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Journal of Inherited Metabolic Disease Jan 2012Disorders of branched-chain amino/keto acid metabolism encompass diverse entities, including maple syrup urine disease (MSUD), the 'classical' organic acidurias... (Review)
Review
Disorders of branched-chain amino/keto acid metabolism encompass diverse entities, including maple syrup urine disease (MSUD), the 'classical' organic acidurias isovaleric acidemia (IVA), propionic acidemia (PA), methylmalonic acidemia (MMA) and, among others, rarely described disorders such as 2-methylbutyryl-CoA dehydrogenase deficiency (MBDD) or isobutyryl-CoA dehydrogenase deficiency (IBDD). Our focus in this review is to highlight the biochemical basis underlying recent advances and ongoing challenges of long-term conservative therapy including precursor/protein restriction, replenishment of deficient substrates, and the use of antioxidants and anaplerotic agents which refill the Krebs cycle. Ongoing clinical assessments of affected individuals in conjunction with monitoring of disease-specific biochemical parameters remain essential. It is likely that mass spectrometry-based 'metabolomics' may be a helpful tool in the future for studying complete biochemical profiles and diverse metabolic phenotypes. Prospective studies are needed to test the effectiveness of adjunct therapies such as antioxidants, ornithine-alpha-ketoglutarate (OKG) or creatine in addition to specialized diets and to optimize current therapeutic strategies in affected individuals. With the individual life-time risk and degree of severity being unknown in asymptomatic individuals with MBDD or IBDD, instructions regarding risks for metabolic stress and fasting avoidance along with clinical monitoring are reasonable interventions at the current time. Overall, it is apparent that carefully designed prospective clinical investigations and multicenter cohort-controlled trials are needed in order to leverage that knowledge into significant breakthroughs in treatment strategies and appropriate approaches.
Topics: Amino Acid Metabolism, Inborn Errors; Amino Acids, Branched-Chain; Animals; Creatinine; Humans; Maple Syrup Urine Disease; Mass Spectrometry; Metabolomics; Mice; Mice, Knockout; Mice, Transgenic; Ornithine; Phenotype; Risk
PubMed: 21290185
DOI: 10.1007/s10545-010-9269-1 -
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 -
Clinical Pharmacokinetics Apr 2022L-Ornithine phenylacetate is an intravenous formulation of the L-ornithine salt of phenylacetic acid under development for the treatment of hepatic encephalopathy. Very...
BACKGROUND AND OBJECTIVE
L-Ornithine phenylacetate is an intravenous formulation of the L-ornithine salt of phenylacetic acid under development for the treatment of hepatic encephalopathy. Very limited clinical data in patients are available, with a phase II study in target patients not designed for dose finding, to support phase III dose selection in a global development program. The objective of the present population pharmacokinetic modeling and simulation was to evaluate dose selection for target patient populations with a low body weight, ethnicity, and hepatic impairment in a global clinical study.
METHODS
A population pharmacokinetic model was developed based on plasma concentrations of L-ornithine, phenylacetic acid, and phenylacetylglutamine data from four clinical trials in healthy subjects and patients with stable cirrhosis or hospitalized adult patients with liver cirrhosis and hepatic encephalopathy. A covariate analysis was conducted to identify source of variability to support dose selection for global clinical development of L-ornithine phenylacetate. Phenylacetylglutamine formation in the pharmacokinetic model also quantified pharmacodynamic effects measured by ammonia removal.
RESULTS
Body weight and hepatic function were significant covariates determining phenylacetic acid exposure. After accounting for body weight, there was no difference between tested Caucasian and Asian populations in phenylacetic acid exposure. Renal dysfunction significantly reduced phenylacetylglutamine excretion. However, renal impairment had no impact on plasma phenylacetic acid and free ammonia levels. Exploratory modeling suggested that L-ornithine might enhance the removal of ammonia.
CONCLUSIONS
With a flat dosing algorithm, special consideration must be given to patients with a small body size (i.e., body weight ≤ 50 kg) and severe hepatic impairment.
Topics: Adult; Ammonia; Clinical Trials as Topic; Hepatic Encephalopathy; Humans; Ornithine; Phenylacetates
PubMed: 34786649
DOI: 10.1007/s40262-021-01075-1 -
Proceedings of the National Academy of... Mar 2023Biocatalytic C-H activation has the potential to merge enzymatic and synthetic strategies for bond formation. Fe/αKG-dependent halogenases are particularly...
