Genomes and Genes
amino acid isomerases
Summary: Enzymes that catalyze either the racemization or epimerization of chiral centers within amino acids or derivatives. EC 5.1.1.
- Buschiazzo A, Goytia M, Schaeffer F, Degrave W, Shepard W, Grégoire C, et al. Crystal structure, catalytic mechanism, and mitogenic properties of Trypanosoma cruzi proline racemase. Proc Natl Acad Sci U S A. 2006;103:1705-10 pubmed
- Ashiuchi M, Misono H. Biochemistry and molecular genetics of poly-gamma-glutamate synthesis. Appl Microbiol Biotechnol. 2002;59:9-14 pubmed..A novel reaction mechanism of PGA synthesis is proposed. ..
- Lundqvist T, Fisher S, Kern G, Folmer R, Xue Y, Newton D, et al. Exploitation of structural and regulatory diversity in glutamate racemases. Nature. 2007;447:817-22 pubmed publisher..These structural, kinetic and mutational studies provide insight into the physiological regulation of these essential enzymes and provide a basis for designing narrow-spectrum antimicrobial agents...
- Spera J, Ugalde J, Mucci J, Comerci D, Ugalde R. A B lymphocyte mitogen is a Brucella abortus virulence factor required for persistent infection. Proc Natl Acad Sci U S A. 2006;103:16514-9 pubmed..We propose that an early and transient nonresponsive immune condition of the host mediated by this B cell polyclonal activator is required for establishing a successful chronic infection by Brucella. ..
- Geng B, Basarab G, Comita Prevoir J, Gowravaram M, Hill P, Kiely A, et al. Potent and selective inhibitors of Helicobacter pylori glutamate racemase (MurI): pyridodiazepine amines. Bioorg Med Chem Lett. 2009;19:930-6 pubmed publisher..pylori activity, marked improved solubility, and reduced plasma protein binding. X-ray co-crystal E-I structures were obtained. These uncompetitive inhibitors bind at the MurI dimer interface. ..
- Ashiuchi M, Kuwana E, Yamamoto T, Komatsu K, Soda K, Misono H. Glutamate racemase is an endogenous DNA gyrase inhibitor. J Biol Chem. 2002;277:39070-3 pubmed..This is the first finding of the enzyme protein participating in both d-amino acid metabolism and DNA processing. ..
- Reina San Martin B, Degrave W, Rougeot C, Cosson A, Chamond N, Cordeiro da Silva A, et al. A B-cell mitogen from a pathogenic trypanosome is a eukaryotic proline racemase. Nat Med. 2000;6:890-7 pubmed..This is the first report to our knowledge of a eukaryotic amino acid racemase gene. Our findings have potential consequences for the development of new immune therapies and drug design against pathogens. ..
- Doublet P, van Heijenoort J, Mengin Lecreulx D. Regulation of the glutamate racemase of Escherichia coli investigated by site-directed mutagenesis. Microb Drug Resist. 1996;2:43-9 pubmed..The attractive hypothesis that the characteristic N-terminal amino acid extension (20 residues) of the E. coli enzyme could be involved in its activation by the nucleotide precursor is disproved by these experiments. ..
- Rubinstein A, Major D. Catalyzing racemizations in the absence of a cofactor: the reaction mechanism in proline racemase. J Am Chem Soc. 2009;131:8513-21 pubmed publisher..This is ascribed to a highly preorganized active site facilitating transition state stabilization via a tight network of hydrogen bonds donated by nearby active site residues. ..
- Ashiuchi M, Soda K, Misono H. A poly-gamma-glutamate synthetic system of Bacillus subtilis IFO 3336: gene cloning and biochemical analysis of poly-gamma-glutamate produced by Escherichia coli clone cells. Biochem Biophys Res Commun. 1999;263:6-12 pubmed..coli cells harboring pgsBCA genes increased both the polymer production and D-glutamate content in the polymer. The polymer produced by the E. coli clone was higher in average molecular size than that produced by B. subtilis IFO 3336. ..
