Structural insights into binding of polyglutamylated tetrahydrofolate by serine hydroxymethyltransferase 8 from soybean

Owuocha, Luckio F.; Mitchum, Melissa G.; Beamer, Lesa J.

doi:10.3389/fpls.2024.1451839

Structural insights into binding of polyglutamylated tetrahydrofolate by serine hydroxymethyltransferase 8 from soybean

Journal Article · Sun Aug 18 00:00:00 EDT 2024 · Frontiers in Plant Science

DOI:https://doi.org/10.3389/fpls.2024.1451839· OSTI ID:2471063

Owuocha, Luckio F. ^[1]; Mitchum, Melissa G. ^[2]; Beamer, Lesa J. ^[1]

University of Missouri, Columbia, MO (United States)
University of Georgia, Athens, GA (United States)

Tetrahydrofolate and its derivatives participate in one-carbon transfer reactions in all organisms. The cellular form of tetrahydrofolate (THF) is modified by multiple glutamate residues and polyglutamylation plays a key role in organellar and cellular folate homeostasis. In addition, polyglutamylation of THF is known to increase the binding affinity to enzymes in the folate cycle, many of which can utilize polyglutamylated THF as a substrate. Here, we use X-ray crystallography to provide a high-resolution view of interactions between the enzyme serine hydroxymethyltransferase (SHMT), which provides one carbon precursors for the folate cycle, and a polyglutamylated form of THF. Our 1.7 Å crystal structure of soybean SHMT8 in complex with diglutamylated 5-formyl-THF reveals, for the first time, a structural rearrangement of a loop at the entrance to the folate binding site accompanied by the formation of novel specific interactions between the enzyme and the diglutamyl tail of the ligand. Biochemical assays show that additional glutamate moieties on the folate ligand increase both enzyme stability and binding affinity. Together these studies provide new information on SHMT structure and function and inform the design of anti-folate agents.

View Accepted Manuscript (DOE)

Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States). Advanced Light Source (ALS)

Sponsoring Organization:: National Institutes of Health (NIH); National Science Foundation (NSF); USDA; USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities (SUF)

Grant/Contract Number:: AC02-05CH11231

OSTI ID:: 2471063

Journal Information:: Frontiers in Plant Science, Journal Name: Frontiers in Plant Science Vol. 15; ISSN 1664-462X

Publisher:: Frontiers Research FoundationCopyright Statement

Country of Publication:: United States

Language:: English

References (48)

