Recent Publications
2022
MF Roberts, and L Hedstrom. High Resolution 31P Field Cycling NMR Reveals Unsuspected Features of Enzyme-Substrate-Cofactor Dynamics. Front. Mol. Biosci. https://doi.org/10.3389/fmolb.2022.865519
DW Wolff, Z Deng, A Bianchi-Smiraglia, CE Foley, Z Han, X Wang, S Shen, MM Rosenberg, S Moparthy, DH Yun, J Chen, BK Baker, MV Roll, AJ Magiera, J Li, E Hurley, ML Feltri, AO Cox, J Lee, CM Furdui, L Liu, W Bshara, LEW LaConte, ES Kandel, EB Pasquale, J Qu, L Hedstrom and MA Nikiforov. Phosphorylation of guanosine monophosphate reductase triggers a GTP-dependent switch from pro- to anti-oncogenic function of EPHA4. Cell Chem. Biol., in press (2022).
MJ Pepi, S Chacko, GM Marqus, V Singh, Z Wang, K Planck, RT Cullinane, PN Meka, DR Gollapalli, TR Ioerger, KY Rhee, GD Cuny, HIM Boshoff and L Hedstrom. A D-Phenylalanine-Benzoxazole Derivative Reveals the Role of the Essential Enzyme Rv3603c in the Pantothenate Biosynthetic Pathway of Mycobacterium tuberculosis. ACS Infect. Dis. 8, 330-342 (2022).
2021
G Modi, GM Marqus, MR Vippila, DR Gollapalli, Y Kim, AC Manna, S Chacko, N Maltseva, X Wang, RT Cullinane, Y Zhang, JLM Kotler, P Kuzmic, M Zhang, AP Lawson, A Joachimiak, A Cheung, BB Snider, DM Rothstein, GD Cuny, and L Hedstrom. The enzymatic activity of inosine 5’-monophosphate dehydrogenase may not be a vulnerable target for Staphylococcus aureus infections. ACS Infect. Dis. 7, 3062-3076 (2021).
2020
MM Rosenberg, TYao, GC Patton, AG Redfield, MF Roberts, and L Hedstrom. Enzyme-substrate-cofactor dynamical networks revealed by high resolution field cycling relaxometry. Biochemistry in press.
R Freedman, R Yu, A Sarkis and L Hedstrom. A structural determinant of mycophenolic acid resistance in eukaryotic inosine 5’-monophosphate dehydrogenases. Protein Science 29, 686-694 (2020).
E Sommerville, ID Rosa, MM Rosenberg, F Bruni, K Thompson, M Rocha, EL Blakely, L He, G Falkous, AM Schaefer, P Yu-Wai-Man, PF Chinnery, L Hedstrom, A Spinazzola, Antonella; RW Taylor and GS Gorman. Identification of a novel heterozygous guanosine monophosphate reductase (GMPR) variant in a patient with a late-onset disorder of mitochondrial DNA maintenance. Clinical Genetics 97, 276-286 (2020).
2019
MC Pawlowic, M Somepalli, A Sateriale,GT Herbert,A Gibson GD Cuny, L Hedstrom, and B Striepen. Genetic ablation of purine salvage in Cryptosporidium parvum reveals nucleotide uptake from the host cell. Proc. Natl. Acad. Sci USA, 116, 21160-21165 (2019).
DM Close, CJ Cooper, X Wang, P Chirania, M Gupta, JR Ossyra, RJ Giannone, N Engle, TJ Tschaplinski, JC Smith,L Hedstrom, JM Parks, and JK Michener. Horizontal transfer of a pathway for coumarate catabolism unexpectedly inhibits purine nucleotide biosynthesis. Mol. Micro. 112, 1784-1797 (2019).
R Yu, Y Kim, N Maltseva, P Braunstein, A Joachimiak and L Hedstrom. Oxanosine monophosphate is a covalent inhibitor of inosine 5’-monophosphate dehydrogenase. Chem. Res. Toxicol. 32, 456-466 (2019). pdf
MJC Long, AP Lawson, R Baggio, Y Qian, L Rozhansky,D Fasci, F El Oualid, E Weerapana, and L Hedstrom. Diarylcarbonates are a new class of deubiquitinating enzyme inhibitor. Bioorg. Med. Chem. Lett. 29: 204-211 (2018). pdf
2018
A Kaushansky, L Hedstrom, A Goldman, J Singh, PL Yang, PK Rathod, M Cynamon, D Wodarz, D Mahadevan,A Tomaras, MA Navia, CA Schiffer, A call to arms: Unifying the fight against resistance. Sci Signal. 11, eaav0442 (2018).
ML Reytor González, M Alonso-del-Rivero Antigua, L Hedstrom, P Kuzmič and JR Pires. Sabellastarte magnifica carboxypetidase inhibitor: the first Kunitz inhibitor simultaneously interacting with carboxypeptidases and serine proteases. Biochimie 50:37-47 (2018).