- Ashiuchi M, Kamei T, Baek D, Shin S, Sung M, Soda K, et al. Isolation of Bacillus subtilis (chungkookjang), a poly-gamma-glutamate producer with high genetic competence. Appl Microbiol Biotechnol. 2001;57:764-9 pubmed..B. subtilis (chungkookjang) harbors no plasmid and is the first B. subtilis strain reported with both naturally high PGA productivity and high genetic competence. ..
- Fotheringham I, Bledig S, Taylor P. Characterization of the genes encoding D-amino acid transaminase and glutamate racemase, two D-glutamate biosynthetic enzymes of Bacillus sphaericus ATCC 10208. J Bacteriol. 1998;180:4319-23 pubmed..The dat gene encodes a 31.4-kDa peptide with 67% primary sequence homology to the D-amino acid transaminase of the thermophilic Bacillus sp. strain YM1. ..
- Chamond N, Goytia M, Coatnoan N, Barale J, Cosson A, Degrave W, et al. Trypanosoma cruzi proline racemases are involved in parasite differentiation and infectivity. Mol Microbiol. 2005;58:46-60 pubmed..These results strongly emphasize that TcPRAC is a potential target for drug design as well as for immunomodulation of parasite-induced B-cell polyclonal activation. ..
- Shatalin K, Neyfakh A. Efficient gene inactivation in Bacillus anthracis. FEMS Microbiol Lett. 2005;245:315-9 pubmed..anthracis strain DeltaANR. Allelic replacements were observed at high frequencies, ranging from approximately 0.5% for racE2 up to 50% for racE1 and comEC. The system can be used for genetic validation of potential drug targets. ..
- Jilek A, Mollay C, Tippelt C, Grassi J, Mignogna G, Müllegger J, et al. Biosynthesis of a D-amino acid in peptide linkage by an enzyme from frog skin secretions. Proc Natl Acad Sci U S A. 2005;102:4235-9 pubmed..After expression of this cDNA in oocytes of Xenopus laevis, isomerase activity could be detected. Polypeptides related to the frog skin enzyme are present in several vertebrate species, including humans. ..
- Koh J, Chow S, Crossett B, Kuchel P. Mammalian peptide isomerase: platypus-type activity is present in mouse heart. Chem Biodivers. 2010;7:1603-11 pubmed publisher..Accordingly, eight mouse tissues were tested and heart was shown to have the activity. This is notable for being the first evidence of a peptide isomerase being present in a higher mammal and heralds finding the activity in man. ..
- Kim K, Bong Y, Park J, Shin K, Hwang K, Kim E. Structural basis for glutamate racemase inhibition. J Mol Biol. 2007;372:434-43 pubmed publisher..In both crystal forms, GluR exists as a dimer and the interactions seen at the dimer interface are almost identical. This agrees well with the results from gel filtration and dynamic light-scattering studies...
- Liu L, Yoshimura T, Endo K, Kishimoto K, Fuchikami Y, Manning J, et al. Compensation for D-glutamate auxotrophy of Escherichia coli WM335 by D-amino acid aminotransferase gene and regulation of murI expression. Biosci Biotechnol Biochem. 1998;62:193-5 pubmed..coli cells, as well as a regulation system for murI expression. ..
- Doublet P, van Heijenoort J, Bohin J, Mengin Lecreulx D. The murI gene of Escherichia coli is an essential gene that encodes a glutamate racemase activity. J Bacteriol. 1993;175:2970-9 pubmed
- Bellais S, Arthur M, Dubost L, Hugonnet J, Gutmann L, van Heijenoort J, et al. Aslfm, the D-aspartate ligase responsible for the addition of D-aspartic acid onto the peptidoglycan precursor of Enterococcus faecium. J Biol Chem. 2006;281:11586-94 pubmed..The Aslfm ligase appears as an attractive target for the development of narrow spectrum antibiotics active against multiresistant E. faecium. ..
