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Arginine Metabolism
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Arginine Metabolism

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Endocrinology and Metabolism".

Deadline for manuscript submissions: closed (30 January 2020) | Viewed by 30081

Special Issue Editors

Prof. Dr. Christian Jung

E-Mail Website
Guest Editor
Medical Faculty, Division of Cardiology, Pulmonology and Vascular Medicine, University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, 40225 Düsseldorf, Germany
Interests: acute coronary syndrome; interventional procedures and pharmacological therapy; reperfusion injury; arginine metabolism; endothelial biology; metabolism and regeneration; microcirculation; cardiogenic shock and heart failure
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. John Pernow

E-Mail Website
Guest Editor
Division of Cardiology, Department of Medicine, Karolinska University Hospital, Stockholm, Sweden
Interests: acute coronary syndrome; reperfusion injury; arginine metabolism; endothelial biology; coronary artery disease; red blood cells; diabetes mellitus and its complications

Special Issue Information

Dear Colleagues,

This Special Issue, “Arginine Metabolism”, will cover a selection of recent research topics and current review articles related to the role of arginine in health and disease. Up-to-date review articles, commentaries, and experimental papers are all welcome.

Arginine plays a central role as amino acid in various conditions, especially as substrate for different enzymes involved in cellular processes. This is especially true for the generation of nitric oxide (NO) in vascular health and disease. In addition, arginine serves as substrate of arginase, which is also important in regulating vascular function. It has been shown to be of relevance in endothelial cells and also in other cell types such as red blood cells. Over the past decades, numerous articles have shown that this is of interest in cardiovascular disease, diabetes mellitus and its complications, cancer, and inflammatory diseases. In addition, arginine is central in cell development and cell hemostasis. Translational aspects are also welcome, for example, studies dealing with vascular function in the context of arterial hypertension, microvascular dysfunction, or modern, innovative possible treatment strategies.

Prof. Dr. Christian Jung
Prof. Dr. John Pernow
Guest Editors

Manuscript Submission Information

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Keywords

  • arginine
  • nitric oxide
  • endothelium
  • cardiovascular disease
  • inflammation

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Published Papers (5 papers)

