2 (1, 2, 9, 10).Among the several transport systems that mediate L-arginine uptake (y ϩ , B 0ϩ

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A mammalian arginine/lysine transporter uses multiple promoters.

Cited by 45 publications

References 35 publications

Modulation of J774.1 Macrophage l- Arginine Metabolism by Intracellular Mycobacterium bovis BCG

Modulation of J774.1 Macrophage l- Arginine Metabolism by Intracellular Mycobacterium bovis BCG

Effects ofMycobacterium bovisBCG Infection on Regulation ofl-Arginine Uptake and Synthesis of Reactive Nitrogen Intermediates in J774.1 Murine Macrophages

Sustained Nitric Oxide Production in Macrophages Requires the Arginine Transporter CAT2

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