The inhibition of sheep liver arginase by some l-amino-acids

Rao, K. Venkata; Reddy, S. Raghupathi Rami; Swami, K. S.

doi:10.1016/0020-711x(73)90021-9

Cited by 18 publications

(3 citation statements)

References 30 publications

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“…However, the mechanistic investigations underlying their anti-infection properties are minimal. Earlier works showed the inhibitory effect of L-proline, L-isoleucine, L-leucine, and L-valine on arginase activities, and this inhibition is relatively specific as other amino acids, such as glycine, L-glutamine, do not influence arginase activities (37–39). Arginase inhibition by L-valine increases NO production in endothelial cells and macrophages in response to LPS treatment (23, 40).…”

Section: Discussionmentioning

confidence: 99%

Metabolites alleviate staphylococcal bloodstream infection in a NO-dependent manner via arginase inhibition

Pang¹,

Su²,

Zhou

et al. 2020

Preprint

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20Staphylococcus aureus is a notorious bacterial pathogen that often causes soft tissue 21 and bloodstream infections and invariably garners resistance mechanisms against new 22 antibiotics. Host innate immunity modulated by metabolites has been proved as a 23 powerful strategy against bacterial infections. However, few studies focus on the 24 application of this strategy against S. aureus infection. Here, we identified four metabolite 25 biomarkers, L-proline, L-isoleucine, L-leucine, and L-valine (PILV), by a metabolomics 26 study. In animal models of S. aureus bloodstream infection, exogenous administration of 27 each metabolite or PILV shows an anti-infective effect, while PILV treatment has higher 28 protection than individual metabolite treatment. Each metabolite targets nitric oxide (NO) 29 to kill S. aureus via arginase inhibition, and PILV exhibits additive inhibition of arginase 30 activity that causes further killing. This suppression also contributes to the 31 metabolite-mediated phagocytic killing of S. aureus in human blood. Our finding 32 demonstrates the metabolite-mediated innate immunity as a therapeutic intervention for 33 S. aureus infection. 34 35 Keywords: metabolite, Staphylococcus aureus, bloodstream infection, nitric oxide, 36 arginase, 37 38The pathogen Staphylococcus aureus is both a human commensal and a significant 39 cause of hospital-and community-acquired diseases including soft tissue infections, 40 pneumonia, osteomyelitis, septic arthritis, bacteremia, endocarditis, and sepsis (1-3). The 41 asymptomatic colonization is common; however, 80% invasive S. aureus strains isolated 42 from the blood of patients with S. aureus bacteremia are genetically indistinguishable to 43 the nasal strains detected at admission (4). Because of the high incidence of 44 hospital-acquired infection, antibiotics are employed both for S. aureus decolonization 45 and prophylaxis of nosocomial disease (5, 6). However, the emergence and spread of 46 drug-resistant strains, designated MRSA (methicillin-resistant S. aureus), led to 47 increased therapeutic failure and mortality rates due to S. aureus infections (6). Therefore, 48 new approaches are especially needed for treating such infections in the clinic. One 49 possible approach would be to enhance the innate immune response of the infected host, 50 restoring the defense ability to kill the bacterial pathogen in a relatively risk-free manner 51 (7). 52 53 Similar to other bacterial infections (8, 9), S. aureus infection causes several metabolisms 54 changed pronouncedly in the host, which contain oxidative phosphorylation, aerobic 55 glycolysis, and amino acid and fatty acid metabolisms (10)(11)(12)(13)(14). A growing body of recent 56 studies shows that bacterial infection-induced shift of metabolisms has two leading roles, 57 which either facilitate the bacterial invasion or benefits to the immune responses against 58 bacterial infection. Host central carbon metabolism is capable of being strongly disturbed 59 by S. aureus, which activates autophagy b...