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Research

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14 pages, 1708 KiB  
Article
Homoarginine- and Creatine-Dependent Gene Regulation in Murine Brains with l-Arginine:Glycine Amidinotransferase Deficiency
by Märit Jensen, Christian Müller, Edzard Schwedhelm, Priyadharshini Arunachalam, Mathias Gelderblom, Tim Magnus, Christian Gerloff, Tanja Zeller and Chi-un Choe
Int. J. Mol. Sci. 2020, 21(5), 1865; https://doi.org/10.3390/ijms21051865 - 9 Mar 2020
Cited by 10 | Viewed by 4565
Abstract
l-arginine:glycine amidinotransferase (AGAT) and its metabolites homoarginine (hArg) and creatine have been linked to stroke pathology in both human and mouse studies. However, a comprehensive understanding of the underlying molecular mechanism is lacking. To investigate transcriptional changes in cerebral AGAT metabolism, we [...] Read more.
l-arginine:glycine amidinotransferase (AGAT) and its metabolites homoarginine (hArg) and creatine have been linked to stroke pathology in both human and mouse studies. However, a comprehensive understanding of the underlying molecular mechanism is lacking. To investigate transcriptional changes in cerebral AGAT metabolism, we applied a transcriptome analysis in brains of wild-type (WT) mice compared to untreated AGAT-deficient (AGAT−/−) mice and AGAT−/− mice with creatine or hArg supplementation. We identified significantly regulated genes between AGAT−/− and WT mice in two independent cohorts of mice which can be linked to amino acid metabolism (Ivd, Lcmt2), creatine metabolism (Slc6a8), cerebral myelination (Bcas1) and neuronal excitability (Kcnip3). While Ivd and Kcnip3 showed regulation by hArg supplementation, Bcas1 and Slc6a8 were creatine dependent. Additional regulated genes such as Pla2g4e and Exd1 need further evaluation of their influence on cerebral function. Experimental stroke models showed a significant regulation of Bcas1 and Slc6a8. Together, these results reveal that AGAT deficiency, hArg and creatine regulate gene expression in the brain, which may be critical in stroke pathology. Full article
(This article belongs to the Special Issue Arginine Metabolism)
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20 pages, 4288 KiB  
Article
Metabolomic Profile of BALB/c Macrophages Infected with Leishmania amazonensis: Deciphering L-Arginine Metabolism
by Sandra Marcia Muxel, Maricruz Mamani-Huanca, Juliana Ide Aoki, Ricardo Andrade Zampieri, Lucile Maria Floeter-Winter, Ángeles López-Gonzálvez and Coral Barbas
Int. J. Mol. Sci. 2019, 20(24), 6248; https://doi.org/10.3390/ijms20246248 - 11 Dec 2019
Cited by 25 | Viewed by 5149
Abstract
Background: Leishmaniases are neglected tropical diseases that are caused by Leishmania, being endemic worldwide. L-arginine is an essential amino acid that is required for polyamines production on mammal cells. During Leishmania infection of macrophages, L-arginine is used by host and parasite arginase [...] Read more.
Background: Leishmaniases are neglected tropical diseases that are caused by Leishmania, being endemic worldwide. L-arginine is an essential amino acid that is required for polyamines production on mammal cells. During Leishmania infection of macrophages, L-arginine is used by host and parasite arginase to produce polyamines, leading to parasite survival; or, by nitric oxide synthase 2 to produce nitric oxide leading to parasite killing. Here, we determined the metabolomic profile of BALB/c macrophages that were infected with L. amazonensis wild type or with L. amazonensis arginase knockout, correlating the regulation of L-arginine metabolism from both host and parasite. Methods: The metabolites of infected macrophages were analyzed by capillary electrophoresis coupled with mass spectrometry (CE-MS). The metabolic fingerprints analysis provided the dual profile from the host and parasite. Results: We observed increased levels of proline, glutamic acid, glutamine, L-arginine, ornithine, and putrescine in infected-L. amazonensis wild type macrophages, which indicated that this infection induces the polyamine production. Despite this, we observed reduced levels of ornithine, proline, and trypanothione in infected-L. amazonensis arginase knockout macrophages, indicating that this infection reduces the polyamine production. Conclusions: The metabolome fingerprint indicated that Leishmania infection alters the L-arginine/polyamines/trypanothione metabolism inside the host cell and the parasite arginase impacts on L-arginine metabolism and polyamine production, defining the infection fate. Full article
(This article belongs to the Special Issue Arginine Metabolism)
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Review