- Dodd D, Reese J, Louer C, Ballard J, Spies M, Blanke S. Functional comparison of the two Bacillus anthracis glutamate racemases. J Bacteriol. 2007;189:5265-75 pubmed..These results suggest that racE1 and racE2 encode functional glutamate racemases with similar, but not identical, active site features. ..
- Ashiuchi M, Kuwana E, Komatsu K, Soda K, Misono H. Differences in effects on DNA gyrase activity between two glutamate racemases of Bacillus subtilis, the poly-gamma-glutamate synthesis-linking Glr enzyme and the YrpC (MurI) isozyme. FEMS Microbiol Lett. 2003;223:221-5 pubmed..The YrpC isozyme, but not the Glr enzyme, was found to influence the activity of DNA gyrase, as did the MurI-type glutamate racemase of Escherichia coli, which is involved in peptidoglycan synthesis during cell division. ..
- Chamond N, Cosson A, Coatnoan N, Minoprio P. Proline racemases are conserved mitogens: characterization of a Trypanosoma vivax proline racemase. Mol Biochem Parasitol. 2009;165:170-9 pubmed publisher..Therefore the product of the novel TvPRAC gene identified in T. vivax and reported herein has the potential to be used as a drug target for this parasite-based trypanosomiasis...
- Kotnik M, Anderluh P, Prezelj A. Development of novel inhibitors targeting intracellular steps of peptidoglycan biosynthesis. Curr Pharm Des. 2007;13:2283-309 pubmed..Naturally occurring inhibitors and the development of low-molecular weight inhibitors of the intracellular part of peptidoglycan synthesis are presented. ..
- Chamond N, Grégoire C, Coatnoan N, Rougeot C, Freitas Junior L, da Silveira J, et al. Biochemical characterization of proline racemases from the human protozoan parasite Trypanosoma cruzi and definition of putative protein signatures. J Biol Chem. 2003;278:15484-94 pubmed
- Torres A, Tsampazi M, Tsampazi C, Kennett E, Belov K, Geraghty D, et al. Mammalian l-to-d-amino-acid-residue isomerase from platypus venom. FEBS Lett. 2006;580:1587-91 pubmed..The isomerase is approximately 50-60 kDa and is inhibited by methanol and the peptidase inhibitor amastatin. This is the first known l-to-d-amino-acid-residue isomerase in a mammal. ..
- Marahiel M, Nakano M, Zuber P. Regulation of peptide antibiotic production in Bacillus. Mol Microbiol. 1993;7:631-6 pubmed
- Chen I, Thiruvengadam V, Lin W, Chang H, Hsu W. Lysine racemase: a novel non-antibiotic selectable marker for plant transformation. Plant Mol Biol. 2010;72:153-69 pubmed publisher..To our knowledge, this is the first report to demonstrate that the lysine racemase selectable marker system is novel, less controversial and inexpensive than the traditional selection systems. ..
- Lam L, Arnold L, Kalantar T, Kelland J, Lane Bell P, Palcic M, et al. Analogs of diaminopimelic acid as inhibitors of meso-diaminopimelate dehydrogenase and LL-diaminopimelate epimerase. J Biol Chem. 1988;263:11814-9 pubmed..Possible mechanisms of epimerase inhibition and significance of the DAP pathway as a target for antibiotics are discussed. ..
- Esaki N, Walsh C. Biosynthetic alanine racemase of Salmonella typhimurium: purification and characterization of the enzyme encoded by the alr gene. Biochemistry. 1986;25:3261-7 pubmed..The inactivator-pyridoxal 5'-phosphate adduct was isolated and shown to be the same structure formed in the dadB racemase inactivation [Roise, D., Soda, K., Yagi, T., & Walsh, C. (1984) Biochemistry 23, 5195]. ..
- Kim P, Duan X, Huang A, Liu C, Ming G, Song H, et al. Aspartate racemase, generating neuronal D-aspartate, regulates adult neurogenesis. Proc Natl Acad Sci U S A. 2010;107:3175-9 pubmed publisher..Because D-aspartate is a potential endogenous ligand for NMDA receptors, the loss of which elicits a phenotype resembling DR depletion, D-aspartate may function as a modulator of adult neurogenesis. ..