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Section: Discussionmentioning

confidence: 99%

Metabolites alleviate staphylococcal bloodstream infection in a NO-dependent manner via arginase inhibition

Pang¹,

Su²,

Zhou

et al. 2020

Preprint

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show abstract

“…However, the mechanisms underlying their anti-infection properties are currently minimally understood. Studies showed an inhibitory effect of L-proline, L-isoleucine, L-leucine, and L-valine on arginase activities; this inhibition is relatively specific as other amino acids, such as glycine and L-glutamine, do not influence arginase activities ( 39 – 41 ). Arginase inhibition by L-valine increases NO production in endothelial cells and macrophages during lipopolysaccharide (LPS) treatment ( 18 , 42 ).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Host Arginase Activity Against Staphylococcal Bloodstream Infection by Different Metabolites

et al. 2020

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Staphylococcus aureus is a notorious bacterial pathogen that often causes soft tissue and bloodstream infections and invariably garners resistance mechanisms against new antibiotics. Modulation of the host immune response by metabolites is a powerful tool against bacterial infections, but has not yet been used against S. aureus infections. In this study, we identified four metabolite biomarkers: L-proline, L-isoleucine, L-leucine, and L-valine (PILV), through a metabolomics study using animal models of S. aureus bloodstream infection. The exogenous administration of each metabolite or of PILV showed anti-infective effects, and a higher protection was achieved with PILV in comparison to individual metabolites. During the staphylococcal infection, the expression of most host arginase and nitric oxide synthase (NOS) isozymes was simultaneously induced in mouse liver, kidney, and blood samples. However, the induction of arginase isozymes was dramatically stronger than that of NOS isozymes. This elevated arginase activity was inhibited by the metabolite biomarkers thus killing S. aureus, and PILV exhibited the strongest inhibition of arginase activity and bacterial inhibition. The suppression of arginase activity also contributed to the metabolite-mediated phagocytic killing of S. aureus in mouse and human blood. Our findings demonstrate the metabolite-mediated arginase inhibition as a therapeutic intervention for S. aureus infection.

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“…Table ). Aliphatic α‐amino acids: glycine ( 5 ), alanine ( 6 ), valine ( 7 ), leucine ( 8 ), and isoleucine ( 9 ) are weak inhibitors of arginase. Ornithine ( 2 ) which is generated in the urea Krebs cycle by arginase activity, lysine ( 10 ), L‐cysteine ( 11 ) and even less L‐glutamic acid ( 12 ) are also inhibitors of arginase .…”

Section: Inhibitors Of Arginasementioning

confidence: 99%

Arginase Inhibitors: A Rational Approach Over One Century

Pudlo

Demougeot

Girard

2016

Medicinal Research Reviews

107

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Arginase (EC 3.5.3.1) is the bimanganese enzyme that converts L-arginine into ornithine and urea. This enzyme was discovered more than a century ago and early α-amino acids were identified as weak inhibitors. It was only during the 90s, after nitric oxide (NO) was reported as one of the most important biological mediators and when tight interrelation of arginase and NO synthase was found, that the development of arginase inhibitors was accelerated. The regulation of arginase activity by the N-hydroxy-L-arginine (3, NOHA) intermediate of the NO synthesis was the starting point of the N-hydroxy-nor-arginine (21, nor-NOHA) that proved to be the first micromolar inhibitor. The previously known manganese and arginase binding by borate inspired the 2(S)-amino-6-boronohexanoic acid (39, ABH) and S-(2-boronoethyl)-L-cysteine (40, BEC) now both considered as reference compounds in arginase inhibition. The high-resolution crystal structure of arginase and molecular modeling has rendered possible the recent design of (53) the strongest α,α-disubstituted derivatives of ABH. Simultaneously, traditional medicinal plants have contributed as a source of molecular diversity to the discovery of arginase inhibitors. This rational, step-by-step approach serves as guide in the present review where emphasis is placed on structure activity relationships. Highlights exhaustive review on arginase inhibitors highlight is made on rational approach to conception and structure activity relationships evaluation model is systematically mentioned with results.

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The inhibition of sheep liver arginase by some l-amino-acids

Cited by 18 publications

References 30 publications

Metabolites alleviate staphylococcal bloodstream infection in a NO-dependent manner via arginase inhibition

Metabolites alleviate staphylococcal bloodstream infection in a NO-dependent manner via arginase inhibition

Inhibition of Host Arginase Activity Against Staphylococcal Bloodstream Infection by Different Metabolites

Arginase Inhibitors: A Rational Approach Over One Century

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