Chemical Biology

E. James Petersson

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First Name: 
E. James
Last Name: 
Petersson
Official Title: 
Associate Professor of Chemistry
Contact Information
Office Location: 
350 N
Email: 
ejpetersson@sas.upenn.edu
Phone: 
215-746-2221
Admin Support: 
Education: 

• A.B. Dartmouth College (1998)

• Ph.D. California Institute of Technology (2005)

• NIH Postdoctoral Fellow, Yale University (2005-2008)

• Searle Scholar (2010)

• Sloan Research Fellow (2012)

• NSF CAREER Award (2012)

• Award for Early Excellence in Physical Organic Chemistry      (2013)

Research Interests: 

Protein motion underlies both proper function and disease in biological systems. Many signaling and transport proteins require complex rearrangements for function, and some proteins, such as amyloids, misfold into toxic conformations. Studying these protein motions not only aids our understanding of diverse biological phenomena, it also contributes to an important fundamental problem in biochemistry: understanding how motions propagate from one end of a protein to another. The Petersson laboratory is developing tools to address questions of how dynamic proteins mediate communication and how the cellular environment catalyzes protein misfolding, from detailed in vitro folding studies to modeling protein motion in living cells. These tools include novel chromophores, which we synthesize and incorporate into proteins through unnatural amino acid mutagenesis and synthetic protein ligation.

Selected Publications: 

Inteins as Traceless Purification Tags for Unnatural Amino Acid Proteins

Batjargal, S.; Walters, C. R.; Petersson, E. J.

J. Am. Chem. Soc. 2015, 137, 1734-1737.

 

Specific Modulation of Protein Activity Through a Bioorthogonal Reaction

Warner, J. B.; Muthusamy, A. K.; Petersson, E. J.

ChemBioChem 2014, 24, 2508-2514.

 

Thioamide-Based Fluorescent Protease Sensors

Goldberg, J. M.; Chen, X. S.; Meinhardt, N.; Greenbaum, D. C.; Petersson, E. J. 

J. Am. Chem. Soc. 2014, 136, 2086-2093.

 

Efficient Synthesis and In Vivo Incorporation of Acridonylalanine, a Fluorescent Amino Acid for Lifetime and Förster Resonance Energy Transfer/Luminescence Resonance Energy Transfer Studies 

Speight, L. C.; Muthusamy, A. K.; Goldberg, J. M.; Warner, J. B.; Wissner, R. F.; Willi, T.; Woodman, B.; Mehl, R. A.; Petersson,     E. J. 

J. Am. Chem. Soc. 2013, 135, 18806-18814.

 

Expressed Protein Ligation at Methionine: N-terminal Attachment of Homocysteine, Ligation, and Masking

Tanaka, T.; Wagner, A. M.; Warner, J. B.; Wang, Y. J.; Petersson, E. J. 

Angew. Chem. Int. Ed. 2013, 52, 6210-6213.

 

Labeling Proteins with Fluorophore/Thioamide FRET Pairs by Combining Unnatural Amino Acid Mutagenesis and Native Chemical Ligation

Wissner, R. F.; Batjargal, S.; Fadzen, C. M.; Petersson, E. J. 

J. Am. Chem. Soc. 2013, 135, 6529-6540.

 

Thioamide Quenching of Fluorescent Probes Through Photoinduced Electron Transfer: Mechanistic Studies and Applications

Goldberg, J. M.; Batjargal, S.; Chen, B. S.; Petersson, E. J. 

