The Mechanism of Enzyme-Catalyzed Ergothioneine Degradation
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QM/MM) Study on Ornithine Cyclodeaminase (OCD): a Tale of Two Iminiums
Int. J. Mol. Sci. 2012, 13, 12994-13011; doi:10.3390/ijms131012994 OPEN ACCESS International Journal of Molecular Sciences ISSN 1422-0067 www.mdpi.com/journal/ijms Article A Molecular Dynamics (MD) and Quantum Mechanics/Molecular Mechanics (QM/MM) Study on Ornithine Cyclodeaminase (OCD): A Tale of Two Iminiums Bogdan F. Ion, Eric A. C. Bushnell, Phil De Luna and James W. Gauld * Department of Chemistry and Biochemistry, University of Windsor, Windsor, ON N9B 3P4, Canada; E-Mails: [email protected] (B.F.I.); [email protected] (E.A.C.B.); [email protected] (P.D.L.) * Author to whom correspondence should be addressed; E-Mail: [email protected]; Tel.: +1-519-253-3000; Fax: +1-519-973-7098. Received: 10 September 2012; in revised form: 27 September 2012 / Accepted: 27 September 2012 / Published: 11 October 2012 Abstract: Ornithine cyclodeaminase (OCD) is an NAD+-dependent deaminase that is found in bacterial species such as Pseudomonas putida. Importantly, it catalyzes the direct conversion of the amino acid L-ornithine to L-proline. Using molecular dynamics (MD) and a hybrid quantum mechanics/molecular mechanics (QM/MM) method in the ONIOM formalism, the catalytic mechanism of OCD has been examined. The rate limiting step is calculated to be the initial step in the overall mechanism: hydride transfer from the + + L-ornithine’s Cα–H group to the NAD cofactor with concomitant formation of a Cα=NH2 Schiff base with a barrier of 90.6 kJ mol−1. Importantly, no water is observed within the + active site during the MD simulations suitably positioned to hydrolyze the Cα=NH2 intermediate to form the corresponding carbonyl. -
Argininosuccinate Lyase Deficiency
©American College of Medical Genetics and Genomics GENETEST REVIEW Argininosuccinate lyase deficiency Sandesh C.S. Nagamani, MD1, Ayelet Erez, MD, PhD1 and Brendan Lee, MD, PhD1,2 The urea cycle consists of six consecutive enzymatic reactions that citrulline together with elevated argininosuccinic acid in the plasma convert waste nitrogen into urea. Deficiencies of any of these enzymes or urine. Molecular genetic testing of ASL and assay of ASL enzyme of the cycle result in urea cycle disorders (UCDs), a group of inborn activity are helpful when the biochemical findings are equivocal. errors of hepatic metabolism that often result in life-threatening However, there is no correlation between the genotype or enzyme hyperammonemia. Argininosuccinate lyase (ASL) catalyzes the activity and clinical outcome. Treatment of acute metabolic decom- fourth reaction in this cycle, resulting in the breakdown of arginino- pensations with hyperammonemia involves discontinuing oral pro- succinic acid to arginine and fumarate. ASL deficiency (ASLD) is the tein intake, supplementing oral intake with intravenous lipids and/ second most common UCD, with a prevalence of ~1 in 70,000 live or glucose, and use of intravenous arginine and nitrogen-scavenging births. ASLD can manifest as either a severe neonatal-onset form therapy. Dietary restriction of protein and dietary supplementation with hyperammonemia within the first few days after birth or as a with arginine are the mainstays in long-term management. Ortho- late-onset form with episodic hyperammonemia and/or long-term topic liver transplantation (OLT) is best considered only in patients complications that include liver dysfunction, neurocognitive deficits, with recurrent hyperammonemia or metabolic decompensations and hypertension. -
Hyperammonemia: Regulation of Argininosuccinate Synthetase and Argininosuccinate Lyase Genes in Aggregating Cell Cultures of Fetal Rat Brain