Biocatalytic C-H activation has the potential to merge enzymatic and synthetic strategies for bond formation. Fe/αKG-dependent halogenases are particularly distinguished for their ability both to control selective C-H activation as well as to direct group transfer of a bound anion along a reaction axis separate from oxygen rebound, enabling the development of new transformations. In this context, we elucidate the basis for the selectivity of enzymes that perform selective halogenation to yield 4-Cl-lysine (BesD), 5-Cl-lysine (HalB), and 4-Cl-ornithine (HalD), allowing us to probe how site-selectivity and chain length selectivity are achieved. We now report the crystal structure of the HalB and HalD, revealing the key role of the substrate-binding lid in positioning the substrate for C vs C chlorination and recognition of lysine vs ornithine. Targeted engineering of the substrate-binding lid further demonstrates that these selectivities can be altered or switched, showcasing the potential to develop halogenases for biocatalytic applications.
Topics: Amino Acids; Lysine; Halogenation; Ornithine
PubMed: 36913566
DOI: 10.1073/pnas.2214512120 -
The Journal of Nutrition Jan 2007Simultaneous administration of alpha-ketoglutarate and ornithine, in a 1:2 molar ratio, may improve the effectiveness of ornithine as an arginine precursor in neonatal...
Coadministration of ornithine and alpha-ketoglutarate is no more effective than ornithine alone as an arginine precursor in piglets enterally fed an arginine-deficient diet.
Simultaneous administration of alpha-ketoglutarate and ornithine, in a 1:2 molar ratio, may improve the effectiveness of ornithine as an arginine precursor in neonatal piglets by shifting ornithine metabolism away from oxidation and toward the synthesis of arginine and other metabolically important compounds. To study this proposed mechanism, enterally fed piglets were allocated to receive 1 of 4 diets for 5 d: an arginine-deficient [1.2 mmol/(kg . d) arginine] diet (basal), or the basal diet supplemented with either alpha-ketoglutarate [4.6 mmol/(kg x d)] (+alpha-KG), ornithine [9.2 mmol/(kg x d)] (+Orn), or both ornithine and alpha-ketoglutarate (+alpha-KG/+Orn, molar ratio 1:2). Primed, constant infusions of [1-(14)C]ornithine given both intragastrically and intraportally were used to measure ornithine kinetics and determine the role of first-pass intestinal metabolism in ornithine metabolism. Whole body arginine and glutamate kinetics were measured using a primed, constant intragastric infusion of [guanido-(14)C]arginine and [3,4-(3)H]glutamate. The diets did not affect plasma arginine or ammonia concentrations, arginine flux, or arginine synthesis from ornithine. Therefore, arginine synthesis was not increased by the simultaneous infusion of ornithine and alpha-ketoglutarate. Piglets that received dietary ornithine had a 2-fold greater rate of proline synthesis from ornithine (P < 0.05) and oxidized a greater (P < 0.05) portion of the infused ornithine than piglets in the basal and +alpha-KG groups. Overall, ornithine addition to an arginine deficient diet had a greater effect on ornithine and arginine metabolism than the addition of alpha-ketoglutarate. First-pass intestinal metabolism was critical for ornithine synthesis and conversion to other metabolites but not for ornithine oxidation.
Topics: Administration, Oral; Ammonia; Animals; Arginine; Ketoglutaric Acids; Male; Ornithine; Swine; Urea
PubMed: 17182801
DOI: 10.1093/jn/137.1.55 -
Journal of Mass Spectrometry : JMS Jul 2013Facile cleavage C-terminal to ornithine residues in gas phase peptides has been observed and termed the ornithine effect. Peptides containing internal or C-terminal...