S Chacko, HIM Boshoff, V Singh, DM Ferraris, DR Gollapalli, M Zhang, AP Lawson, A Joachimiak, M Rizzi,V Mizrahi, GD Cuny, Gregory D.; and L Hedstrom. Expanding benzoxazole based inosine 5’-monophosphate dehydrogenase (IMPDH) inhibitor structure-activity as potential anti-tuberculosis agents. J. Med. Chem. 61, 4739-4756 (2018).
MM Rosenberg, AG Redfield, MF Roberts and L Hedstrom. Dynamic characteristics of GMP reductase complexes revealed by high resolution 31P field cycling NMR relaxometry. Biochemistry 57, 3146-3154 (2018).
2017
B Krishnan, L Hedstrom, DN Hebert, LM Gierasch and A Gershenson. Expression and purification of active recombinant human alpha-1 antitrypsin (AAT) from Escherichia coli. Alpha-1 antitrypsin Deficiency, Methods in Mol. Biol. 1639, 195-209 (2017).
SK Gorla, Y Zhang, MM Rabideau, A Qin, S Chacko, AL House, CR Johnson, K Mandapati, HM Bernstein,* ES McKenney, H Boshoff, M Zhang, IJ Glomski, JB Goldberg, GD Cuny, BJ Mann, and L Hedstrom. Benzoxazoles, phthalazinones, and arylurea-based compounds with IMPDH-independent antibacterial activity against Francisella tularensis. Antimicrob. Agents Chemother. 61, e00939-17 (2017).
G Modi, S Chacko and L Hedstrom. Targeting purine biosynthesis for antibacterial drug design. Chapter 2 in “Antibiotic Drug Discovery: New Targets and Molecular Entities”. edited by Steven M. Firestine and Troy Lister. Drug Discovery Series No. 58, Royal Society of Chemistry, p 20-42 (2017).
AP Lawson, DW Bak, DA Shannon, MJC Long, T Vijaykumar, R Yu, F El Oualid, E Weerapana, Eranthie and L Hedstrom. Identification of deubiquitinase targets of isothiocyanates using SILAC-assisted quantitative mass spectrometry. Oncotarget 8, 51296-51316 (2017). PMC5584250
S Zhang, KE Burns-Huang, GV Janssen, H Li, E Weber-Ban, H Ovaa, L Hedstrom and K Darwin. Mycobacterium tuberculosis proteasome accessory factor A (PafA) can transfer prokaryotic ubiquitin-like protein (Pup) between substrates. MBio 8, e00122-17 (2017). PMC5358908
L Hedstrom. The bare essentials of antibiotic target validation. ACS Infect Dis. 3, 2-4 (2017). PMC5520969
2016
Y Shi, MJC Long, MM Rosenberg, S Li, A Kobjack, P Lessans, Philip; RT Coffey and L Hedstrom. Boc3Arg-linked ligands induce degradation by localizing target proteins to the 20S proteasome. ACS Chemical Biology 11, 3328-3337 (2016). PMC5524191
Y Wei, P Kuzmič, R Yu, G Modi and L Hedstrom. Inhibition of IMPDH from Bacillus anthracis: mechanism revealed by pre-steady state kinetics. Biochemistry 55, 5279-88 (2016). PMC5524190
MM Rosenberg, AG Redfield, MF Roberts and L Hedstrom. Substrate and cofactor dynamics on guanosine monophosphate reductase probed by high resolution field cycling 31P NMR relaxometry. J. Biol. Chem. 291, 22988-22998 (2016). PMC5087720
RT Coffey, Y Shi, MJC Long, MT Marr II and L Hedstrom. Ubiquilin Mediated Small Molecule Inhibition of Mammalian Target of Rapamycin Complex 1 (mTORC1) Signaling. J. Biol. Chem. 291, 5221-33 (2016). PMC4777855
2015
AP Lawson, MJC Long, RT Coffey, Y Qian, E Weerapana, F El Oualid and L Hedstrom. Naturally occurring isothiocyanates inhibit deubiquitinating enzymes. Cancer Research 75, 5130-5142 (2015). PMC4668232
M Makowska-Grzyska, Y Kim, SK Gorla, Y Wei, K Mandapati, M Zhang, N Maltseva, G Modi, HI Boshoff, M Gu, C Aldrich, GD Cuny, L Hedstrom and A Joachimiak. Mycobacterium tuberculosis IMPDH in complexes with substrates, products and antitubercular compounds. PLoS ONE 10, e0138976 (2015). PMC4594927
L Hedstrom. Cryptosporidium: a first step toward tractability. Trends in Parasitology 31, 401-2 (2015). PMC4568825