View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Serveur académique lausannois Neuroscience Letters (1999) 266: 89-92 Hyperammonemia: Regulation of Argininosuccinate Synthetase and Argininosuccinate Lyase Genes in Aggregating Cell Cultures of Fetal Rat Brain. Olivier Braissant1, Paul Honegger2, Marc Loup1, Katsuro Iwase3*, Masaki Takiguchi3* and Claude Bachmann1. 1 Central Clinical Chemistry Laboratory, University Hospital, CH-1011 Lausanne, Switzerland. 2 Physiology Institute, University of Lausanne, CH-1011 Lausanne, Switzerland. 3 Department of Molecular Genetics, Kumamoto University School of Medicine, Kumamoto 862-0976, Japan. * Present address: Department of Biochemistry, Chiba University School of Medicine, Chiba 260-8670, Japan Keywords: brain, argininosuccinate, arginine, citrulline-NO cycle, astrocyte, hyperammonemia Correspondence to : Olivier Braissant Central Clinical Chemistry Laboratory, University Hospital, CH-1011 Lausanne, Switzerland Tél : (+41.21) 314.41.52 Fax : (+41.21) 314.42.88 e-mail : [email protected] 1 Abstract Hyperammonemia in the brain leads to poorly understood alterations of nitric oxide (NO) synthesis. Arginine, the substrate of nitric oxide synthases, might be recycled from the citrulline produced with NO by argininosuccinate synthetase (AS) and argininosuccinate lyase (AL). The regulation of AS and AL genes during hyperammonemia is unknown in the brain. We used brain cell aggregates cultured from dissociated telencephalic cortex of rat embryos to analyse the regulation of AS and AL genes in hyperammonemia. Using RNase protection assay and non-radioactive in situ hybridization on aggregate cryosections, we show that both AS and AL genes are induced in astrocytes but not in neurons of aggregates exposed to 5 mM NH4Cl. -
The Microbiota-Produced N-Formyl Peptide Fmlf Promotes Obesity-Induced Glucose
Page 1 of 230 Diabetes Title: The microbiota-produced N-formyl peptide fMLF promotes obesity-induced glucose intolerance Joshua Wollam1, Matthew Riopel1, Yong-Jiang Xu1,2, Andrew M. F. Johnson1, Jachelle M. Ofrecio1, Wei Ying1, Dalila El Ouarrat1, Luisa S. Chan3, Andrew W. Han3, Nadir A. Mahmood3, Caitlin N. Ryan3, Yun Sok Lee1, Jeramie D. Watrous1,2, Mahendra D. Chordia4, Dongfeng Pan4, Mohit Jain1,2, Jerrold M. Olefsky1 * Affiliations: 1 Division of Endocrinology & Metabolism, Department of Medicine, University of California, San Diego, La Jolla, California, USA. 2 Department of Pharmacology, University of California, San Diego, La Jolla, California, USA. 3 Second Genome, Inc., South San Francisco, California, USA. 4 Department of Radiology and Medical Imaging, University of Virginia, Charlottesville, VA, USA. * Correspondence to: 858-534-2230, [email protected] Word Count: 4749 Figures: 6 Supplemental Figures: 11 Supplemental Tables: 5 1 Diabetes Publish Ahead of Print, published online April 22, 2019 Diabetes Page 2 of 230 ABSTRACT The composition of the gastrointestinal (GI) microbiota and associated metabolites changes dramatically with diet and the development of obesity. Although many correlations have been described, specific mechanistic links between these changes and glucose homeostasis remain to be defined. Here we show that blood and intestinal levels of the microbiota-produced N-formyl peptide, formyl-methionyl-leucyl-phenylalanine (fMLF), are elevated in high fat diet (HFD)- induced obese mice. Genetic or pharmacological inhibition of the N-formyl peptide receptor Fpr1 leads to increased insulin levels and improved glucose tolerance, dependent upon glucagon- like peptide-1 (GLP-1). Obese Fpr1-knockout (Fpr1-KO) mice also display an altered microbiome, exemplifying the dynamic relationship between host metabolism and microbiota. -