J. Am. Chem. Soc. 2013, 135, 18651-18658.

Ronen Marmorstein

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First Name: 
Ronen
Last Name: 
Marmorstein
Official Title: 
Professor, Department of Biochemistry and Biophysics Investigator, Abramson Family Cancer Research Institute

Biological Chemistry

Additional Titles: 
Wistar Institute Professor of Chemistry
Contact Information
Office Location: 
BRB II/III, Room 454
Email: 
marmor@mail.med.upenn.edu
Phone: 
215-898-7740
Fax: 
215-746-5511
Education: 
  • B.S. University of California at Davis (1984)
  • M.S. University of Chicago (1989)
  • Ph.D. University of Chicago (1989)
  • Postdoctoral Fellow, Harvard University (1989-1994)
Research Interests: 

The laboratory uses a broad range of molecular, biochemical and biophysical research tools centered around X-ray crystal structure determination to understand the mechanism of chromatin recognition and assembly and post-translational histone and protein modification in the regulation of gene expression; and kinase signaling pathways. The laboratory is particularly interested in gene regulatory proteins and their upstream signaling kinases that are aberrantly regulated in cancer and age-related metabolic disorders such as type II diabetes and obesity, and the use of high-throughput small molecule screening and structure-based design strategies towards the development of protein-specific small-molecule probes to be used to further interrogate protein function and for development into therapeutic agents.

Chromatin recognition and assembly and histone modification in gene regulation. DNA within the eukaryotic nucleus is compacted into chromatin containing histone proteins and its appropriate regulation orchestrates all DNA-templated reactions such as DNA transcription, replication, repair, mitosis, and apoptosis. Among the many proteins that regulate chromatin, the proteins that recognize DNA, assemble chromatin, called histone chaperones, and that modify the histones through the addition or removal of functional groups such as acetyl, methyl or phosphate play important roles. We are studying the DNA binding proteins p53, FoxO and the Gal4 family; the histone chaperones HIRA, Asf1, Vps75 and their associated factors; and the family of histone acetyltransferase (HAT) and histone deacetylase (HDAC) enzymes. We are particularly interested in how DNA binding proteins navigate the recognition of their cognate DNA targets, how histone chaperones coordinate the assembly of distinct chromatin complexes correlated with different DNA regulatory processes, and how histone modification enzymes link catalysis to their substrate specific activities for their respective biological activities. More recently, we have been studying how the binding of accessory and regulatory protein subunits regulates the various activities of these proteins and in some cases we are developing small molecule protein specific inhibitors.

 

Enzymes associated with aging and age-related disorders.Sirtuin enzymes are NAD+-dependent histone and protein deactylases and/or ADP-ribotransferases that have been implicated in the regulation of gene expression, cellular aging, adipogenesis, type II diabetes and several neurodegenerative disorders. We have determined the structure of these enzymes in several liganded forms and have developed novel small molecule sirtuin inhibitors. Together with associated biochemical studies, these studies have provided insights into the mode of catalysis and substrate-specific recognition by this protein family and have illuminated new avenues for small molecule effector design. We are currently working towards understanding the factors that distinguish different sirtuin proteins and how the functions of these proteins are modulated by other protein factors. We are also pursuing structure/function studies of other proteins that are implicated in aging and age-related disorders.

 

Tumor suppressors and oncoproteins. We are carrying out biochemical and structural studies on the tumor suppressor proteins pRb, p53 and p300/CBP, both alone and in complex with their relevant protein targets. We are also interested in the mode of inactivation of these tumor suppressors by the viral oncoproteins E7 and E6 from human papillomavirus (HPV), the etiological agent for cervical cancer, and Adenovirus (Ad) E1A. We are also combining structural studies with small molecule screening to prepare small molecule HPV-E7 and for HPV-E6 inhibitors. Most recently we have begun to exploit structure-based design strategies to develop inhibitors of oncogenic kinases, such as PI3K, BRAF and PAK1 implicated in melanoma and other cancers. Our goal for these studies is to derive functional and structural information that will lead to the design of small molecule compounds that may have therapeutic applications.

Tumor suppressors and viral oncoproteins- We are pursuing biochemical and structural studies on the tumor suppressor proteins p18INK4c, pRb, p53 and p300/CBP, both alone and in complex with their relevant protein targets. The activity of pRb is inhibited by several known DNA viral oncoproteins, including human papillomavirus (HPV) E7, the etiological agent for cervical cancer, and Adenovirus (Ad) E1A. We have most recently characterized the binding properties of pRb to HPV-E7 and Ad-E1a and are now determining their structures both alone and in complex with pRb. Our goal for these studies is to derive functional and structural information that will lead to the design of small molecule compounds that may have clinical applications against cancer.

