Bio

Professional Education


  • Bachelor of Science, University of Toronto (2011)
  • Doctor of Philosophy, Harvard University (2017)

Research & Scholarship

Lab Affiliations


Publications

All Publications


  • Structure-Based Evolution of Low Nanomolar O-GlcNAc Transferase Inhibitors. Journal of the American Chemical Society Martin, S. E., Tan, Z., Itkonen, H. M., Duveau, D. Y., Paulo, J. A., Janetzko, J., Boutz, P. L., Tork, L., Moss, F. A., Thomas, C. J., Gygi, S. P., Lazarus, M. B., Walker, S. 2018

    Abstract

    Reversible glycosylation of nuclear and cytoplasmic proteins is an important regulatory mechanism across metazoans. One enzyme, O-linked N-acetylglucosamine transferase (OGT), is responsible for all nucleocytoplasmic glycosylation and there is a well-known need for potent, cell-permeable inhibitors to interrogate OGT function. Here we report the structure-based evolution of OGT inhibitors culminating in compounds with low nanomolar inhibitory potency and on-target cellular activity. In addition to disclosing useful OGT inhibitors, the structures we report provide insight into how to inhibit glycosyltransferases, a family of enzymes that has been notoriously refractory to inhibitor development.

    View details for DOI 10.1021/jacs.8b07328

    View details for PubMedID 30285435

  • Aspartate Glycosylation Triggers Isomerization to Isoaspartate JOURNAL OF THE AMERICAN CHEMICAL SOCIETY Janetzko, J., Walker, S. 2017; 139 (9): 3332-3335

    Abstract

    O-Linked ?-N-acetylglucosamine transferase (OGT) is an essential human enzyme that glycosylates numerous nuclear and cytoplasmic proteins on serine and threonine. It also cleaves Host cell factor 1 (HCF-1) by a mechanism in which the first step involves glycosylation on glutamate. Replacing glutamate with aspartate in an HCF-1 proteolytic repeat was shown to prevent peptide backbone cleavage, but whether aspartate glycosylation occurred was not examined. We report here that OGT glycosylates aspartate much faster than it glycosylates glutamate in an otherwise identical model peptide substrate; moreover, once formed, the glycosyl aspartate reacts further to form a succinimide intermediate that hydrolyzes to produce the corresponding isoaspartyl peptide. Aspartate-to-isoaspartate isomerization in proteins occurs in cells but was previously thought to be exclusively non-enzymatic. Our findings suggest it may also be enzyme-catalyzed. In addition to OGT, enzymes that may catalyze aspartate to isoaspartate isomerization include PARPs, enzymes known to ribosylate aspartate residues in the process of poly(ADP-ribosyl)ation.

    View details for DOI 10.1021/jacs.6b12866

    View details for Web of Science ID 000396185700007

    View details for PubMedID 28207246

    View details for PubMedCentralID PMC5431074

  • How the glycosyltransferase OGT catalyzes amide bond cleavage NATURE CHEMICAL BIOLOGY Janetzko, J., Trauger, S. A., Lazarus, M. B., Walker, S. 2016; 12 (11): 899-?

    Abstract

    The essential human enzyme O-linked ?-N-acetylglucosamine transferase (OGT), known for modulating the functions of nuclear and cytoplasmic proteins through serine and threonine glycosylation, was unexpectedly implicated in the proteolytic maturation of the cell cycle regulator host cell factor-1 (HCF-1). Here we show that HCF-1 cleavage occurs via glycosylation of a glutamate side chain followed by on-enzyme formation of an internal pyroglutamate, which undergoes spontaneous backbone hydrolysis.