Functional Characterization of an Ornithine Cyclodeaminase-Like Protein of Arabidopsis Thaliana Sandeep Sharma, Suhas Shinde and Paul E Verslues*
Sharma et al. BMC Plant Biology 2013, 13:182 http://www.biomedcentral.com/1471-2229/13/182 RESEARCH ARTICLE Open Access Functional characterization of an ornithine cyclodeaminase-like protein of Arabidopsis thaliana Sandeep Sharma, Suhas Shinde and Paul E Verslues* Abstract Background: In plants, proline synthesis occurs by two enzymatic steps starting from glutamate as a precursor. Some bacteria, including bacteria such as Agrobacterium rhizogenes have an Ornithine Cyclodeaminase (OCD) which can synthesize proline in a single step by deamination of ornithine. In A. rhizogenes, OCD is one of the genes transferred to the plant genome during the transformation process and plants expressing A. rhizogenes OCD have developmental phenotypes. One nuclear encoded gene of Arabidopsis thaliana has recently been annotated as an OCD (OCD-like; referred to here as AtOCD) but nothing is known of its function. As proline metabolism contributes to tolerance of low water potential during drought, it is of interest to determine if AtOCD affects proline accumulation or low water potential tolerance. Results: Expression of AtOCD was induced by low water potential stress and by exogenous proline, but not by the putative substrate ornithine. The AtOCD protein was plastid localized. T-DNA mutants of atocd and AtOCD RNAi plants had approximately 15% higher proline accumulation at low water potential while p5cs1-4/atocd double mutants had 40% higher proline than p5cs1 at low water potential but no change in proline metabolism gene expression which could directly explain the higher proline level. AtOCD overexpression did not affect proline accumulation. Enzymatic assays with bacterially expressed AtOCD or AtOCD purified from AtOCD:Flag transgenic plants did not detect any activity using ornithine, proline or several other amino acids as substrates. -
Biosynthesis of Natural Products Containing Β-Amino Acids
Natural Product Reports Biosynthesis of natural products containing β -amino acids Journal: Natural Product Reports Manuscript ID: NP-REV-01-2014-000007.R1 Article Type: Review Article Date Submitted by the Author: 21-Apr-2014 Complete List of Authors: Kudo, Fumitaka; Tokyo Institute Of Technology, Department of Chemistry Miyanaga, Akimasa; Tokyo Institute Of Technology, Department of Chemistry Eguchi, T; Tokyo Institute Of Technology, Department of Chemistry and Materials Science Page 1 of 20 Natural Product Reports NPR RSC Publishing REVIEW Biosynthesis of natural products containing βββ- amino acids Cite this: DOI: 10.1039/x0xx00000x Fumitaka Kudo, a Akimasa Miyanaga, a and Tadashi Eguchi *b Received 00th January 2014, We focus here on β-amino acids as components of complex natural products because the presence of β-amino acids Accepted 00th January 2014 produces structural diversity in natural products and provides characteristic architectures beyond that of ordinary DOI: 10.1039/x0xx00000x α-L-amino acids, thus generating significant and unique biological functions in nature. In this review, we first survey the known bioactive β-amino acid-containing natural products including nonribosomal peptides, www.rsc.org/ macrolactam polyketides, and nucleoside-β-amino acid hybrids. Next, the biosynthetic enzymes that form β-amino acids from α-amino acids and de novo synthesis of β-amino acids are summarized. Then, the mechanisms of β- amino acid incorporation into natural products are reviewed. Because it is anticipated that the rational swapping of the β-amino acid moieties with various side chains and stereochemistries by biosynthetic engineering should lead to the creation of novel architectures and bioactive compounds, the accumulation of knowledge regarding β- amino acid-containing natural product biosynthetic machinery could have a significant impact in this field. -