 

Protein-DNA recognition- As a model to understand sequence-specific DNA recognition by transcriptional regulatory proteins, we are studying the structure and function of three families of DNA binding proteins, the fungal specific Zn2Cys6 binuclear cluster proteins, the higher eukaryotic Ets proteins and p53. We have determined several structures of these proteins either alone or in complex with their associated DNA targets and are continuing to use these proteins as a model to understand DNA recognition by protein and protein complexes. With regard to p53, we are studying its unique mode of DNA recognition and are developing structure-based strategies for the repair of tumor-derived p53 mutations.

Other Affiliations: 

Ivan J. Dmochowski

Photo: 
First Name: 
Ivan J.
Last Name: 
Dmochowski
Official Title: 
Professor of Chemistry

Bioinorganic, Bioorganic, Biophysical Chemistry

Contact Information
Office Location: 
348 N, Lab: 332, 334, 336, 338 N
Email: 
ivandmo@sas.upenn.edu
Phone: 
215-898-6459
Twitter: 
@DmochowskiUPenn
Admin Support: 
Education: 
  • B.A. Harvard College (1994)
  • Research Fellow, Johannes Gutenberg Universitaet, Mainz, DE (1994-1995)
  • Ph.D. California Institute of Technology (2000)
  • Caltech Herbert Newby McCoy Award (2000)
  • Helen Hay Whitney Postdoctoral Fellow, Biophysics, Caltech (2000-2002)
  • Camille and Henry Dreyfus New Faculty Award (2003)
  • National Science Foundation CAREER Award (2005)
  • Camille and Henry Dreyfus Teacher-Scholar Award (2007)
Research Interests: 

Our lab is developing chemical and biophysical tools to study and manipulate complex biological systems. Projects span many areas of synthetic organic, inorganic, and biophysical chemistry; molecular, cell, and developmental biology; and bioengineering. We are particularly interested in developing new technologies for biomolecular imaging and the fabrication of functional bio-nanomaterials.

Hyperpolarized 129Xe Biosensors for Early Cancer Detection

Molecular imaging technologies hold great promise for early cancer diagnosis and intervention. Our goal is to develop new reagents that extend the capabilities of magnetic resonance imaging (MRI) for monitoring multiple cancer markers simultaneously in vivo. 129Xe has found increasing use for biological imaging applications, due to its biological compatibility (xenon is an anesthetic at high concentrations), hyperpolarizability (this enhances signals 1,000-fold), and high affinity for organic cages such as cryptophanes. The chemical shift of 129Xe varies by a remarkable 200 ppm, depending on its molecular environment: Thus, a 129Xe atom encapsulated inside a cryptophane is a sensitive reporter of perturbations outside the cage. Based on this principle, our lab is generating new biosensors that will identify biomarkers associated with cancers of the breast, lungs, brain, and pancreas. The long-range goal of this project is to use MRI to detect aberrant proteins that cause cancer in humans, years before the formation of a tumor.

Ferritin Templates for Nanoparticle Synthesis and Assembly

The goal of this project is to use ferritin proteins as templates for synthesizing and assembling inorganic nanoparticles with nanometer precision. Ferritins contain 24 four-helix bundle subunits that self-assemble to create a large central cavity. We have made water-stable, 10-12-nm gold and silver nanoparticles inside ferritin (gray sphere). Particles are fully characterized using facilities at the UPenn Laboratory for Research on the Structure of Matter (LRSM). We are functionalizing the surface of these ferritin-metal nanoparticles for sensing and nano/biomaterials applications. We are also performing computational protein design, in collaboration with the Saven lab, to mutate residues inside the ferritin cavity to enhance their metal-binding properties. Methods for organizing ferritin metal nanoparticles in 2- and 3-dimensions are being developed, in order to build very small conducting circuits. 

