Discovery of a novel amino acid racemase through exploration of natural variation in Arabidopsis thaliana

Strauch, Renee C.; Svedin, Elisabeth; Dilkes, Brian; Chapple, Clint; Li, Xu

doi:10.1073/pnas.1503272112

Title: Discovery of a novel amino acid racemase through exploration of natural variation in Arabidopsis thaliana

Journal Article · Mon Aug 31 00:00:00 EDT 2015 · Proceedings of the National Academy of Sciences of the United States of America

DOI:https://doi.org/10.1073/pnas.1503272112· OSTI ID:1348406

Strauch, Renee C. ^[1]; Svedin, Elisabeth ^[2]; Dilkes, Brian ^[2]; Chapple, Clint ^[2]; Li, Xu ^[1]

North Carolina State Univ., Kannapolis, NC (United States); North Carolina State Univ., Raleigh, NC (United States)
Purdue Univ., West Lafayette, IN (United States)

Plants produce diverse low-molecular-weight compounds via specialized metabolism. Discovery of the pathways underlying production of these metabolites is an important challenge for harnessing the huge chemical diversity and catalytic potential in the plant kingdom for human uses, but this effort is often encumbered by the necessity to initially identify compounds of interest or purify a catalyst involved in their synthesis. Here, as an alternative approach, we have performed untargeted metabolite profiling and genome-wide association analysis on 440 natural accessions of Arabidopsis thaliana. This approach allowed us to establish genetic linkages between metabolites and genes. Investigation of one of the metabolite-gene associations led to the identification of N-malonyl-D-allo-isoleucine, and the discovery of a novel amino acid racemase involved in its biosynthesis. This finding provides, to our knowledge, the first functional characterization of a eukaryotic member of a large and widely conserved phenazine biosynthesis protein PhzF-like protein family. Unlike most of known eukaryotic amino acid racemases, the newly discovered enzyme does not require pyridoxal 5'-phosphate for its activity. In conclusion, this study thus identifies a new d-amino acid racemase gene family and advances our knowledge of plant d-amino acid metabolism that is currently largely unexplored. As a result, it also demonstrates that exploitation of natural metabolic variation by integrating metabolomics with genome-wide association is a powerful approach for functional genomics study of specialized metabolism.

View Accepted Manuscript (DOE)

Cite

Export

Save

Research Organization:: Purdue Univ., West Lafayette, IN (United States)

Sponsoring Organization:: USDOE

Grant/Contract Number:: FG02-07ER15905

OSTI ID:: 1348406

Journal Information:: Proceedings of the National Academy of Sciences of the United States of America, Vol. 112, Issue 37; ISSN 0027-8424

Publisher:: National Academy of SciencesCopyright Statement

Country of Publication:: United States

Language:: English

Citation Metrics:

Cited by: 45 works

Citation information provided by
Web of Science

References (46)