U-Crystallin Is a Mammalian Homologue of Agrobacterium
Proc. Natl. Acad. Sci. USA Vol. 89, pp. 9292-92%, October 1992 Evolution ,u-Crystallin is a mammalian homologue of Agrobacterium ornithine cyclodeaminase and is expressed in human retina (crystallin recritme t/molecular evolution/amino add metabolism) ROBERT Y. KIM*, ROBIN GASSERt, AND GRAEME J. WISTOW*t *Section on Molecular Structure and Function, Laboratory of Molecular and Developmental Biology, National Eye Institute, National Institutes of Health, Bethesda, MD 20892; and tThe University of Melbourne, School of Veterinary Science, Werribee, Victoria 3030, Australia Communicated by Charles Sibley, July 6, 1992 (received for review June 4, 1992) ABSTRACT I-Crystallin is the major component of the MATERIALS AND METHODS in Australian marsupials. The complete se- eye lens several RNA Extraction and cDNA Cloning. Total RNA was ex- of kangaroo -crystalln has now been obtained by quence tracted from gray kangaroo lenses by the guanidinium thio- cDNA cloning. The predicted amino acid sequence shows with RNazol reagents (Tel-Test, Friends- tu- cyanate method (7) similary with ornithine cyclodeaminases encoded by the wood, TX). Five micrograms of poly(A)+ RNA was then mor-inducing (Ti) plasmids of Agrobacterium tumefaciens. purified by using Dynabeads (Dynal, Great Neck, NY). Until now, neither ornithine cyclodeaminase nor any structur- cDNA was synthesized using the Lambda Zap kit from ally related enzymes have been observed in eukaryotes. RNA Stratagene, following manufacturer's specifications. A cDNA analysis ofkangaroo tissues shows that It-crystallin is expressed probe for j.-crystallin was produced by PCR of 1 pug of at high abundance in lens, but outside the lens #-crystallin is kangaroo lens total RNA with oligo primers GARGGGGTG- preferentially expressed in neural tissues, retina, and brain. -
Nitro Analogs of Substrates for Argininosuccinate Synthetase and Argininosuccinate Lyase’
ARCHIVESOF BIOCHEMISTRY AND BIOPHYSICS Vol. 232, No. 2, August 1, pp. 520-525, 1984 Nitro Analogs of Substrates for Argininosuccinate Synthetase and Argininosuccinate Lyase’ FRANK M. RAUSHEL Lkpartment of Chemistry, Team A&M University, College Station, Texas ?‘z?@ Received December 27, 1933, and in revised form March 20, 1982 The nitro analogs of aspartate and argininosuccinate were synthesized and tested as substrates and inhibitors of argininosuccinate synthetase and argininosuccinate lyase, respectively. The V,,,,, for 3-nitro-2-aminopropionic acid was found to be 60% of the maximal rate of aspartate utilization in the reaction catalyzed by argininosuccinate synthetase. Only the nitronate form of this substrate, in which the C-3 hydrogen is ionized, was substrate active, indicating a requirement for a negatively charged group at the /3 carbon. The V/K of the nitro analog of aspartate was 85% of the value of aspartate after correcting for the percentage of the active nitronate species. The nitro analog of argininosuccinate, N3-(L-1-carboxy-2-nitroethyl)-L-arginine, was a strong competitive inhibitor of argininosuccinate lyase but was not a substrate. The pH de- pendence of the observed pKi was consistent with the ionized carbon acid (pK = 8.2) in the nitronate configuration as the inhibitory material. The pH-independent pK+ of 2.7 PM is 20 times smaller than the Km of argininosuccinate at pH 7.5. These results suggest that the tighter binding of the nitro analog relative to the substrate is due to the similarity in structure to a carbanionic intermediate in the reaction pathway. It has recently been demonstrated (l-5) mediate formation of a carbanionic species with a number of enzyme systems that the (ElcB mechanism). -