Laser-Activated Chemical Biology: Controlling Genes with Light

The goal of this project is to develop methods for turning genes "on" and "off" with light inside neurons and developing zebrafish embryos with high spatial and temporal control. As a first step, we have developed methods for incorporating a photoactive blocking group in the middle of a DNA or RNA oligonucleotide. In one application, we modulated primer extension by DNA polymerase (KF) using UV light. Photoactivation was monitored using a fluorescent reporter. We are now developing methods to control protein translation by the ribosome using similarly caged RNA. Blocking groups mask the messenger RNA start codon, and are designed to prevent translation until photocleavage. We will control complex gradients of proteins involved in cell signaling during zebrafish development and wound healing, using a state-of-the-art UV confocal microscope in the lab.

Selected Publications: 

 

X. Tang, J. Swaminathin, A.M. Gewirtz, I.J. Dmochowski, Regulating gene expression in human leukemia cells using light-activated oligodeoxynucleotides, Nucl. Acids Res. (36) 559-569, 2008.

 

J.A. Aaron, J.M. Chambers, K.M. Jude, L. Di Costanzo, I.J. Dmochowski, D.W. Christianson, Structure of a 129Xe-cryptophane biosensor complexed with human carbonic anhydrase II, J. Am. Chem. Soc. (130) 6942-6943, 2008.

 

G.K. Seward, Q. Wei, I.J. Dmochowski, Peptide-mediated cellular uptake of cryptophane, Bioconjug. Chem. (19) 2129-2135, 2008.

 

J.L. Richards, X. Tang, A. Turetsky, I.J. Dmochowski, RNA bandages for photomodulating in vitro protein synthesis, Bioorg. Med. Chem. Lett. (18) 6255-6258, 2008.

 

C. Butts, J. Swift, S.-G. Kang, L. Di Costanzo, D.W. Christianson, J.G. Saven, I.J. Dmochowski, Directing noble metal ion chemistry within a designed ferritin protein, Biochemistry (47) 12729-12739, 2008.

 

J.L. Chambers, P.A. Hill, J.A. Aaron, Z. Han, D.W. Christianson, N.N. Kuzma, I.J. Dmochowski, Cryptophane xenon-129 nuclear magnetic resonance biosensors targeting human carbonic anhydrase, J. Am. Chem. Soc. (131) 563-569, 2009.

 

P.A. Hill, Q. Wei, T. Troxler, I.J. Dmochowski, Substituent effects on xenon binding affinity and solution behavior of water-soluble cryptophanes, J. Am. Chem. Soc. (131) 3069-3077, 2009.

 

G.P. Robbins, M. Jimbo, J. Swift, M.J. Therien, D.A. Hammer, I.J. Dmochowski, Photo-initiated destruction of composite porphyrin-protein polymersomes, J. Am. Chem. Soc., (131) 3872-3874, 2009. 

 

J. Swift, C. Butts, J. Cheung-Lau, V. Yerubandi, I.J. Dmochowski, Efficient self-assembly of Archaeoglobus fulgidus ferritin around metallic cores, Langmuir, (25) 5219-5225, 2009.

 

C.A. Butts, J. Xi, G. Brannigan, M.L. Klein, R.G. Eckenhoff, I.J. Dmochowski, Identification of a fluorescent general anesthetic, 1-aminoanthracene, Proc. Natl. Acad. Sci. U.S.A. (106) 6501-6506, 2009.

 

I.J. Dmochowski, Xenon out of its shell, Nature Chemistry, ‘In Your Element’ invited feature article, vol. 1, 250, June 2009.

 

O. Taratula, I.J. Dmochowski, Functionalized 129Xe contrast agents for magnetic resonance imaging, Curr. Opin. Chem. Biol. (14) 97-104, 2010.