Facile cleavage C-terminal to ornithine residues in gas phase peptides has been observed and termed the ornithine effect. Peptides containing internal or C-terminal ornithine residues, which are formed from deguanidination of arginine in solution, were fragmented to produce either a y-ion or water loss, respectively, and the complementary b-ion. The fragmentation patterns of several peptides containing arginine were compared to those of the ornithine analogues. Conversion of arginine to ornithine results in a decrease of the gas phase proton affinity of the residue, thereby increasing the mobility of the ionizing proton. This alteration allows the nucleophilic amine to facilitate a neighboring group reaction to induce a cleavage of the adjacent amide bond. The selective cleavage at the ornithine residue is proposed to result from the highly favorable generation of a six-membered lactam ring. The ornithine effect was compared with the well-known proline and aspartic acid effects in peptide fragmentation using angiotensin II, DRVYIHPF and the ornithine analogue, DOVYIHPF. Under conditions favorable to either the aspartic acid (i.e. singly protonated peptide) or proline effect (i.e. doubly protonated peptide), the ornithine effect was consistently observed to be the more favorable fragmentation pathway. The highly selective nature of the ornithine effect opens up the possibility for conversion of arginine to ornithine residues to induce selective cleavages in polypeptide ions. Such an approach may complement strategies that seek to generate non-selective cleavages of the related peptides.
Topics: Amino Acid Sequence; Angiotensin II; Cations; Gases; Humans; Lactams; Molecular Sequence Data; Oligopeptides; Ornithine; Peptide Fragments; Tandem Mass Spectrometry
PubMed: 23832942
DOI: 10.1002/jms.3233 -
Journal of Bacteriology Apr 1977During growth on minimal medium, cells of Neurospora contain three pools of ornithine. Over 95% of the ornithine is in a metabolically inactive pool in vesicles, about...
During growth on minimal medium, cells of Neurospora contain three pools of ornithine. Over 95% of the ornithine is in a metabolically inactive pool in vesicles, about 1% is in the cytosol, and about 3% is in the mitochondria. By using a ureaseless strain, we measured the rapid flux of ornithine across the membrane boundaries of these pools. High levels of ornithine and the catabolic enzyme ornithine aminotransferase coexist during growth on minimal medium but, due to the compartmentation of the ornithine, only 11% was catabolized. Most of the ornithine was used for the synthesis of arginine. Upon the addition of arginine to the medium, ornithine was produced catabolically via the enzyme arginasn early enzyme of ornithine synthesis. The biosynthesis of arginine itself, from ornithine and carbamyl phosphate, was halted after about three generations of growth on arginine via the repression of carbamyl phosphate synthetase A. The catabolism of arginine produced ornithine at a greater rate than it had been produced biosynthetically, but this ornithine was not stored; rather it was catabolized in turn to yield intermediates of the proline pathway. Thus, compartmentation, feedback inhibition, and genetic repression all play a role to minimize the simultaneous operation of anabolic and catabolic pathways for ornithine and arginine.
Topics: Arginine; Carbamoyl-Phosphate Synthase (Ammonia); Cytosol; Enzyme Repression; Kinetics; Mitochondria; Neurospora; Neurospora crassa; Organoids; Ornithine; Ornithine-Oxo-Acid Transaminase
PubMed: 140162
DOI: 10.1128/jb.130.1.274-284.1977 -
American Journal of Physiology.... Mar 2001Arginine serves multiple roles in the pathophysiological response to burn injury. Our previous studies in burn patients demonstrated a limited net rate of arginine de... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
Arginine serves multiple roles in the pathophysiological response to burn injury. Our previous studies in burn patients demonstrated a limited net rate of arginine de novo synthesis despite a significantly increased arginine turnover (flux), suggesting that this amino acid is a conditionally indispensable amino acid after major burns. This study used [15N2-guanidino-5,5-2H2]arginine and [5-13C]ornithine as tracers to assess the rate of arginine disposal via its conversion to and subsequent oxidation of ornithine; [5,5-2H2]proline and [5,5,5-2H3]leucine were also used to assess proline and protein kinetics. Nine severely burned patients were studied during a protein-free fast ("basal" or fast) and total parenteral nutrition (TPN) feedings. Compared with values from healthy volunteers, burn injury significantly increased 1) fluxes of arginine, ornithine, leucine, and proline; 2) arginine-to-ornithine conversion; 3) ornithine oxidation; and 4) arginine oxidation. TPN increased arginine-to-ornithine conversion and proportionally increased irreversible arginine oxidation. The elevated arginine oxidation, with limited net de novo synthesis from its immediate precursors, further implies that arginine is a conditionally indispensable amino acid in severely burned patients receiving TPN.
