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The Journal of Nutrition Jun 2007Inborn errors of lysine, arginine, and ornithine metabolism are very rare: only a few patients affected with these disorders have been carefully investigated, and very... (Review)
Review
Inborn errors of lysine, arginine, and ornithine metabolism are very rare: only a few patients affected with these disorders have been carefully investigated, and very few reports on long-term outcome are available. These rare data make it difficult to define safety limits of these amino acids and useful biomarkers from these disorders. Only 4 disorders give rise to an important increase of the plasma amino acid concentration proximal to the metabolic block: lysine in 2-aminoadipic semialdehyde synthase deficiency, arginine in arginase deficiency, ornithine in ornithine amino transferase deficiency, and hyperammonemia hyperornithinemia homocitrullinuria syndrome. There is an obvious discrepancy between the important physiological role of these amino acids in cell metabolism and nutrition and the clinical consequences that are actually observed in these disorders.
Topics: Amino Acid Metabolism, Inborn Errors; Amino Acids; Arginine; Biomarkers; Humans; Lysine; Ornithine
PubMed: 17513445
DOI: 10.1093/jn/137.6.1669S -
Biomolecules Jun 2022is an opportunistic pathogen that can cause acute and severe infections. Increasing resistance to antibiotics has given rise to the urgent need for an alternative...
is an opportunistic pathogen that can cause acute and severe infections. Increasing resistance to antibiotics has given rise to the urgent need for an alternative antimicrobial agent. A promising strategy is the inhibition of iron sequestration in the bacteria. The current work aimed to screen for inhibitors of pyoverdine-mediated iron sequestration in . As a drug target, we choose l-ornithine-N5-monooxygenase (PvdA), an enzyme involved in the biosynthesis of pyoverdine that catalyzes the FAD-dependent hydroxylation of the side chain amine of ornithine. As drug repurposing is a fast and cost-efficient way of discovering new applications for known drugs, the approach may help to solve emerging clinical problems. In this study, we use data about molecules from drug banks for screening. A total of 15 drugs that are similar in structure to l-ornithine, the substrate of PvdA, and 30 drugs that are sub-structures of l-ornithine were virtually docked against PvdA. N-2-succinyl ornithine and cilazapril were found to be the top binders with a binding energy of -12.8 and -9.1 kcal mol, respectively. As the drug-likeness and ADME properties of the drugs were also found to be promising, molecular dynamics studies were performed to further confirm the stability of the complexes. The results of this in silico study indicate that N-2-succinyl ornithine could potentially be explored as a drug for the treatment of infections.
Topics: Drug Repositioning; Humans; Iron; Mixed Function Oxygenases; Ornithine; Pseudomonas Infections; Pseudomonas aeruginosa
PubMed: 35883443
DOI: 10.3390/biom12070887 -
The Journal of Nutrition Aug 2010Dietary arginine is the main dietary precursor for citrulline synthesis, but it is not known if other precursors can compensate when arginine is absent in the diet. To...
Dietary arginine is the main dietary precursor for citrulline synthesis, but it is not known if other precursors can compensate when arginine is absent in the diet. To address this question, the contributions of plasma and dietary precursors were determined by using multitracer protocols in conscious mice infused i.g. either an arginine-sufficient diet [Arg(+)] or an arginine-free diet [Arg(-)]. The plasma entry rate of citrulline and arginine did not differ between the 2 diet groups (156 +/- 6 and 564 +/- 30 micromol kg(-1) h(-1), respectively); however, the entry rate of ornithine was greater in the mice fed the Arg(+) than the Arg(-) diet (332 +/- 33 vs. 180 +/- 16 micromol kg(-1) h(-1)). There was a greater utilization of plasma ornithine for the synthesis of citrulline (49 +/- 4 vs. 36 +/- 3 micromol kg(-1) h(-1), 30 +/- 3% vs. 24 +/- 2% of citrulline entry rate) in the mice fed the Arg(-) diet than the Arg(+) diet. The utilization of plasma arginine did not differ between the 2 diet groups for citrulline synthesis, either through plasma ornithine (approximately 29 +/- 3 micromol kg(-1) h(-1)) or at the site of citrulline synthesis (approximately 12 +/- 3 micromol kg(-1) h(-1)). The contribution of dietary proline to the synthesis of citrulline was mainly at the site of citrulline production (17 +/- 1 micromol kg(-1) h(-1)), rather than through plasma ornithine (5 +/- 0.4 micromol kg(-1) h(-1)). Dietary glutamine was utilized only at the site of citrulline synthesis (4 +/- 0.2 micromol kg(-1) h(-1)). Dietary glutamine and proline made a greater contribution to the synthesis of citrulline in mice fed the Arg(-) diet but remained minor sources for citrulline production. Plasma arginine and ornithine are able to support citrulline synthesis during arginine-free feeding.