 

J.L. Richards, G.K. Seward, Y. Huang, I.J. Dmochowski, Turning DNAzymes on and off with light, ChemBioChem (11) 320-324, 2010.

 

J. Lampe, Z. Liao, I.J. Dmochowski, P.S. Ayyaswamy, D.M. Eckmann, Imaging macromolecular interactions at an interface, Langmuir (26) 2452-2459, 2010.

Courses Taught: 
  • Chemistry 101, "General Chemistry"
  • Chemistry 559, "Biomolecular Imaging"
  • Chemistry 567, “Bioinorganic Chemistry”

David W. Christianson

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First Name: 
David W.
Last Name: 
Christianson
Official Title: 
Roy and Diana Vagelos Professor in Chemistry and Chemical Biology

Biological Chemistry

Additional Titles: 
Department Chair
Contact Information
Office Location: 
2001 IAST, Lab: 2070 IAST
Email: 
chris@sas.upenn.edu
Phone: 
(215) 898-5714
Twitter: 
@ChristiansonLab
Admin Support: 
Education: 
  • A.B. Harvard College (1983)
  • A.M. Harvard University (1985)
  • Ph.D. Harvard University (1987)
  • Searle Scholar Award (1989–1992)
  • Young Investigator Award, Office of Naval Research (1989–1992)
  • Alfred P. Sloan Foundation Research Fellow (1992–1994)
  • Camille and Henry Dreyfus Teacher-Scholar Award (1993–1994)
  • Pfizer Award in Enzyme Chemistry, American Chemical Society (1999)
  • Fellow in Natural Sciences (Chemistry), Sidney Sussex College, University of Cambridge (2006)
  • Underwood Fellowship, Department of Biochemistry, University of Cambridge (2006–2007)
  • Senior Fellow, American Asthma Foundation (2006)
  • Fellow of the John Simon Guggenheim Memorial Foundation (2006–2007)
  • National Academies Board on Chemical Sciences and Technology (2011–2017)
  • The Repligen Award in Chemistry of Biological Processes, American Chemical Society (2013)
  • Fellow of the Royal Society of Chemistry (London) (2013)
  • Elizabeth S. and Richard M. Cashin Fellow, Radcliffe Institute for Advanced Study, Harvard University
  • Visiting Professor of Chemistry and Chemical Biology, Harvard University
Research Interests: 

We are interested in structural aspects of the mechanisms of hydrolytic metalloenzymes in the arginase-deacetylase family. To date, we have determined the crystal structures of rat arginase I, human arginase I, human arginase II, and arginases from Plasmodium falciparum, Leishmania mexicana, and Schistosoma mansoni. Structural and enzymological data suggest a mechanism for arginine hydrolysis in which both manganese ions activate a bridging hydroxide ion for nucleophilic attack at the guanidinium group of arginine in the first step of catalysis. Based on our structural and mechanistic analyses, we designed and synthesized boronic acid analogues of arginine such as 2-amino-6-boronohexanoic acid (ABH, Kd = 5 nM) [Baggio et al. (1997) J. Am. Chem. Soc. 119, 8107]. The boronic acid moiety of ABH similarly undergoes nucleophilic attack by the metal-bridging hydroxide ion to yield a metal-bound boronate anion that mimics the tetrahedral intermediate and its flanking transition states in catalysis (Figure 1), as shown in X-ray crystallographic studies of rat arginase I [Cox et al. (1999) Nature Struct. Biol. 6, 1043], human arginase I [Di Costanzo et al. (2005) Proc. Natl. Acad. Sci. USA, 102, 13058], P. falciparum arginase [Dowling et al. (2010) Biochemistry 49 5600], and L. mexicana arginase [D' Antonio et al. (2013) Arch. Biochem. Biophys. 535, 163]

Figure 1: Human arginase I-ABH complex. (a) Omit electron density map of ABH bound in the enzyme active site at 1.29 Å resolution. Water molecules appears as red spheres and Mn(II) ions appears as larger pink spheres. (b) Summary of arginase-ABH interactions; manganese coordination interactions are designated by green dashed lines, and hydrogen bonds are indicated by black dashed lines. (c) Stabilization of the tetrahedral intermediate (and flanking transition states) in the arginase mechanism based on the binding mode of ABH.