Two sesquiterpene synthases are responsible for the complex mixture of sesquiterpenes emitted from Arabidopsis flowers: Sesquiterpene synthases in Arabidopsis flower Tholl, Dorothea; Chen, Feng; Petri, Jana The Plant Journal, Vol. 42, Issue 5 https://doi.org/10.1111/j.1365-313X.2005.02417.x	journal	April 2005
Drug Discovery Targeting Amino Acid Racemases Conti, Paola; Tamborini, Lucia; Pinto, Andrea Chemical Reviews, Vol. 111, Issue 11 https://doi.org/10.1021/cr2000702	journal	November 2011
Kinetic and Mechanistic Studies of the Deuterium Exchange in Classical Keto−Enol Tautomeric Equilibrium Reactions Nichols, Michael A.; Waner, Mark J. Journal of Chemical Education, Vol. 87, Issue 9 https://doi.org/10.1021/ed100292r	journal	September 2010
NMDA Receptor Regulation by D-serine: New Findings and Perspectives Wolosker, Herman Molecular Neurobiology, Vol. 36, Issue 2 https://doi.org/10.1007/s12035-007-0038-6	journal	September 2007
The genetics of plant metabolism Keurentjes, Joost J. B.; Fu, Jingyuan; de Vos, C. H. Ric Nature Genetics, Vol. 38, Issue 7 https://doi.org/10.1038/ng1815	journal	June 2006
Variance component model to account for sample structure in genome-wide association studies Kang, Hyun Min; Sul, Jae Hoon; Service, Susan K. Nature Genetics, Vol. 42, Issue 4 https://doi.org/10.1038/ng.548	journal	March 2010
Genome-Wide Insertional Mutagenesis of Arabidopsis thaliana Alonso, J. M.; Stepanova, Anna N.; Leisse, Thomas J. Science, Vol. 301, Issue 5633, p. 653-657 https://doi.org/10.1126/science.1086391	journal	August 2003
Chromatographic separation of enantiomers of non-protein α-amino acids after derivatization with Marfey’s reagent and its four variants Bhushan, R.; Kumar, Virender; Tanwar, Shivani Amino Acids, Vol. 36, Issue 3 https://doi.org/10.1007/s00726-008-0135-5	journal	July 2008
Characterization of DcsC, a PLP-independent racemase involved in the biosynthesis of d-cycloserine Dietrich, David; van Belkum, Marco J.; Vederas, John C. Organic & Biomolecular Chemistry, Vol. 10, Issue 11 https://doi.org/10.1039/c2ob06864h	journal	January 2012
Genome-wide association analyses provide genetic and biochemical insights into natural variation in rice metabolism Chen, Wei; Gao, Yanqiang; Xie, Weibo Nature Genetics, Vol. 46, Issue 7 https://doi.org/10.1038/ng.3007	journal	June 2014
Formation and occurrence of N -malonylphenylalanine and related compounds in plants Rosa, N.; Neish, A. C. Canadian Journal of Biochemistry, Vol. 46, Issue 8 https://doi.org/10.1139/o68-121	journal	August 1968
Uptake of organic nitrogen by plants: Tansley review Näsholm, Torgny; Kielland, Knut; Ganeteg, Ulrika New Phytologist, Vol. 182, Issue 1 https://doi.org/10.1111/j.1469-8137.2008.02751.x	journal	February 2009
Functional genomics for plant natural product biosynthesis Yonekura-Sakakibara, Keiko; Saito, Kazuki Natural Product Reports, Vol. 26, Issue 11 https://doi.org/10.1039/b817077k	journal	January 2009
XCMS: Processing Mass Spectrometry Data for Metabolite Profiling Using Nonlinear Peak Alignment, Matching, and Identification Smith, Colin A.; Want, Elizabeth J.; O'Maille, Grace Analytical Chemistry, Vol. 78, Issue 3 https://doi.org/10.1021/ac051437y	journal	February 2006
Structure and function of the phenazine biosynthetic protein PhzF from Pseudomonas fluorescens Blankenfeldt, W.; Kuzin, A. P.; Skarina, T. Proceedings of the National Academy of Sciences, Vol. 101, Issue 47 https://doi.org/10.1073/pnas.0407371101	journal	November 2004
Gene Duplication in the Diversification of Secondary Metabolism: Tandem 2-Oxoglutarate–Dependent Dioxygenases Control Glucosinolate Biosynthesis in Arabidopsis Kliebenstein, Daniel J.; Lambrix, Virginia M.; Reichelt, Michael The Plant Cell, Vol. 13, Issue 3 https://doi.org/10.1105/tpc.13.3.681	journal	March 2001