Potent Inhibitors of Plasmodial Serine Hydroxymethyltransferase (SHMT) Featuring a Spirocyclic Scaffold Schwertz, Geoffrey; Witschel, Matthias C.; Rottmann, Matthias ChemMedChem, Vol. 13, Issue 9 https://doi.org/10.1002/cmdc.201800053	journal	April 2018
Looking for protein stabilizing drugs with thermal shift assay: Thermal shift assay for pharmacological chaperones Andreotti, Giuseppina; Monticelli, Maria; Cubellis, Maria Vittoria Drug Testing and Analysis, Vol. 7, Issue 9 https://doi.org/10.1002/dta.1798	journal	April 2015
Improvements to the APBS biomolecular solvation software suite: Improvements to the APBS Software Suite Jurrus, Elizabeth; Engel, Dave; Star, Keith Protein Science, Vol. 27, Issue 1 https://doi.org/10.1002/pro.3280	journal	October 2017
UCSF ChimeraX: Tools for structure building and analysis Meng, Elaine C.; Goddard, Thomas D.; Pettersen, Eric F. Protein Science, Vol. 32, Issue 11 https://doi.org/10.1002/pro.4792	journal	October 2023
Crystal structure at 2.4 Å resolution of E. coli serine hydroxymethyltransferase in complex with glycine substrate and 5-formyl tetrahydrofolate 1 1Edited by I. A. Wilson Scarsdale, J. Neel; Radaev, S.; Kazanina, G. Journal of Molecular Biology, Vol. 296, Issue 1 https://doi.org/10.1006/jmbi.1999.3453	journal	February 2000
C-h⋯π-interactions in proteins Brandl, Maria; Weiss, Manfred S.; Jabs, Andreas Journal of Molecular Biology, Vol. 307, Issue 1 https://doi.org/10.1006/jmbi.2000.4473	journal	March 2001
Enzymatic synthesis and function of folylpolyglutamates McGuire, John J.; Bertino, Joseph R. Molecular and Cellular Biochemistry, Vol. 38, Issue 1 https://doi.org/10.1007/BF00235686	journal	January 1981
Interaction of folylpolyglutamates with enzymes in one-carbon metabolism Schirch, Verne; Strong, William B. Archives of Biochemistry and Biophysics, Vol. 269, Issue 2 https://doi.org/10.1016/0003-9861(89)90120-3	journal	March 1989
Graphical determination of the dissociation constants for two-substrate enzyme systems Florini, James R.; Vestling, Carl S. Biochimica et Biophysica Acta, Vol. 25 https://doi.org/10.1016/0006-3002(57)90529-2	journal	January 1957
Folate polyglutamylation eliminates dependence of activity on enzyme concentration in mitochondrial serine hydroxymethyltransferases from Arabidopsis thaliana Wei, Zhaoyang; Sun, Kehan; Sandoval, Francisco J. Archives of Biochemistry and Biophysics, Vol. 536, Issue 1 https://doi.org/10.1016/j.abb.2013.06.004	journal	August 2013
Mangiferin is a new potential antimalarial and anticancer drug for targeting serine hydroxymethyltransferase Maenpuen, Somchart; Mee-udorn, Pitchayathida; Pinthong, Chatchadaporn Archives of Biochemistry and Biophysics, Vol. 745 https://doi.org/10.1016/j.abb.2023.109712	journal	September 2023
Mechanisms of folate metabolism-related substances affecting Staphylococcus aureus infection Jin, Qiyuan; Xie, Xiaolu; Zhai, Yaxuan International Journal of Medical Microbiology, Vol. 313, Issue 2 https://doi.org/10.1016/j.ijmm.2023.151577	journal	March 2023
The complexity of folate polyglutamylation in plants: Postharvest ripening and ethylene modulate polyglutamylated profiles in climacteric fruits plus systematic analysis of the glutamyl tail-editing enzymes Garza-Aguilar, Sara M.; García-Salinas, Carolina; Mejía-Ponce, Paulina M. Scientia Horticulturae, Vol. 273 https://doi.org/10.1016/j.scienta.2020.109588	journal	November 2020
Validation of Structures in the Protein Data Bank Gore, Swanand; Sanz García, Eduardo; Hendrickx, Pieter M. S. Structure, Vol. 25, Issue 12 https://doi.org/10.1016/j.str.2017.10.009	journal	December 2017
Structural Characterization of 5-Substituted Pyrrolo[3,2-d]pyrimidine Antifolate Inhibitors in Complex with Human Serine Hydroxymethyl Transferase 2 Katinas, Jade M.; Nayeen, Md. Junayed; Schneider, Mathew Biochemistry https://doi.org/10.1021/acs.biochem.3c00613	journal	February 2024
Antimalarial Inhibitors Targeting Serine Hydroxymethyltransferase (SHMT) with in Vivo Efficacy and Analysis of their Binding Mode Based on X-ray Cocrystal Structures Schwertz, Geoffrey; Witschel, Matthias C.; Rottmann, Matthias Journal of Medicinal Chemistry, Vol. 60, Issue 12 https://doi.org/10.1021/acs.jmedchem.7b00008	journal	June 2017