- Kimura K, Tran L, Itoh Y. Roles and regulation of the glutamate racemase isogenes, racE and yrpC, in Bacillus subtilis. Microbiology. 2004;150:2911-20 pubmed..Thus, both racemase genes appear necessary to complete the catabolism of exogenous d-glutamate generated from gamma-PGA. ..
- Jin Y, Burakoff S, Bierer B. Molecular cloning of a 25-kDa high affinity rapamycin binding protein, FKBP25. J Biol Chem. 1992;267:10942-5 pubmed..These data demonstrate that FKBP25 has a higher affinity for rapamycin than for FK506 and suggest that this cellular receptor may be an important target molecule for immunosuppression by rapamycin. ..
- Kada S, Nanamiya H, Kawamura F, Horinouchi S. Glr, a glutamate racemase, supplies D-glutamate to both peptidoglycan synthesis and poly-gamma-glutamate production in gamma-PGA-producing Bacillus subtilis. FEMS Microbiol Lett. 2004;236:13-20 pubmed..Phylogenetic analysis of glutamate racemases from eubacteria showed that YrpC is distinct from other glutamate racemases. ..
- Ho H, Falk P, Ervin K, Krishnan B, Discotto L, Dougherty T, et al. UDP-N-acetylmuramyl-L-alanine functions as an activator in the regulation of the Escherichia coli glutamate racemase activity. Biochemistry. 1995;34:2464-70 pubmed..With 6.5 microM regulator added, the N-terminal truncated enzyme displayed a loss of more than 80% of the activity compared to the full-length enzyme.(ABSTRACT TRUNCATED AT 250 WORDS) ..
- Yoshimura T, Ashiuchi M, Esaki N, Kobatake C, Choi S, Soda K. Expression of glr (murI, dga) gene encoding glutamate racemase in Escherichia coli. J Biol Chem. 1993;268:24242-6 pubmed..We partially purified the enzyme to characterize it. The enzyme consists of two identical subunits with a molecular weight of about 31,000 in contrast to the P. pentosaceus enzyme, a monomer protein. ..
- Jiang F, Qi G, Ji Z, Zhang S, Liu J, Ma X, et al. Expression of glr gene encoding glutamate racemase in Bacillus licheniformis WX-02 and its regulatory effects on synthesis of poly-?-glutamic acid. Biotechnol Lett. 2011;33:1837-40 pubmed publisher..This is the first report that overexpression of the glr gene could enhance the L- and D-glutamate conversion in B. licheniformis WX-02 and increase the proportion of D-glutamate in ?-PGA and the yield of ?-PGA. ..
- Whalen K, Tussey K, Blanke S, Spies M. Nature of allosteric inhibition in glutamate racemase: discovery and characterization of a cryptic inhibitory pocket using atomistic MD simulations and pKa calculations. J Phys Chem B. 2011;115:3416-24 pubmed publisher..The potential for future drug development is discussed. ..
- Gething M, Sambrook J. Protein folding in the cell. Nature. 1992;355:33-45 pubmed
- Sengupta S, Shah M, Nagaraja V. Glutamate racemase from Mycobacterium tuberculosis inhibits DNA gyrase by affecting its DNA-binding. Nucleic Acids Res. 2006;34:5567-76 pubmed..The sequestration of the gyrase by MurI results in inhibition of all reactions catalysed by DNA gyrase. MurI is thus not a typical potent inhibitor of DNA gyrase and instead its role could be in modulation of the gyrase activity. ..
- Pucci M, Thanassi J, Ho H, Falk P, Dougherty T. Staphylococcus haemolyticus contains two D-glutamic acid biosynthetic activities, a glutamate racemase and a D-amino acid transaminase. J Bacteriol. 1995;177:336-42 pubmed..These data suggest that S. haemolyticus, and probably S. aureus, contains genes for two D-glutamic acid biosynthetic activities, a glutamate racemase (dga gene) and a D-amino acid transaminase (dat gene). ..