 

We have also used ABH as a chemical tool for probing the role of arginase in regulating arginine bioavailability for nitric oxide (NO) biosynthesis in tissues and in live animals. We discovered that arginase inhibition by ABH enhances smooth muscle relaxation in ex vivo organ bath studies. Since smooth muscle relaxation in the corpus cavernosum of the penis is necessary for erection, we concluded that human penile arginase is a potential target for the development of new therapies in the treatment of erectile dysfunction [Cox et al. (1999) Nature Struct. Biol. 6, 1043]. Our subsequent in vivo studies demonstrated that arginase inhibition by ABH enhances erectile function and vasocongestion in the male and female genitalia, so we concluded that both male erectile dysfunction and female sexual arousal disorder are potentially treatable by ABH [Cama et al. (2003) Biochemistry 42, 8445; Christianson (2005) Acc. Chem. Res. 38, 191]. More recent studies show that ABH may also be useful in the treatment of certain cardiovascular disorders such as atherosclerosis [Santhanam et al. (2007) Circulation Res. 101, 692; Ryoo et al. (2008) Circulation Res. 102, 923]. The biopharmaceutical company Arginetix was founded in 2008 based on our arginase inhibitor technology.

 

Our work with metal-dependant histone deacetylases recently yielded the first crystal structure of a histone deacetylase complexed with a macrocyclic depsipeptide inhibitor (Figure 2) [Cole et al. (2011) J. Am. Chem. Soc. 133, 12474]. Additionally, we recently showed that mutations in histone deacetylase 8 identified in patients diagnosed with Cornelia de Lange Syndrome compromise catalytic activity by causing structural changes in the active site that perturb substrate binding and catalysis [Deardorff et al. (2012) Nature 489, 313; Decroos et al. (2014) ACS Chem. Biol., in press.]. In addition to our work with arginase, we are studying other metalloenzymes that adopt the arginase fold, such as polyamine deacetylase [Lombardi et al. (2011) Biochemistry 50, 1808].

 

In other metalloenzyme work, we have determined the crystal structure of A. aeolicus LpxC, a zinc-requiring enzyme that catalyzes the first step of lipid A biosynthesis in Gram-negative bacteria [Whittington et al. (2003) Proc. Natl. Acad. Sci. USA 100, 8146] (Figure 3). Subsequent structural studies have allowed us to pinpoint regions of the active site that interact with the fatty acid and diphosphate moieties of the substrate [Gennadios et al. (2006) Biochemistry 45, 7940; 15216], and these studies have guided the first steps in the structure-based design of new LpxC inhibitors that may ultimately be useful in the treatment of Gram-negative bacterial infections [Shin et al. (2007) Bioorg. Med. Chem. 15, 2617]. To date, we have broadened these structural studies to include LpxC enzymes from Gram-negative pathogens Y. pestis (bubonic plague) and F. tularensis (tularemia) [Cole et al. (2011) Biochemistry 50, 258.]

 

Figure 3: Structure and biological function of LpxC. This zinc enzyme catalyzes the first committed step of lipid A biosynthesis; lipid A is the hydrophobic anchor of lipopolysaccharide, which comprises the outer leaflet of the outer membrane of Gram-negative bacteria. The crystal structure of LpxC reveals a hydrophobic tunnel in the active site that accommodates the fatty acid moiety of the substrate, and this binding interaction is required for the active site to adopt a catalytically-active conformation.