Topics: Animals; Arginine; Citrulline; Diet; Glutamine; Male; Mice; Ornithine; Phenylalanine; Proline
PubMed: 20573946
DOI: 10.3945/jn.110.125377 -
Microbiological Reviews Mar 1985
Review
Topics: Arginine; Aspergillus nidulans; Bacteria; Bacteriophages; Biodegradation, Environmental; Carboxy-Lyases; Eflornithine; Escherichia coli; Fungi; Guanine Nucleotides; Mutation; Neurospora crassa; Ornithine; Ornithine Decarboxylase; Physarum; Polyamines; Protein Biosynthesis; Saccharomyces cerevisiae; Spermine
PubMed: 3157043
DOI: 10.1128/mr.49.1.81-99.1985 -
Journal of Atherosclerosis and... Oct 2023The long-term prognostic value of the bioavailability of L-arginine, an important source of nitric oxide for the maintenance of vascular endothelial function, has not...
AIMS
The long-term prognostic value of the bioavailability of L-arginine, an important source of nitric oxide for the maintenance of vascular endothelial function, has not been investigated fully. We therefore investigated the relationship between amino acid profile and long-term prognosis in patients with a history of standby coronary angiography.
METHODS
We measured the serum concentrations of L-arginine, L-citrulline, and L-ornithine by high-speed liquid chromatography. We examined the relationship between the L-arginine/L-ornithine ratio and the incidence of all-cause death, cardiovascular death, and major adverse cardiovascular events (MACEs) in 262 patients (202 men and 60 women, age 65±13 years) who underwent coronary angiography over a period of ≤ 10 years.
RESULTS
During the observation period of 5.5±3.2 years, 31 (12%) patients died, including 20 (8%) of cardiovascular death, while 32 (12%) had MACEs. Cox regression analysis revealed that L-arginine/L-ornithine ratio was associated with an increased risk for all-cause death (unadjusted hazard ratio, 95% confidence interval) (0.940, 0.888-0.995) and cardiovascular death (0.895, 0.821-0.965) (p<0.05 for all). In a model adjusted for age, sex, hypertension, hyperlipidemia, diabetes, current smoking, renal function, and log-transformed brain natriuretic peptide level, cardiovascular death (0.911, 0.839-0.990, p=0.028) retained an association with a low L-arginine/ L-ornithine ratio. When the patients were grouped according to an L-arginine/L-ornithine ratio of 1.16, the lower L-arginine/L-ornithine ratio group had significantly higher incidence of all-cause death, cardiovascular death, and MACEs.
CONCLUSION
A low L-arginine/L-ornithine ratio may be associated with increased 10-year cardiac mortality.