Molecular cloning and expression in Escherichia coli of an active fused Zea mays L. D-amino acid oxidase Gholizadeh, A.; Kohnehrouz, B. B. Biochemistry (Moscow), Vol. 74, Issue 2 https://doi.org/10.1134/S0006297909020035	journal	February 2009
Exploiting Natural Variation of Secondary Metabolism Identifies a Gene Controlling the Glycosylation Diversity of Dihydroxybenzoic Acids in Arabidopsis thaliana Li, Xu; Svedin, Elisabeth; Mo, Huaping Genetics, Vol. 198, Issue 3 https://doi.org/10.1534/genetics.114.168690	journal	August 2014
Genetics and biochemistry of secondary metabolites in plants: an evolutionary perspective Pichersky, Eran; Gang, David R. Trends in Plant Science, Vol. 5, Issue 10 https://doi.org/10.1016/S1360-1385(00)01741-6	journal	October 2000
Genetic Control of Natural Variation in Arabidopsis Glucosinolate Accumulation Kliebenstein, Daniel J.; Kroymann, Juergen; Brown, Paul Plant Physiology, Vol. 126, Issue 2 https://doi.org/10.1104/pp.126.2.811	journal	June 2001
D-Amino Acids Govern Stationary Phase Cell Wall Remodeling in Bacteria Lam, H.; Oh, D. -C.; Cava, F. Science, Vol. 325, Issue 5947 https://doi.org/10.1126/science.1178123	journal	September 2009
Identification, Purification, and Characterization of a Novel Amino Acid Racemase, Isoleucine 2-Epimerase, from Lactobacillus Species Mutaguchi, Y.; Ohmori, T.; Wakamatsu, T. Journal of Bacteriology, Vol. 195, Issue 22 https://doi.org/10.1128/JB.00709-13	journal	September 2013
A cross-platform toolkit for mass spectrometry and proteomics Chambers, Matthew C.; Maclean, Brendan; Burke, Robert Nature Biotechnology, Vol. 30, Issue 10 https://doi.org/10.1038/nbt.2377	journal	October 2012
Crystal structure of YHI9, the yeast member of the phenazine biosynthesis PhzF enzyme superfamily Liger, Dominique; Quevillon-Cheruel, Sophie; Sorel, Isabelle Proteins: Structure, Function, and Bioinformatics, Vol. 60, Issue 4 https://doi.org/10.1002/prot.20548	journal	July 2005
Cloning and functional characterization of Arabidopsis thaliana d-amino acid aminotransferase - d-aspartate behavior during germination: d-Amino acid aminotransferase in A. thaliana Funakoshi, Miya; Sekine, Masae; Katane, Masumi FEBS Journal, Vol. 275, Issue 6 https://doi.org/10.1111/j.1742-4658.2008.06279.x	journal	March 2008
Occurrence of D-serine in rice and characterization of rice serine racemase Gogami, Yoshitaka; Ito, Katsuyoshi; Kamitani, Yuji Phytochemistry, Vol. 70, Issue 3 https://doi.org/10.1016/j.phytochem.2009.01.003	journal	February 2009
Alanine racemase of alfalfa seedlings (Medicago sativa L.): First evidence for the presence of an amino acid racemase in plants Ono, Kazutoshi; Yanagida, Kazuki; Oikawa, Tadao Phytochemistry, Vol. 67, Issue 9 https://doi.org/10.1016/j.phytochem.2006.02.017	journal	May 2006
MAWBP and MAWD inhibit proliferation and invasion in gastric cancer Li, Dong-Mei World Journal of Gastroenterology, Vol. 19, Issue 18 https://doi.org/10.3748/wjg.v19.i18.2781	journal	January 2013
Crystal structure, catalytic mechanism, and mitogenic properties of Trypanosoma cruzi proline racemase Buschiazzo, A.; Goytia, M.; Schaeffer, F. Proceedings of the National Academy of Sciences, Vol. 103, Issue 6 https://doi.org/10.1073/pnas.0509010103	journal	January 2006
d -Aspartic acid is a novel endogenous neurotransmitter D'Aniello, Salvatore; Somorjai, Ildiko; Garcia-Fernàndez, Jordi The FASEB Journal, Vol. 25, Issue 3 https://doi.org/10.1096/fj.10-168492	journal	March 2011