Y Kim, M Makowska-Grzyska, SK Gorla, DR Gollapalli, GD Cuny, A Joachimiak and L Hedstrom. Structure of Cryptosporidium IMP dehydrogenase bound to an inhibitor with in vivo antiparasitic activity. Acta Crystallogr. F Struct. Biol. Commun. 71, 531-538 (2015). PMC4427161
M Makowska-Grzyska , Y Kim, N Maltseva, J Osipiuk, M Gu, M Zhang, K Mandapati, DR Gollapalli, SK Gorla, L Hedstrom and A Joachimiak. A novel cofactor binding mode in bacterial IMP dehydrogenases explains inhibitor selectivity. J. Biol. Chem. 290, 5893-911 (2015). PMC4342496
Z Sun, J Khan,M Makowska-Grzyska, M Zhang, JH Cho, C Suebsuwong, P Vo, DR Gollapalli, Y Kim, A Joachimiak, L Hedstrom and GD Cuny. Synthesis, in vitro evaluation and co-crystal structure of 4-oxo-[1]benzopyrano[4,3-c]pyrazole Cryptosporidium parvum inosine 5′-monophosphate dehydrogenase (CpIMPDH) inhibitors. J. Med. Chem. 57, 10544-10550 (2015). PMC4281095
2014
J Wang, X Han, CCL Wong, H Cheng, A Aslanian, T Xu, P Leavis, H Roder, L Hedstrom, JR Yates, III, and A Kashina. Arginylation of intact proteins in vivo involves a novel type of Arg linkage to amino acid side chains. Nat. Chem. Biol, 21, 331-7 (2014). abstract
SK Gorla, NN McNair, G Yang, S Gao, M Hu, VR Jala, B Haribabu, B Striepen, GD Cuny, JR Mead and L Hedstrom. Validation of IMP dehydrogenase inhibitors in a mouse model of cryptosporidiosis. Antimicrob. Agents Chemother. 58, 1603-14 (2014). abstract
2013
SK Gorla, M Kavitha, M Zhang , JEW Chin*, X Liu, B Striepen, M Makowska-Grzyska, Y Kim, A Joachimiak, L Hedstrom and GD Cuny. Optimization of benzoxazole-based inhibitors of Cryptosporidium parvum inosine 5’-monophosphate dehydrogenase. J. Med. Chem. 56, 4028-43 (2013). abstract
CR Johnson, SK Gorla, M Kavitha, M Zhang, X Liu, B Striepen, JR Mead, GD Cuny and L Hedstrom. Phthalazinone inhibitors of inosine-5’-monophosphate dehydrogenase from Cryptosporidium parvum. Biorg. Med. Chem. Lett. 23, 1004-7 (2013). abstract
2012
MJC Long, DR Gollapalli and L Hedstrom. Inhibitor Mediated Protein Degradation. Chemistry & Biology 19, 629-37 (2012). Nature News & Views, abstract
SK Gorla, M Kavitha, M Zhang, X Liu, L Sharling, DR Gollapalli, B Striepen, L Hedstrom and GD Cuny. Selective and potent urea inhibitors of Cryptosporidium parvum inosine 5’-monophosphate dehydrogenase. J. Med. Chem. 55, 7759-71 (2012). abstract
Makowska-Grzyska, M.; Kim, Y.; W., R.; Wilton, R.; Gollapalli, D.R.; *Wang, X.K.; Zhang, R.; Jedrzejczak, R.; Mack, J.C.; Maltseva, N.; Mulligan, R.; Binkowski, T.A; Gornicki, P.; Kuhn, M.; Anderson, W.F.; Hedstrom, L and Joachimiak, A. Bacillus anthracis IMP dehydrogenase in action: structures of apoenzyme and in complex with substrate and product. Biochemistry 51, 6148-63 (2012). abstract
Y Gao, MJC Long, J Shi, L Hedstrom and B Xu. Using supramolecular hydrogel to discover the interactions between proteins and molecular nanofibers of small molecules. Chem. Commun. (Camb) 48, 8404-6 (2012). abstract
MJC Long and L Hedstrom. Mushroom tyrosinase oxidizes tyrosine-rich sequences, allowing selective protein functionalization. ChemBiochem 13, 1818-25 (2012). abstract
L. Hedstrom. The dynamic determinants of reaction specificity in the IMPDH/GMPR family of (β/α)8 barrel enzymes. Critical Reviews In Biochemistry & Molecular Biology 47, 250-63 (2012). abstract
S Kirubakaran, SK Gorla, L Sharling, M Zhang, X Liu, SS Ray, IS MacPherson, B Striepen, L Hedstrom and GD Cuny. Structure-activity relationship study of selective benzimidazole-based inhibitors of Cryptosporidium parvum IMPDH. Bioorg Med Chem Lett. 22, 1985-8 (2012). abstract
*indicates undergraduate author