    View details for DOI 10.1038/NCHEMBIO.2173

    View details for Web of Science ID 000386798800007

    View details for PubMedID 27618188

    View details for PubMedCentralID PMC5172607

  • Development and Characterization of Potent Cyclic Acyldepsipeptide Analogues with Increased Antimicrobial Activity JOURNAL OF MEDICINAL CHEMISTRY Goodreid, J. D., Janetzko, J., Maria, J. P., Wong, K. S., Leung, E., Eger, B. T., Bryson, S., Pai, E. F., Gray-Owen, S. D., Walker, S., Houry, W. A., Batey, R. A. 2016; 59 (2): 624-646

    Abstract

    The problem of antibiotic resistance has prompted the search for new antibiotics with novel mechanisms of action. Analogues of the A54556 cyclic acyldepsipeptides (ADEPs) represent an attractive class of antimicrobial agents that act through dysregulation of caseinolytic protease (ClpP). Previous studies have shown that ADEPs are active against Gram-positive bacteria (e.g., MRSA, VRE, PRSP (penicillin-resistant Streptococcus pneumoniae)); however, there are currently few studies examining Gram-negative bacteria. In this study, the synthesis and biological evaluation of 14 novel ADEPs against a variety of pathogenic Gram-negative and Gram-positive organisms is outlined. Optimization of the macrocyclic core residues and N-acyl side chain culminated in the development of 26, which shows potent activity against the Gram-negative species Neisseria meningitidis and Neisseria gonorrheae and improved activity against the Gram-positive organisms Staphylococcus aureus and Enterococcus faecalis in comparison with known analogues. In addition, the co-crystal structure of an ADEP-ClpP complex derived from N. meningitidis was solved.

    View details for DOI 10.1021/acs.jmedchem.5b01451

    View details for Web of Science ID 000369115700010

    View details for PubMedID 26818454

  • A Small Molecule That Inhibits OGT Activity in Cells ACS CHEMICAL BIOLOGY Ortiz-Meoz, R. F., Jiang, J., Lazarus, M. B., Orman, M., Janetzko, J., Fan, C., Duveau, D. Y., Tan, Z., Thomas, C. J., Walker, S. 2015; 10 (6): 1392-1397

    Abstract

    O-GlcNAc transferase (OGT) is an essential mammalian enzyme that regulates numerous cellular processes through the attachment of O-linked N-acetylglucosamine (O-GlcNAc) residues to nuclear and cytoplasmic proteins. Its targets include kinases, phosphatases, transcription factors, histones, and many other intracellular proteins. The biology of O-GlcNAc modification is still not well understood, and cell-permeable inhibitors of OGT are needed both as research tools and for validating OGT as a therapeutic target. Here, we report a small molecule OGT inhibitor, OSMI-1, developed from a high-throughput screening hit. It is cell-permeable and inhibits protein O-GlcNAcylation in several mammalian cell lines without qualitatively altering cell surface N- or O-linked glycans. The development of this molecule validates high-throughput screening approaches for the discovery of glycosyltransferase inhibitors, and further optimization of this scaffold may lead to yet more potent OGT inhibitors useful for studying OGT in animal models.

    View details for DOI 10.1021/acschembio.5b00004

    View details for Web of Science ID 000356845400005

    View details for PubMedID 25751766

    View details for PubMedCentralID PMC4475500

  • The Making of a Sweet Modification: Structure and Function of O-GlcNAc Transferase JOURNAL OF BIOLOGICAL CHEMISTRY Janetzko, J., Walker, S. 2014; 289 (50): 34424-34432

    Abstract

    O-GlcNAc transferase is an essential mammalian enzyme responsible for transferring a single GlcNAc moiety from UDP-GlcNAc to specific serine/threonine residues of hundreds of nuclear and cytoplasmic proteins. This modification is dynamic and has been implicated in numerous signaling pathways. An unexpected second function for O-GlcNAc transferase as a protease involved in cleaving the epigenetic regulator HCF-1 has also been reported. Recent structural and biochemical studies that provide insight into the mechanism of glycosylation and HCF-1 cleavage will be described, with outstanding questions highlighted.