Supplementary Informations SI2. Supplementary Table 1
Supplementary Informations SI2. Supplementary Table 1. M9, soil, and rhizosphere media composition. LB in Compound Name Exchange Reaction LB in soil LBin M9 rhizosphere H2O EX_cpd00001_e0 -15 -15 -10 O2 EX_cpd00007_e0 -15 -15 -10 Phosphate EX_cpd00009_e0 -15 -15 -10 CO2 EX_cpd00011_e0 -15 -15 0 Ammonia EX_cpd00013_e0 -7.5 -7.5 -10 L-glutamate EX_cpd00023_e0 0 -0.0283302 0 D-glucose EX_cpd00027_e0 -0.61972444 -0.04098397 0 Mn2 EX_cpd00030_e0 -15 -15 -10 Glycine EX_cpd00033_e0 -0.0068175 -0.00693094 0 Zn2 EX_cpd00034_e0 -15 -15 -10 L-alanine EX_cpd00035_e0 -0.02780553 -0.00823049 0 Succinate EX_cpd00036_e0 -0.0056245 -0.12240603 0 L-lysine EX_cpd00039_e0 0 -10 0 L-aspartate EX_cpd00041_e0 0 -0.03205557 0 Sulfate EX_cpd00048_e0 -15 -15 -10 L-arginine EX_cpd00051_e0 -0.0068175 -0.00948672 0 L-serine EX_cpd00054_e0 0 -0.01004986 0 Cu2+ EX_cpd00058_e0 -15 -15 -10 Ca2+ EX_cpd00063_e0 -15 -100 -10 L-ornithine EX_cpd00064_e0 -0.0068175 -0.00831712 0 H+ EX_cpd00067_e0 -15 -15 -10 L-tyrosine EX_cpd00069_e0 -0.0068175 -0.00233919 0 Sucrose EX_cpd00076_e0 0 -0.02049199 0 L-cysteine EX_cpd00084_e0 -0.0068175 0 0 Cl- EX_cpd00099_e0 -15 -15 -10 Glycerol EX_cpd00100_e0 0 0 -10 Biotin EX_cpd00104_e0 -15 -15 0 D-ribose EX_cpd00105_e0 -0.01862144 0 0 L-leucine EX_cpd00107_e0 -0.03596182 -0.00303228 0 D-galactose EX_cpd00108_e0 -0.25290619 -0.18317325 0 L-histidine EX_cpd00119_e0 -0.0068175 -0.00506825 0 L-proline EX_cpd00129_e0 -0.01102953 0 0 L-malate EX_cpd00130_e0 -0.03649016 -0.79413596 0 D-mannose EX_cpd00138_e0 -0.2540567 -0.05436649 0 Co2 EX_cpd00149_e0 -
Enzymes Involved in the Biosynthesis of Arginine from Ornithine in Maritime Pine (Pinus Pinaster Ait.)
plants Article Enzymes Involved in the Biosynthesis of Arginine from Ornithine in Maritime Pine (Pinus pinaster Ait.) José Alberto Urbano-Gámez, Jorge El-Azaz, Concepción Ávila , Fernando N. de la Torre * and Francisco M. Cánovas * Grupo de Biología Molecular y Biotecnología, Departamento de Biología Molecular y Bioquímica, Universidad de Málaga, Campus Universitario de Teatinos, 29071 Málaga, Spain; [email protected] (J.A.U.-G.); [email protected] (J.E.-A.); [email protected] (C.Á.) * Correspondence: [email protected] (F.N.d.l.T.); [email protected] (F.M.C.) Received: 11 September 2020; Accepted: 24 September 2020; Published: 27 September 2020 Abstract: The amino acids arginine and ornithine are the precursors of a wide range of nitrogenous compounds in all living organisms. The metabolic conversion of ornithine into arginine is catalyzed by the sequential activities of the enzymes ornithine transcarbamylase (OTC), argininosuccinate synthetase (ASSY) and argininosuccinate lyase (ASL). Because of their roles in the urea cycle, these enzymes have been purified and extensively studied in a variety of animal models. However, the available information about their molecular characteristics, kinetic and regulatory properties is relatively limited in plants. In conifers, arginine plays a crucial role as a main constituent of N-rich storage proteins in seeds and serves as the main source of nitrogen for the germinating embryo. In this work, recombinant PpOTC, PpASSY and PpASL enzymes from maritime pine (Pinus pinaster Ait.) were produced in Escherichia coli to enable study of their molecular and kinetics properties. The results reported here provide a molecular basis for the regulation of arginine and ornithine metabolism at the enzymatic level, suggesting that the reaction catalyzed by OTC is a regulatory target in the homeostasis of ornithine pools that can be either used for the biosynthesis of arginine in plastids or other nitrogenous compounds in the cytosol. -