 

Structural Basis of Terpenoid Biosynthesis

 

The family of terpenoid natural products currently numbers more than 70,000 members found in all forms of life. Terpenoids, are involved in diverse biological functions such as the mediation of plant-parasite interactions or the modulation of membrane fluidity. Since times of antiquity, terpenoid natural products have also been essential components of the pharmacopeia as analgesics, antibiotics, and anti-cancer compounds (e.g., Taxol). We are interested in the enzymes that catalyze the biosynthesis of different cyclic terpenoids [Christianson (2006) Chem. Rev. 106, 3412; Christianson (2008) Curr. Opin. Chem. Biol. 12, 141]. We have determined the three-dimensional crystal structures of terpenoid cyclases from various bacterial, fungal, and plant sources, such as epi-isozizaene synthase from S. colicolor [Aaron et al. (2010) Biochemistry 49, 1787], bornyl diphosphate synthase from culinary sage [Whittington et al. (2002), Proc. Natl. Acad. Sci. USA 99, 15375], aristolochene synthase from A. terreus [Shishova et al. (2007) Biochemistry 46, 1941], trichodiene synthase from F. sporotrichioides [Rynkiewicz et al. (2001) Proc. Natl. Acad. Sci. USA 98, 13543], δ-cadinene synthase from cotton [Gennadios et al. (2009) Biochemistry 48, 6175] and taxadiene synthase from the Pacific yew (which catalyzes the first committed step in the biosynthesis of Taxol, a potent cancer chemotherapeutic compound), [Köksal et al. (2011) Nature 469, 116]. To illustrate, structures of bornyl diphosphate synthase and taxadiene synthase are shown in Figures 4 and 5, respectively. These structures guide the study of site-specific mutants and alternative substrates as we explore the structural basis of diversity in terpenoid biosynthesis [e.g., see: Vedula et al. (2005) Biochemistry 44, 12719; Vedula et al. (2008) Arch. Biochem. Biophys. 469, 184; Christianson (2007) Science 316, 60], Köksal et al. (2012) Biochemistry 51, 3003, 301.

 

Figure 4: Reaction catalyzed by bornyl diphosphate synthase. Aza analogues of carbocation intermediates are shown in boxes; crystal structures of their complexes with the synthase reveal structural inferences on catalysis. The enzyme undergoes significant conformational changes upon the binding of 3 Mg2+ ions and pyrophosphate (or a substrate diphosphate group). These conformational changes sequester the active site from bulk solvent and trigger substrate ionization to initiate catalysis [Whittington et al. (2002) Proc. Natl. Acad. Sci. USA 99, 15375].

Figure 5: Structural relationships among terpenoid cyclases.The class I terpenoid cyclase fold of pentalenene synthase (blue) contains metal-binding motifs DDXXD and (N,D)DXX(S,T)XXXE (red and orange, respectively); in 5-epi-aristolochene synthase, this domain is linked to a smaller, vestigial domain (green). A related domain is found in the class II terpenoid cyclase fold of squalene-hopene cyclase, where it contains the general acid motif DXDD (brown) and a second domain (yellow) inserted between the first and second helices; a hydrophobic plateau flanking helix 8 (gray stripes) enables membrane insertion. Taxadiene synthase contains both class I and class II terpenoid cyclase folds, but only the class I domain is catalytically active. The role of N-termini (purple) in class I plant cyclases is to "cap" the active site, as shown for 5-epi-aristolochene synthase.

Selected Publications: 

Köksal, M., Jin, Y., Coates, R.M., Croteau, R., Christianson, D.W. (2011) Taxadiene Synthase Structure and Evolution of Modular Architecture in Terpene Biosynthesis. Nature 469, 116-120. 

 

Cole, K.E., Gattis, S.G., Angell, H.D., Fierke, C.A., Christianson, D.W. (2011) Structure of the Metal-Dependent Deacetylase LpxC from Yersinia enterocolitica Complexed with the Potent Inhibitor CHIR-090. Biochemistry 50, 258-265.

 

Lombardi, P.M., Angell, H.D., Whittington, D.A., Flynn, E.F., Rajashankar, K.R., Christianson, D.W. (2011) Structure of Prokaryotic Polyamine Deacetylase Reveals Evolutionary Functional Relationships with Eukaryotic Histone Deacetylases. Biochemistry 50, 1808-1817.