- Ashiuchi M, Soda K, Misono H. Characterization of yrpC gene product of Bacillus subtilis IFO 3336 as glutamate racemase isozyme. Biosci Biotechnol Biochem. 1999;63:792-8 pubmed..In addition, YrpC showed higher affinity and lower catalytic efficiency for L-glutamate than Glr. This is the first example showing the occurrence and properties of a glutamate racemase isozyme. ..
- Yoshimura T, Goto M. D-amino acids in the brain: structure and function of pyridoxal phosphate-dependent amino acid racemases. FEBS J. 2008;275:3527-37 pubmed publisher..We compared the eukaryotic serine racemase with bacterial alanine racemase, the best-studied enzyme among the PLP-dependent amino acid racemases, and thus suggested a putative reaction mechanism for mammalian D-serine synthesis. ..
- Kino K, Sato M, Yoneyama M, Kirimura K. Synthesis of DL-tryptophan by modified broad specificity amino acid racemase from Pseudomonas putida IFO 12996. Appl Microbiol Biotechnol. 2007;73:1299-305 pubmed..L-Trp (20 mM) was successfully racemized, and the proportion of D-Trp was reached 43% using I384M mutant BAR, while wild-type BAR racemized only 6% of initial L-Trp. ..
- Murkin A, Tanner M. Dehydroalanine-based inhibition of a peptide epimerase from spider venom. J Org Chem. 2002;67:8389-94 pubmed..The observed inhibition by 4 can be attributed to the sp(2)-hybridization of the alpha-carbon in the dehydroalanine unit that mimics the planar geometry of the anionic intermediate. ..
- Lam H, Oh D, Cava F, Takacs C, Clardy J, de Pedro M, et al. D-amino acids govern stationary phase cell wall remodeling in bacteria. Science. 2009;325:1552-5 pubmed publisher..Thus, synthesis of D-amino acids may be a common strategy for bacteria to adapt to changing environmental conditions. ..
- Taal M, Sedelnikova S, Ruzheinikov S, Baker P, Rice D. Expression, purification and preliminary X-ray analysis of crystals of Bacillus subtilis glutamate racemase. Acta Crystallogr D Biol Crystallogr. 2004;60:2031-4 pubmed..1 A resolution on a synchrotron-radiation source and are suitable for structural studies. Determination of the structure may provide insight into the molecular basis of substrate recognition and catalysis by this enzyme. ..
- Liger D, Quevillon Cheruel S, Sorel I, Bremang M, Blondeau K, Aboulfath I, et al. Crystal structure of YHI9, the yeast member of the phenazine biosynthesis PhzF enzyme superfamily. Proteins. 2005;60:778-86 pubmed..Evolution of this protein by gene duplication, gene fusion and domain swapping from an ancestral gene containing the "hot dog" fold, identifies the protein as a "kinked double hot dog" fold. ..
- Ashiuchi M, Tani K, Soda K, Misono H. Properties of glutamate racemase from Bacillus subtilis IFO 3336 producing poly-gamma-glutamate. J Biochem. 1998;123:1156-63 pubmed..subtilis IFO 3336. These results suggest that the glutamate racemase is mainly concerned in D-glutamate synthesis for poly-gamma-glutamate production in B. subtilis IFO 3336. ..
- Chen I, Lin W, Hsu S, Thiruvengadam V, Hsu W. Isolation and characterization of a novel lysine racemase from a soil metagenomic library. Appl Environ Microbiol. 2009;75:5161-6 pubmed publisher..7 kDa. The enzyme exhibited higher specific activity toward lysine in the l-lysine-to-d-lysine direction than in the reverse reaction. ..
- Schönfeld D, Bornscheuer U. Polarimetric assay for the medium-throughput determination of alpha-amino acid racemase activity. Anal Chem. 2004;76:1184-8 pubmed..Thus, the method described can be used to determine racemase activity in an automatic manner. It should be also applicable for the screening of enzyme libraries created by directed evolution. ..