Enzymologic and Metabolic Studies in Two Families Affected by Argininosuccinic Aciduria
Pediat. Res. 12: 256-262 (1978) Argininosuccinic aciduria erythrocyte enzymes argininosuccinic acid lyase urea cycle disorder enzyme kinetics protein tolerance test Enzymologic and Metabolic Studies in Two Families Affected by Argininosuccinic Aciduria I. A. QURESHI. J. LETARTE,'*' R. OUELLET, AND B. LEMIEUX Centre de Recherche Pidiatrique, Hbpital Sainfe-Justine and Universiti de Montrial, Monfrial; Diparternent de Pidiatrie, Centre Hospitalier Universitaire, UniversitP de Sherbrooke, Quebec, Canada Summaw Familial studies on argininosuccinic aciduria have also generally employed ASAL activity measurements in red blood cells. It has Both the affected families studied provide another example of been possible to identify the heterozygous or normal relatives of the autosomal recessive inheritance of argininosuccinic aciduria. the patient on the basis of the level of active enzyme in The fasting plasma levels of argininosuccinic acid in the two erythrocytes (5,7,8,14-17,21,22,25,30,35). propositi did not correlate with the levels of argininosuccinic As a part of the Quebec Network of Genetic Medicine acid lyase (ASAL) in erythrocytes. There was 210 pM argin- program in 1973 we studied two families of French-Canadian inosuccinic acid with indications of anhydride B content in the origin in which, on routine neonatal screening, one child in each family 1 propositus, having an enzyme activity of W%; while was discovered to excrete argininosuccinic acid. The diagnosis the family I1 propositus gave an argininosuccinic acidemia was confirmed by follow-up studies and erythrocyte enzyme reading of 64.6 pM with no activity of RBC ASAL. There was measurement in early 1975. This paper describes the results of a reduced enzyme activity in all the members of affected the familial biochemical, nutritional, and enzymologic studies families due to a signir~cantlyreduced V,,, value as compared undertaken recently. -
Nitric-Oxide Supplementation for Treatment of Long-Term
Please cite this article in press as: Nagamani et al., Nitric-Oxide Supplementation for Treatment of Long-Term Complications in Arginino- succinic Aciduria, The American Journal of Human Genetics (2012), doi:10.1016/j.ajhg.2012.03.018 ARTICLE Nitric-Oxide Supplementation for Treatment of Long-Term Complications in Argininosuccinic Aciduria Sandesh C.S. Nagamani,1,10 Philippe M. Campeau,1,10 Oleg A. Shchelochkov,1,10 Muralidhar H. Premkumar,2 Kilian Guse,1 Nicola Brunetti-Pierri,1 Yuqing Chen,1,9 Qin Sun,1 Yaoping Tang,3 Donna Palmer,1 Anilkumar K. Reddy,4 Li Li,5 Timothy C. Slesnick,6 Daniel I. Feig,6 Susan Caudle,6 David Harrison,5 Leonardo Salviati,7 Juan C. Marini,8 Nathan S. Bryan,3 Ayelet Erez,1,11 and Brendan Lee1,9,11,* Argininosuccinate lyase (ASL) is required for the synthesis and channeling of L-arginine to nitric oxide synthase (NOS) for nitric oxide (NO) production. Congenital ASL deficiency causes argininosuccinic aciduria (ASA), the second most common urea-cycle disorder, and leads to deficiency of both ureagenesis and NO production. Subjects with ASA have been reported to develop long-term complications such as hypertension and neurocognitive deficits despite early initiation of therapy and the absence of documented hyperammonemia. In order to distinguish the relative contributions of the hepatic urea-cycle defect from those of the NO deficiency to the phenotype, we performed liver-directed gene therapy in a mouse model of ASA. Whereas the gene therapy corrected the ureagenesis defect, the systemic hypertension in mice could be corrected by treatment with an exogenous NO source.