CAMERA: An Integrated Strategy for Compound Spectra Extraction and Annotation of Liquid Chromatography/Mass Spectrometry Data Sets Kuhl, Carsten; Tautenhahn, Ralf; Böttcher, Christoph Analytical Chemistry, Vol. 84, Issue 1 https://doi.org/10.1021/ac202450g	journal	December 2011
Molecular and Structural Discrimination of Proline Racemase and Hydroxyproline-2-Epimerase from Nosocomial and Bacterial Pathogens Goytia, Maira; Chamond, Nathalie; Cosson, Alain PLoS ONE, Vol. 2, Issue 9 https://doi.org/10.1371/journal.pone.0000885	journal	September 2007
Analyses of Arabidopsis ecotypes reveal metabolic diversity to convert D-amino acids Gördes, Dirk; Koch, Grit; Thurow, Kerstin SpringerPlus, Vol. 2, Issue 1 https://doi.org/10.1186/2193-1801-2-559	journal	January 2013
Crystal Structure of Diaminopimelate Epimerase from Arabidopsis thaliana, an Amino Acid Racemase Critical for l-Lysine Biosynthesis Pillai, Bindu; Moorthie, Vijayalakshmi A.; van Belkum, Marco J. Journal of Molecular Biology, Vol. 385, Issue 2 https://doi.org/10.1016/j.jmb.2008.10.072	journal	January 2009
GWAPP: A Web Application for Genome-Wide Association Mapping in Arabidopsis Seren, Ümit; Vilhjálmsson, Bjarni J.; Horton, Matthew W. The Plant Cell, Vol. 24, Issue 12 https://doi.org/10.1105/tpc.112.108068	journal	December 2012
Glutamate Receptor-Like Genes Form Ca2+ Channels in Pollen Tubes and Are Regulated by Pistil D-Serine Michard, E.; Lima, P. T.; Borges, F. Science, Vol. 332, Issue 6028 https://doi.org/10.1126/science.1201101	journal	March 2011
Emerging knowledge of regulatory roles of d-amino acids in bacteria Cava, Felipe; Lam, Hubert; de Pedro, Miguel A. Cellular and Molecular Life Sciences, Vol. 68, Issue 5 https://doi.org/10.1007/s00018-010-0571-8	journal	December 2010
Serine racemases from barley, Hordeum vulgare L., and other plant species represent a distinct eukaryotic group: Gene cloning and recombinant protein characterization☆ Fujitani, Yoshiyuki; Horiuchi, Terumi; Ito, Kazutoshi Phytochemistry, Vol. 68, Issue 11 https://doi.org/10.1016/j.phytochem.2007.03.040	journal	June 2007
D-amino acids in higher plants Robinson, Trevor Life Sciences, Vol. 19, Issue 8 https://doi.org/10.1016/0024-3205(76)90244-7	journal	October 1976
d-Tryptophan in höheren Pflanzen Zenk, M. H.; Scherf, H. Biochimica et Biophysica Acta, Vol. 71 https://doi.org/10.1016/0006-3002(63)91152-1	journal	January 1963
Whole-genome sequencing of multiple Arabidopsis thaliana populations Cao, Jun; Schneeberger, Korbinian; Ossowski, Stephan Nature Genetics, Vol. 43, Issue 10 https://doi.org/10.1038/ng.911	journal	August 2011
Uptake and conversion of d-amino acids in Arabidopsis thaliana Gördes, Dirk; Kolukisaoglu, Üner; Thurow, Kerstin Amino Acids, Vol. 40, Issue 2 https://doi.org/10.1007/s00726-010-0674-4	journal	July 2010
Molecular and biochemical characterization of a serine racemase from Arabidopsis thaliana☆ Fujitani, Y.; Nakajima, N.; Ishihara, K. Phytochemistry, Vol. 67, Issue 7 https://doi.org/10.1016/j.phytochem.2006.01.003	journal	April 2006
A Gene Controlling Variation in Arabidopsis Glucosinolate Composition Is Part of the Methionine Chain Elongation Pathway Kroymann, J. PLANT PHYSIOLOGY, Vol. 127, Issue 3 https://doi.org/10.1104/pp.127.3.1077	journal	November 2001
The ARABIDOPSIS Accession Pna-10 Is a Naturally Occurring sng1 Deletion Mutant Li, X. u.; Bergelson, Joy; Chapple, Clint Molecular Plant, Vol. 3, Issue 1 https://doi.org/10.1093/mp/ssp090	journal	January 2010
A Gene Controlling Variation in Arabidopsis Glucosinolate Composition Is Part of the Methionine Chain Elongation Pathway Kroymann, Juergen; Textor, Susanne; Tokuhisa, Jim G. Plant Physiology, Vol. 127, Issue 3 https://doi.org/10.1104/pp.010416	journal	November 2001