A Review of Small-Molecule Inhibitors of One-Carbon Enzymes: SHMT2 and MTHFD2 in the Spotlight Cuthbertson, Christine R.; Arabzada, Zahra; Bankhead, Armand ACS Pharmacology & Translational Science, Vol. 4, Issue 2 https://doi.org/10.1021/acsptsci.0c00223	journal	March 2021
Interaction of tetrahydropteroylpolyglutamates with two enzymes from mitochondria Strong, William B.; Cook, Robert; Schirch, Verne Biochemistry, Vol. 28, Issue 1 https://doi.org/10.1021/bi00427a016	journal	January 1989
In vitro conversion of formate to serine: effect of tetrahydropteroylpolyglutamates and serine hydroxymethyltransferase on the rate of 10-formyltetrahydrofolate synthetase Strong, William B.; Schirch, Verne Biochemistry, Vol. 28, Issue 24 https://doi.org/10.1021/bi00450a028	journal	November 1989
Interactions of pig liver serine hydroxymethyltransferase with methyl tetrahydropteroylpolyglutamate inhibitors and with tetrahydropteroylpolyglutamate substrates Matthews, Rowena G.; Ross, Jonathan; Baugh, Charles M. Biochemistry, Vol. 21, Issue 6 https://doi.org/10.1021/bi00535a019	journal	March 1982
Serine Transhydroxymethylase. Affinity of Tetrahydrofolate Compounds for the Enzyme and Enzyme-Glycine Complex ^* Schirch, LaVerne; Ropp, Marjorie Biochemistry, Vol. 6, Issue 1 https://doi.org/10.1021/bi00853a039	journal	January 1967
Thermodynamic Analysis of the Binding of the Polyglutamate Chain of 5-Formyltetrahydropteroylpolyglutamates to Serine Hydroxymethyltransferase Huang, Teng; Wang, Changqing; Maras, Bruno Biochemistry, Vol. 37, Issue 39 https://doi.org/10.1021/bi980827u	journal	September 1998
Inhibitors of Plasmodial Serine Hydroxymethyltransferase (SHMT): Cocrystal Structures of Pyrazolopyrans with Potent Blood- and Liver-Stage Activities Witschel, Matthias C.; Rottmann, Matthias; Schwab, Anatol Journal of Medicinal Chemistry, Vol. 58, Issue 7 https://doi.org/10.1021/jm501987h	journal	March 2015
A soybean cyst nematode resistance gene points to a new mechanism of plant resistance to pathogens Liu, Shiming; Kandoth, Pramod K.; Warren, Samantha D. Nature, Vol. 492, Issue 7428 https://doi.org/10.1038/nature11651	journal	October 2012
The soybean GmSNAP18 gene underlies two types of resistance to soybean cyst nematode Liu, Shiming; Kandoth, Pramod K.; Lakhssassi, Naoufal Nature Communications, Vol. 8, Issue 1 https://doi.org/10.1038/ncomms14822	journal	March 2017
Folate metabolism: a re-emerging therapeutic target in haematological cancers Zarou, Martha M.; Vazquez, Alexei; Vignir Helgason, G. Leukemia, Vol. 35, Issue 6 https://doi.org/10.1038/s41375-021-01189-2	journal	March 2021
Structural basis of methotrexate and pemetrexed action on serine hydroxymethyltransferases revealed using plant models Ruszkowski, Milosz; Sekula, Bartosz; Ruszkowska, Agnieszka Scientific Reports, Vol. 9, Issue 1 https://doi.org/10.1038/s41598-019-56043-4	journal	December 2019
Serine hydroxymethyltransferase as a potential target of antibacterial agents acting synergistically with one-carbon metabolism-related inhibitors Makino, Yuko; Oe, Chihiro; Iwama, Kazuya Communications Biology, Vol. 5, Issue 1 https://doi.org/10.1038/s42003-022-03555-x	journal	June 2022
Interaction between glycine decarboxylase, serine hydroxymethyltransferase and tetrahydrofolate polyglutamates in pea leaf mitochondria Rebeille, F.; Neuburger, M.; Douce, R. Biochemical Journal, Vol. 302, Issue 1 https://doi.org/10.1042/bj3020223	journal	August 1994
The Affinity of Pyridoxal 5′-Phosphate for Folding Intermediates of Escherichia coli Serine Hydroxymethyltransferase Cai, Kang; Schirch, Douglas; Schirch, Verne Journal of Biological Chemistry, Vol. 270, Issue 33 https://doi.org/10.1074/jbc.270.33.19294	journal	August 1995
Polyglutamylation of Folate Coenzymes Is Necessary for Methionine Biosynthesis and Maintenance of Intact Mitochondrial Genome in Saccharomyces cerevisiae Cherest, Hélène; Thomas, Dominique; Surdin-Kerjan, Yolande Journal of Biological Chemistry, Vol. 275, Issue 19 https://doi.org/10.1074/jbc.275.19.14056	journal	May 2000
Location of the Pteroylpolyglutamate-binding Site on Rabbit Cytosolic Serine Hydroxymethyltransferase Fu, Tzu-Fun; Scarsdale, J. Neel; Kazanina, Galina Journal of Biological Chemistry, Vol. 278, Issue 4 https://doi.org/10.1074/jbc.M210649200	journal	November 2002
Plant γ-Glutamyl Hydrolases and Folate Polyglutamates: CHARACTERIZATION, COMPARTMENTATION, AND CO-OCCURRENCE IN VACUOLES Orsomando, Giuseppe; de la Garza, Rocío Díaz; Green, Brian J. Journal of Biological Chemistry, Vol. 280, Issue 32 https://doi.org/10.1074/jbc.M504306200	journal	June 2005