    View details for DOI 10.1074/jbc.R114.604405

    View details for Web of Science ID 000346260800002

    View details for PubMedID 25336649

    View details for PubMedCentralID PMC4263849

  • Organoboron-Based Allylation Approach to the Total Synthesis of the Medium-Ring Dilactone (+)-Antimycin A(1b) JOURNAL OF ORGANIC CHEMISTRY Janetzko, J., Batey, R. A. 2014; 79 (16): 7415-7424

    Abstract

    The stereoselective synthesis of (+)-antimycin A1b has been accomplished in 12 linear steps and 18% overall yield from (-)-ethyl lactate. A robust, scalable, and highly diastereoselective montmorillonite K10-promoted allylation reaction between an ?-silyloxy aldehyde and a substituted potassium allyltrifluoroborate salt provides a general approach to the core stereochemical triad of the antimycin A family. The requisite (Z)-substituted potassium allyltrifluoroborate salt was synthesized using a syn-selective hydroboration/protodeboration of an alkynylboronate ester, followed by a Matteson homologation reaction. The total synthesis leverages an MNBA (Shiina's reagent)-mediated macrolactonization to generate the 9-membered dilactone ring and a late-stage PyBOP-mediated amide coupling employing an unprotected 3-formamidosalicylic acid fragment, thereby shortening the longest linear sequence and, perhaps most notably, generating the antimycin A C7-C8-C9 stereotriad in a single step using a single chiral pool-derived stereocenter.

    View details for DOI 10.1021/jo501134d

    View details for Web of Science ID 000340517600016

    View details for PubMedID 25019929

  • HCF-1 Is Cleaved in the Active Site of O-GlcNAc Transferase SCIENCE Lazarus, M. B., Jiang, J., Kapuria, V., Bhuiyan, T., Janetzko, J., Zandberg, W. F., Vocadlo, D. J., Herr, W., Walker, S. 2013; 342 (6163): 1235-1239

    Abstract

    Host cell factor-1 (HCF-1), a transcriptional co-regulator of human cell-cycle progression, undergoes proteolytic maturation in which any of six repeated sequences is cleaved by the nutrient-responsive glycosyltransferase, O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT). We report that the tetratricopeptide-repeat domain of O-GlcNAc transferase binds the carboxyl-terminal portion of an HCF-1 proteolytic repeat such that the cleavage region lies in the glycosyltransferase active site above uridine diphosphate-GlcNAc. The conformation is similar to that of a glycosylation-competent peptide substrate. Cleavage occurs between cysteine and glutamate residues and results in a pyroglutamate product. Conversion of the cleavage site glutamate into serine converts an HCF-1 proteolytic repeat into a glycosylation substrate. Thus, protein glycosylation and HCF-1 cleavage occur in the same active site.

    View details for DOI 10.1126/science.1243990

    View details for Web of Science ID 000327857900048

    View details for PubMedID 24311690

    View details for PubMedCentralID PMC3930058

  • Palladium beta-diiminate chemistry: Reactivity towards monodentate ligands and arylboronic acids INORGANICA CHIMICA ACTA Annibale, V. T., Tan, R., Janetzko, J., Lund, L. M., Song, D. 2012; 380: 308-321
  • Indium-Promoted Chemo- and Diastereoselective Allylation of alpha,beta-Epoxy Ketones with Potassium Allyltrifluoroborate ORGANIC LETTERS Nowrouzi, F., Janetzko, J., Batey, R. A. 2010; 12 (23): 5490-5493

    Abstract

    A practical method for the chemo- and diastereoselective allylation of ?,?-epoxy ketones has been developed by using the convenient air and moisture stable reagent potassium allyltrifluoroborate. Indium metal was found to promote addition in stoichiometric or catalytic amounts, to afford ?,?-epoxyhomoallylic tertiary alcohols in high yields and diastereoselectivities, without competing ring-scission of the epoxide.

    View details for DOI 10.1021/ol1023757

    View details for Web of Science ID 000284555600034

    View details for PubMedID 21070014

  • Novel dinuclear and trinuclear palladium beta-diiminate complexes containing amido-chloro double-bridges DALTON TRANSACTIONS Hadzovic, A., Janetzko, J., Song, D. 2008: 3279-3281

    Abstract

    We report the formation of an unexpected trinuclear palladium beta-diiminate complex from the decomposition of [Pd(Ph(2)nacnac)(Cl)(4-H(2)NC(6)H(4)-(t)Bu)] (nacnac = beta-diiminate derived from acetylacetone), the proposed reaction pathway, and the synthesis of the first dinuclear palladium complex with an amido-chloro double-bridge.

    View details for DOI 10.1039/b804792h

    View details for Web of Science ID 000256832300004

    View details for PubMedID 18560659

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