Cited By (19)

Exploiting natural variation for accelerating discoveries in plant specialized metabolism Wager, Amanda; Li, Xu Phytochemistry Reviews, Vol. 17, Issue 1 https://doi.org/10.1007/s11101-017-9524-2	journal	August 2017
Combined Use of Genome-Wide Association Data and Correlation Networks Unravels Key Regulators of Primary Metabolism in Arabidopsis thaliana Wu, Si; Alseekh, Saleh; Cuadros-Inostroza, Álvaro PLOS Genetics, Vol. 12, Issue 10 https://doi.org/10.1371/journal.pgen.1006363	journal	October 2016
A Guide to Genome-Wide Association Mapping in Plants: Genome-Wide Association Mapping in Plants Burghardt, Liana T.; Young, Nevin D.; Tiffin, Peter Current Protocols in Plant Biology, Vol. 2, Issue 1 https://doi.org/10.1002/cppb.20041	journal	March 2017
PLP-independent racemization: mechanistic and mutational studies of O -ureidoserine racemase (DcsC) Ahn, Yeong-Chan; Fischer, Conrad; van Belkum, Marco J. Organic & Biomolecular Chemistry, Vol. 16, Issue 7 https://doi.org/10.1039/c7ob03013d	journal	January 2018
Metabolic GWAS-based dissection of genetic bases underlying the diversity of plant metabolism Fang, Chuanying; Luo, Jie The Plant Journal, Vol. 97, Issue 1 https://doi.org/10.1111/tpj.14097	journal	November 2018
AraPheno and the AraGWAS Catalog 2020: a major database update including RNA-Seq and knockout mutation data for Arabidopsis thaliana Matteo, Togninalli,; Ümit, Seren,; A., Freudenthal, Jan ETH Zurich https://doi.org/10.3929/ethz-b-000390118	text	January 2020
D-amino acids in nature, agriculture and biomedicine Grishin, D. V.; Zhdanov, D. D.; Pokrovskaya, M. V. All Life, Vol. 13, Issue 1 https://doi.org/10.1080/21553769.2019.1622596	journal	May 2019
AraPheno and the AraGWAS Catalog 2020: a major database update including RNA-Seq and knockout mutation data for Arabidopsis thaliana Togninalli, Matteo; Seren, Ümit; Freudenthal, Jan A. Nucleic Acids Research https://doi.org/10.1093/nar/gkz925	journal	October 2019
Metabolomics for Plant Improvement: Status and Prospects Kumar, Rakesh; Bohra, Abhishek; Pandey, Arun K. Frontiers in Plant Science, Vol. 8 https://doi.org/10.3389/fpls.2017.01302	journal	August 2017
Stimulation of root growth and enhanced nitrogenous metabolite content in habanero pepper (Capsicum chinense Jacq.) treated with a d-amino acid mixture Serralta-Interian, Angélica Anahi; Miranda-Ham, María de Lourdes; Echevarría-Machado, Ileana Theoretical and Experimental Plant Physiology, Vol. 32, Issue 1 https://doi.org/10.1007/s40626-020-00165-y	journal	January 2020
A gene encoding maize caffeoyl-CoA O-methyltransferase confers quantitative resistance to multiple pathogens Yang, Qin; He, Yijian; Kabahuma, Mercy Nature Genetics, Vol. 49, Issue 9 https://doi.org/10.1038/ng.3919	journal	July 2017
Bioprospecting Plant Growth-Promoting Rhizobacteria That Mitigate Drought Stress in Grasses Jochum, Michael D.; McWilliams, Kelsey L.; Borrego, Eli J. Frontiers in Microbiology, Vol. 10 https://doi.org/10.3389/fmicb.2019.02106	journal	September 2019