Topics: Adult; Aged; Aged, 80 and over; Arginine; Burns; Carbon Isotopes; Deuterium; Female; Humans; Kinetics; Leucine; Male; Middle Aged; Nitrogen Isotopes; Ornithine; Oxidation-Reduction; Parenteral Nutrition, Total; Proline
PubMed: 11171607
DOI: 10.1152/ajpendo.2001.280.3.E509 -
Biogerontology Oct 2022Understanding the pathophysiology behind age-related diseases is an urgent need as the elderly population continues to grow. With age, there is a high risk of...
Understanding the pathophysiology behind age-related diseases is an urgent need as the elderly population continues to grow. With age, there is a high risk of musculoskeletal deterioration and associated morbidity and mortality. Although the exact mechanism behind age-related degeneration is unknown, it is well established that alteration in cellular metabolism is one of the important contributing factors. Alteration in signaling pathways with age leads to the accumulation or depletion of several metabolites that play a vital role in musculoskeletal pathophysiology. This study aimed to identify age-related changes in bone tissue metabolites in C57BL/6 mice. We then correlated the differentially expressed metabolites with their functions in bone biology. In both aged males and females, hydroxyproline, glutamine, and alpha-linolenic acid levels were decreased. In aged females, Ornithine (p value = 0.001), L-Proline (p value = 0.008), Uridine (p value = 0.001), Aspartic Acid (p value = 0.004) levels were significantly decreased, and glutamate (p value = 0.002) was elevated. In aged males, N-acetyl-D-glucosamine (pvalue = 0.010), Adrenic acid (pvalue = 0.0099), Arachidonic acid (p value = 0.029) and Allantoin (p value = 0.004) levels were decreased. Metabolic pathway analysis revealed that purine and D-glutamine and D-glutamate metabolism were significantly altered in both sexes, while arginine biosynthesis in females and lipid metabolism in males were highly affected. These differences in metabolic signaling might be one of the reasons for the discrepancy in musculoskeletal disease manifestation between the two sexes. Understanding the role of these metabolites play in the aging bone will allow for new sex-specific targeted therapies against the progression of musculoskeletal diseases.
Topics: Aged; Aging; Animals; Bone and Bones; Female; Humans; Lipid Metabolism; Male; Mice; Mice, Inbred C57BL; Ornithine
PubMed: 36056226
DOI: 10.1007/s10522-022-09986-7 -
Journal of Bacteriology Nov 1968Resting cells of Clostridium sticklandii fermented l-ornithine as a single substrate by a coupled oxidation-reduction with proline as the electron acceptor. The products...
Resting cells of Clostridium sticklandii fermented l-ornithine as a single substrate by a coupled oxidation-reduction with proline as the electron acceptor. The products of the fermentation of ornithine alone were ammonia, alanine, acetate, and delta-aminovalerate, in order of concentration. Traces of CO(2), butyrate, and proline were also found. When an equimolar amount of proline was added along with ornithine, very little delta-aminovalerate was produced from the ornithine, but essentially all of the proline was reduced to this compound. The ratios of the other primary products were changed by the addition of proline. The primary products from ornithine fermented in the presence of proline were acetate, ammonia, alanine, and CO(2), in order of concentration. Studies with dl-ornithine-1-(14)C, dl-ornithine-2-(14)C, and dl-ornithine-5-(14)C demonstrated that the primary cleavage of this amino acid occurred between carbons 3 and 4. A high percentage of the isotope from carbons 1 and 2 was found in alanine, and most of that from carbon 5 was found in volatile acid. The CO(2) formed was derived from the carboxyl carbon. All of the radioactivity from the fermentation of dl-alanine-1-(14)C was found in (14)CO(2). The alanine from ornithine was oxidized by d-amino acid oxidase to the same extent as dl-alanine, indicating that it was dl-alpha-alanine. Preliminary experiments with cell extracts indicated proline is an intermediate in the reduction of ornithine to delta-aminovaleric acid.
Topics: Alanine; Carbon Isotopes; Clostridium; Ornithine; Oxidation-Reduction; Proline; Pyruvates
PubMed: 5726303
DOI: 10.1128/jb.96.5.1617-1622.1968