Impaired folate binding of serine hydroxymethyltransferase 8 from soybean underlies resistance to the soybean cyst nematode Korasick, David A.; Kandoth, Pramod K.; Tanner, John J. Journal of Biological Chemistry, Vol. 295, Issue 11 https://doi.org/10.1074/jbc.RA119.012256	journal	March 2020
Folate Polyglutamylation Is Involved in Chromatin Silencing by Maintaining Global DNA Methylation and Histone H3K9 Dimethylation in Arabidopsis Zhou, H. -R.; Zhang, F. -F.; Ma, Z. -Y. The Plant Cell, Vol. 25, Issue 7 https://doi.org/10.1105/tpc.113.114678	journal	July 2013
Coot model-building tools for molecular graphics Emsley, Paul; Cowtan, Kevin Acta Crystallographica Section D Biological Crystallography, Vol. 60, Issue 12, p. 2126-2132 https://doi.org/10.1107/S0907444904019158	journal	November 2004
MolProbity : all-atom structure validation for macromolecular crystallography Chen, Vincent B.; Arendall, W. Bryan; Headd, Jeffrey J. Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 1 https://doi.org/10.1107/S0907444909042073	journal	December 2009
XDS Kabsch, Wolfgang Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2 https://doi.org/10.1107/S0907444909047337	journal	January 2010
PHENIX: a comprehensive Python-based system for macromolecular structure solution Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2, p. 213-221 https://doi.org/10.1107/S0907444909052925	journal	January 2010
Overview of the CCP 4 suite and current developments Winn, Martyn D.; Ballard, Charles C.; Cowtan, Kevin D. Acta Crystallographica Section D Biological Crystallography, Vol. 67, Issue 4 https://doi.org/10.1107/S0907444910045749	journal	March 2011
Towards automated crystallographic structure refinement with phenix.refine Afonine, Pavel V.; Grosse-Kunstleve, Ralf W.; Echols, Nathaniel Acta Crystallographica Section D Biological Crystallography, Vol. 68, Issue 4 https://doi.org/10.1107/S0907444912001308	journal	March 2012
How good are my data and what is the resolution? Evans, Philip R.; Murshudov, Garib N. Acta Crystallographica Section D Biological Crystallography, Vol. 69, Issue 7 https://doi.org/10.1107/S0907444913000061	journal	June 2013
Polder maps: improving OMIT maps by excluding bulk solvent Liebschner, Dorothee; Afonine, Pavel V.; Moriarty, Nigel W. Acta Crystallographica Section D Structural Biology, Vol. 73, Issue 2, p. 148-157 https://doi.org/10.1107/S2059798316018210	journal	February 2017
Structural and functional analysis of two SHMT8 variants associated with soybean cyst nematode resistance Korasick, David A.; Owuocha, Luckio F.; Kandoth, Pramod K. The FEBS Journal, Vol. 291, Issue 2 https://doi.org/10.1111/febs.16971	journal	October 2023
Folate Biosynthesis, Reduction, and Polyglutamylation and the Interconversion of Folate Derivatives Green, Jacalyn M.; Matthews, Rowena G. EcoSal Plus, Vol. 2, Issue 2 https://doi.org/10.1128/ecosalplus.3.6.3.6	journal	December 2007
SHMT as a Potential Therapeutic Target for Renal Cell Carcinoma Situ, Yongli; Zhang, Juying; Liao, Wenyu Frontiers in Bioscience-Landmark, Vol. 28, Issue 9 https://doi.org/10.31083/j.fbl2809196	journal	September 2023
Chloroplastic Serine Hydroxymethyltransferase From Medicago truncatula: A Structural Characterization Ruszkowski, Milosz; Sekula, Bartosz; Ruszkowska, Agnieszka Frontiers in Plant Science, Vol. 9 https://doi.org/10.3389/fpls.2018.00584	journal	May 2018
Functional Identification of Serine Hydroxymethyltransferase as a Key Gene Involved in Lysostaphin Resistance and Virulence Potential of Staphylococcus aureus Strains Batool, Nayab; Ko, Kwan Soo; Chaurasia, Akhilesh Kumar International Journal of Molecular Sciences, Vol. 21, Issue 23 https://doi.org/10.3390/ijms21239135	journal	November 2020

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59 BASIC BIOLOGICAL SCIENCES
X-ray crystallography
crystal structure
enzyme
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plant sciences
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structural biology
structure-function

Structural insights into binding of polyglutamylated tetrahydrofolate by serine hydroxymethyltransferase 8 from soybean

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References (48)

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