Discovering variation of secondary metabolite diversity and its relationship with disease resistance in Cornus florida L. Pais, Andrew L.; Li, Xu; Jenny Xiang, Qiu-Yun Ecology and Evolution, Vol. 8, Issue 11 https://doi.org/10.1002/ece3.4090	journal	May 2018
Catalytic mechanism and properties of pyridoxal 5′-phosphate independent racemases: how enzymes alter mismatched acidity and basicity Fischer, Conrad; Ahn, Yeong-Chan; Vederas, John C. Natural Product Reports, Vol. 36, Issue 12 https://doi.org/10.1039/c9np00017h	journal	January 2019
Comprehensive transcriptome analyses correlated with untargeted metabolome reveal differentially expressed pathways in response to cell wall alterations Reem, Nathan T.; Chen, Han-Yi; Hur, Manhoi Plant Molecular Biology, Vol. 96, Issue 4-5 https://doi.org/10.1007/s11103-018-0714-0	journal	March 2018
Ultrahigh resolution metabolomics for S-containing metabolites Nakabayashi, Ryo; Saito, Kazuki Current Opinion in Biotechnology, Vol. 43 https://doi.org/10.1016/j.copbio.2016.07.003	journal	February 2017
Genetic dissection of metabolite variation in Arabidopsis seeds: evidence for mQTL hotspots and a master regulatory locus of seed metabolism Knoch, Dominic; Riewe, David; Meyer, Rhonda Christiane Journal of Experimental Botany, Vol. 68, Issue 7 https://doi.org/10.1093/jxb/erx049	journal	March 2017
AtDAT1 is a key enzyme of D-amino acid stimulated ethylene production in Arabidopsis thaliana Suarez, Juan; Hener, Claudia; Lehnhardt, Vivien-Alisa bioRxiv https://doi.org/10.1101/716373	journal	July 2019
D-Amino Acids in Plants: New Insights and Aspects, but also More Open Questions Kolukisaoglu, Üner; Suarez, Juan Amino Acid - New Insights and Roles in Plant and Animal https://doi.org/10.5772/intechopen.68539	book	June 2017

Similar Records

Genome‐wide association identifies a BAHD acyltransferase activity that assembles an ester of glucuronosylglycerol and phenylacetic acid

Journal Article · Mon Apr 01 00:00:00 EDT 2024 · The Plant Journal · OSTI ID:1348406

Simpson, Jeffrey P.; Kim, Colin Y.; Kaur, Amanpreet; +3 more

Genetic dissection of bioenerrgy traits in sorghum

Technical Report · Fri Jun 15 00:00:00 EDT 2012 · OSTI ID:1348406

Vermerris, Wilfred; Kresovich, Stephen; Murray, Seth; +3 more

SNPeffect: identifying functional roles of SNPs using metabolic networks

Journal Article · Fri Mar 13 00:00:00 EDT 2020 · The Plant Journal · OSTI ID:1348406

Sarkar, Debolina; Maranas, Costas D.

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
d-amino acid
genome-wide association
natural variation
racemase
secondary metabolism

Title: Discovery of a novel amino acid racemase through exploration of natural variation in Arabidopsis thaliana

Citation Formats

References (46)

Cited By (19)

Similar Records

Related Subjects