Topics: Male; Humans; Female; Middle Aged; Aged; Arginine; Hypertension; Citrulline; Prognosis; Ornithine
PubMed: 36775332
DOI: 10.5551/jat.63779 -
Biochemistry. Biokhimiia Oct 2001Our introduction of the molecular correlation concept and the key enzyme concept and the use of biologically meaningful tumor models and control systems resulted in the... (Review)
Review
Our introduction of the molecular correlation concept and the key enzyme concept and the use of biologically meaningful tumor models and control systems resulted in the discovery of an ordered pattern of enzymic and metabolic imbalance and the elucidation of the linkage with transformation and progression. We showed that the biochemical and enzymic pattern of alterations was the result of a reprogramming of gene expression that was both quantitative and qualitative and was characteristic to neoplasia, since no similar pattern of imbalance was observed in any of the control normal, regenerating, or differentiating tissues. Important aspects of gene logic were identified. These include demonstration of operation of reciprocal control of activities of opposing key enzymes and antagonistic pathways of synthesis and catabolism in pyrimidine, purine, ornithine, and carbohydrate metabolism and recently in signal transduction. The extent of increase in the activities of key enzymes of pyrimidine and purine biosynthesis related to the absolute activity of the enzymes in resting liver. The qualitative alterations in gene expression included the isozyme shift of key regulatory enzymes. We identified a segment of gene expression that is essential for neoplasia. We pointed out the selective advantages that reprogramming of gene expression confers to cancer cells. Understanding these alterations in the enzymology and biochemistry of cancer cells made it possible to identify potentially sensitive targets for anticancer chemotherapy. In recent clinical studies we targeted the increased IMP dehydrogenase activity in leukemic blast cells by an inhibitor drug, tiazofurin, and achieved 77% responses, including complete remissions.
Topics: Animals; Disease Progression; Gene Expression Regulation, Neoplastic; Glycolysis; Humans; Molecular Biology; Neoplasms; Organ Specificity; Ornithine; Purines; Pyrimidines
PubMed: 11736638
DOI: 10.1023/a:1012493232344 -
Current Drug Targets 2015Human proteins are subjected to more than 200 known post-translational modifications (PTMs) (e.g., phosphorylation, glycosylation, ubiquitination, S-nitrosylation,... (Review)
Review
Human proteins are subjected to more than 200 known post-translational modifications (PTMs) (e.g., phosphorylation, glycosylation, ubiquitination, S-nitrosylation, methylation, Nacetylation, and citrullination) and these PTMs can alter protein structure and function with consequent effects on the multitude of pathways necessary for maintaining the physiological homeostasis. When dysregulated, however, the enzymes that catalyze these PTMs can impact the genesis of countless diseases. In this review, we will focus on protein citrullination, a PTM catalyzed by the Protein Arginine Deiminase (PAD) family of enzymes. Specifically, we will describe the roles of the PADs in both normal human physiology and disease. The development of PAD inhibitors and their efficacy in a variety of autoimmune disorders and cancer will also be discussed.
Topics: Animals; Apoptosis; Arthritis, Rheumatoid; Citrulline; Humans; Hydrolases; Ornithine; Protein Processing, Post-Translational; Protein-Arginine Deiminases; Psoriasis
PubMed: 25642720
DOI: 10.2174/1389450116666150202160954 -
Molecules (Basel, Switzerland) Mar 2020The success of innovative drugs depends on an interdisciplinary and holistic approach to their design and development. The supramolecular architecture of living systems... (Review)
Review
A Supramolecular Approach to Structure-Based Design with A Focus on Synthons Hierarchy in Ornithine-Derived Ligands: Review, Synthesis, Experimental and in Silico Studies.