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24 pages, 815 KiB  
Review
Arginine Derivatives in Cerebrovascular Diseases: Mechanisms and Clinical Implications
by Gerrit M. Grosse, Edzard Schwedhelm, Hans Worthmann and Chi-un Choe
Int. J. Mol. Sci. 2020, 21(5), 1798; https://doi.org/10.3390/ijms21051798 - 5 Mar 2020
Cited by 38 | Viewed by 7310
Abstract
The amino acid L-arginine serves as substrate for the nitric oxide synthase which is crucial in vascular function and disease. Derivatives of arginine, such as asymmetric (ADMA) and symmetric dimethylarginine (SDMA), are regarded as markers of endothelial dysfunction and have been implicated in [...] Read more.
The amino acid L-arginine serves as substrate for the nitric oxide synthase which is crucial in vascular function and disease. Derivatives of arginine, such as asymmetric (ADMA) and symmetric dimethylarginine (SDMA), are regarded as markers of endothelial dysfunction and have been implicated in vascular disorders. While there is a variety of studies consolidating ADMA as biomarker of cerebrovascular risk, morbidity and mortality, SDMA is currently emerging as an interesting metabolite with distinct characteristics in ischemic stroke. In contrast to dimethylarginines, homoarginine is inversely associated with adverse events and mortality in cerebrovascular diseases and might constitute a modifiable protective risk factor. This review aims to provide an overview of the current evidence for the pathophysiological role of arginine derivatives in cerebrovascular ischemic diseases. We discuss the complex mechanisms of arginine metabolism in health and disease and its potential clinical implications in diverse aspects of ischemic stroke. Full article
(This article belongs to the Special Issue Arginine Metabolism)
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16 pages, 1561 KiB  
Review
The Second Life of Methylarginines as Cardiovascular Targets
by Natalia Jarzebska, Arduino A. Mangoni, Jens Martens-Lobenhoffer, Stefanie M. Bode-Böger and Roman N. Rodionov
Int. J. Mol. Sci. 2019, 20(18), 4592; https://doi.org/10.3390/ijms20184592 - 17 Sep 2019
Cited by 48 | Viewed by 4791
Abstract
Endogenous methylarginines were proposed as cardiovascular risk factors more than two decades ago, however, so far, this knowledge has not led to the development of novel therapeutic approaches. The initial studies were primarily focused on the endogenous inhibitors of nitric oxide synthases asymmetric [...] Read more.
Endogenous methylarginines were proposed as cardiovascular risk factors more than two decades ago, however, so far, this knowledge has not led to the development of novel therapeutic approaches. The initial studies were primarily focused on the endogenous inhibitors of nitric oxide synthases asymmetric dimethylarginine (ADMA) and monomethylarginine (MMA) and the main enzyme regulating their clearance dimethylarginine dimethylaminohydrolase 1 (DDAH1). To date, all the screens for DDAH1 activators performed with the purified recombinant DDAH1 enzyme have not yielded any promising hits, which is probably the main reason why interest towards this research field has started to fade. The relative contribution of the second DDAH isoenzyme DDAH2 towards ADMA and MMA clearance is still a matter of controversy. ADMA, MMA and symmetric dimethylarginine (SDMA) are also metabolized by alanine: glyoxylate aminotransferase 2 (AGXT2), however, in addition to methylarginines, this enzyme also has several cardiovascular protective substrates, so the net effect of possible therapeutic targeting of AGXT2 is currently unclear. Recent studies on regulation and functions of the enzymes metabolizing methylarginines have given a second life to this research direction. Our review discusses the latest discoveries and controversies in the field and proposes novel directions for targeting methylarginines in clinical settings. Full article
(This article belongs to the Special Issue Arginine Metabolism)
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18 pages, 1337 KiB  
Review
The Biological Axis of Protein Arginine Methylation and Asymmetric Dimethylarginine
by Melody D. Fulton, Tyler Brown and Y. George Zheng
Int. J. Mol. Sci. 2019, 20(13), 3322; https://doi.org/10.3390/ijms20133322 - 6 Jul 2019
Cited by 60 | Viewed by 7565
Abstract
Protein post-translational modifications (PTMs) in eukaryotic cells play important roles in the regulation of functionalities of the proteome and in the tempo-spatial control of cellular processes. Most PTMs enact their regulatory functions by affecting the biochemical properties of substrate proteins such as altering [...] Read more.
Protein post-translational modifications (PTMs) in eukaryotic cells play important roles in the regulation of functionalities of the proteome and in the tempo-spatial control of cellular processes. Most PTMs enact their regulatory functions by affecting the biochemical properties of substrate proteins such as altering structural conformation, protein–protein interaction, and protein–nucleic acid interaction. Amid various PTMs, arginine methylation is widespread in all eukaryotic organisms, from yeasts to humans. Arginine methylation in many situations can drastically or subtly affect the interactions of substrate proteins with their partnering proteins or nucleic acids, thus impacting major cellular programs. Recently, arginine methylation has become an important regulator of the formation of membrane-less organelles inside cells, a phenomenon of liquid–liquid phase separation (LLPS), through altering π-cation interactions. Another unique feature of arginine methylation lies in its impact on cellular physiology through its downstream amino acid product, asymmetric dimethylarginine (ADMA). Accumulation of ADMA in cells and in the circulating bloodstream is connected with endothelial dysfunction and a variety of syndromes of cardiovascular diseases. Herein, we review the current knowledge and understanding of protein arginine methylation in regards to its canonical function in direct protein regulation, as well as the biological axis of protein arginine methylation and ADMA biology. Full article
(This article belongs to the Special Issue Arginine Metabolism)
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