The success of innovative drugs depends on an interdisciplinary and holistic approach to their design and development. The supramolecular architecture of living systems is controlled by non-covalent interactions to a very large extent. The latter are prone to extensive cooperation and like a virtuoso play a symphony of life Thus, the design of effective ligands should be based on thorough knowledge on the interactions at either a molecular or high topological level. In this work, we emphasize the importance of supramolecular structure and ligand-based design keeping the potential of supramolecular H-bonding synthons in focus. In this respect, the relevance of supramolecular chemistry for advanced therapies is appreciated and undisputable. It has developed tools, such as Hirshfeld surface analysis, using a huge data on supramolecular interactions in over one million structures which are deposited in the Cambridge Structure Database (CSD). In particular, molecular interaction surfaces are useful for identification of macromolecular active sites followed by docking experiments. Ornithine-derived compounds are a new, promising class of multi-targeting ligands for innovative therapeutics and cosmeceuticals. In this work, we present the synthesis together with the molecular and supramolecular structure of a novel ornithine derivative, namely -α,-δ)-dibenzoyl-(α)-hydroxymethylornithine, . It was investigated by modern experimental and methods in detail. The incorporation of an aromatic system into the ornithine core induces stacking interactions, which are vital in biological processes. In particular, rare C=Oπ intercontacts have been identified in . Supramolecular interactions were analyzed in all structures of ornithine derivatives deposited in the CSD. The influence of substituent was assessed by the Hirshfeld surface analysis. It revealed that the crystal packing is stabilized mainly by HO, OH, CH, Cl (Br, F)H and OO interactions. Additionally, ππ, C-Hπ and N-Oπ interactions were also observed. All relevant H-bond energies were calculated using the Lippincott and Schroeder H-bond model. A library of synthons is provided. In addition, the large synthons () were considered. The DFT optimization either or yields very similar molecular species. The major difference with the relevant crystal structure was related to the conformation of terminal benzoyl C15-C20 ring. Furthermore, prediction of the extensive physicochemical ADME profile (absorption, distribution, metabolism and excretion) related to the drug-likeness and medicinal chemistry friendliness revealed that a novel ornithine derivative has the potential to be a new drug candidate. It has shown good absorption and very low toxicity.
Topics: Databases, Factual; Hydrogen Bonding; Molecular Conformation; Molecular Structure; Ornithine
PubMed: 32138329
DOI: 10.3390/molecules25051135 -
Toxins May 2018To test if arginine and ornithine, both components of the Krebs-Henseleit cycle, or zeolite, a potential ammonium absorber, can modulate the excretion of harmful...
To test if arginine and ornithine, both components of the Krebs-Henseleit cycle, or zeolite, a potential ammonium absorber, can modulate the excretion of harmful bacterial metabolites, intestinal microbial protein fermentation was stimulated by feeding a high-protein (60.3%) diet as a single daily meal to 10 adult cats. The diet was supplemented without or with arginine (+50, 75, 100% compared to arginine in the basal diet), ornithine (+100, 150, 200% compared to arginine in the basal diet), or zeolite (0.125, 0.25, 0.375 g/kg body weight/day). The cats received each diet for 11 days. Urine, feces, and blood were collected during the last 4 days. Arginine and ornithine enhanced the postprandial increase of blood urea, but renal urea excretion was not increased. Zeolite decreased renal ammonium excretion and fecal biogenic amines. The data indicate an increased detoxification rate of ammonia by arginine and ornithine supplementation. However, as urea was not increasingly excreted, detrimental effects on renal function cannot be excluded. Zeolite had beneficial effects on the intestinal nitrogen metabolism, which should be further evaluated in diseased cats. Clinical studies should investigate whether dietary arginine and ornithine might improve hepatic ammonia detoxification or could be detrimental for renal function.
Topics: Animals; Arginine; Cats; Dietary Supplements; Feces; Ornithine; Proteins; Toxins, Biological; Urea; Uremia; Zeolites
PubMed: 29783632
DOI: 10.3390/toxins10050206 -
Scientific Reports Oct 2020Eukaryotic complex phototrophs exhibit a colorful evolutionary history. At least three independent endosymbiotic events accompanied by the gene transfer from the...
Eukaryotic complex phototrophs exhibit a colorful evolutionary history. At least three independent endosymbiotic events accompanied by the gene transfer from the endosymbiont to host assembled a complex genomic mosaic. Resulting patchwork may give rise to unique metabolic capabilities; on the other hand, it can also blur the reconstruction of phylogenetic relationships. The ornithine-urea cycle (OUC) belongs to the cornerstone of the metabolism of metazoans and, as found recently, also photosynthetic stramenopiles. We have analyzed the distribution and phylogenetic positions of genes encoding enzymes of the urea synthesis pathway in eukaryotes. We show here that metazoan and stramenopile OUC enzymes share common origins and that enzymes of the OUC found in primary algae (including plants) display different origins. The impact of this fact on the evolution of stramenopiles is discussed here.
Topics: Animals; Biological Evolution; Databases, Genetic; Ornithine; Phylogeny; Stramenopiles; Symbiosis; Urea
PubMed: 33028894
DOI: 10.1038/s41598-020-73715-8