 

Köksal, M., Hu, H., Coates, R.M., Peters, R.J., Christianson, D.W. (2011) Structure and Mechanism of the Diterpene Cyclase ent-Copalyl Diphosphate Synthase. Nature Chem. Biol. 7, 431-433.

 

Cole, K.E., Dowling, D.P., Boone, M.A., Phillips, A.J., Christianson, D.W. (2011) Structural Basis of the Antiproliferative Activity of Largazole, a Depsipeptide Inhibitor of the Histone Deacetylases. J. Am. Chem. Soc. 133, 12474-12477 (Communication to the Editor).

 

Ilies, M., Di Costanzo, L., Dowling, D.P., Thorn, K.J., Christianson, D.W. (2011) Binding of α, α-Disubstituted Amino Acids to Arginase Suggests New Avenues for Inhibitor Design. J. Med. Chem. 54, 5432-5443.

 

Lombardi, P.M., Cole, K.A., Dowling, D.P., Christianson, D.W. (2011) Structure, Mechanism, and Inhibition of Histone Deacetylases and Related Metalloenzymes. Curr. Op. Struct. Biol. 21, 735-743 (invited review). 

 

Köksal, M., Chou, W.K.W., Cane, D.E., Christianson, D.W. (2012) Structure of 2-Methylisoborneol Synthase from Streptomyces coelicolor and Implications for the Cyclization of a Noncanonical C-Methylated Monoterpenoid Substrate. Biochemistry 51, 3011-3020.

 

Deardorff, M.A., Bando, M., Nakato, R., Watrin, E., Itoh, T., Minamino, M., Saitoh, K., Komata, M., Katou, Y., Clark, D., Cole, K.E., De Baere, E., Decroos, C., Di Donato, N., Ernst, S., Francey, L.J., Gyftodimou, Y., Hirashima, K., Hullings, M., Ishikawa, Y., Jaulin, C., Kaur, M., Kiyono, T., Lombardi, P.M., Magnaghi-Jaulin, L., Mortier, G.R., Nozaki, N., Petersen, M.B., Seimiya, H., Siu, V.M., Suzuki, Y., Takagaki, K., Wilde, J.J., Willems, P.J., Prigent, C., Gillessen-Kaesbach, G., Christianson, D.W., Kaiser, F.J., Jackson, L.G., Hirota, T., Krantz, I.D., Shirahige, K. (2012) HDAC8 Mutations in Cornelia de Lange Syndrome Affect the Cohesin Acetylation Cycle. Nature 489, 313-317.

 

D'Antonio, E.L., Hai, Y., Christianson, D.W. (2012) Structure and Function of Non-Native Metal Clusters in Human Arginase I. Biochemistry 51, 8399-8409.

 

D'Antonio, E.L., Ullman, B., Roberts, S.C., Gaur Dixit, U., Wilson, M.E., Hai, Y., Christianson, D.W. (2013) Crystal Structure of Arginase from Leishmania mexicana and Implications for the Inhibition of Polyamine Biosynthesis in Parasitic Infections. Arch. Biochem. Biophys. 535, 163-176.

 

Genshaft, A., Moser, J.-A.S., D'Antonio, E.L., Bowman, C.M., Christianson, D.W. (2013) Energetically Unfavorable Amide Conformations for N6-Acetyllysine Side Chains in Refined Protein Structures. Proteins: Struct., Funct., Bioinf. 81, 1051–1057

 

Köksal, M., Chou, W.K.W., Cane, D.E., Christianson, D.W. (2013) Unexpected Reactivity of 2-Fluorolinalyl Diphosphate in the Active Site of Crystalline 2-Methylisoborneol Synthase. Biochemistry 52, 5247-5255.

 

Chen, M., Al-lami, N., Janvier, M., D'Antonio, E.L., Faraldos, J.A., Cane, D.E., Allemann, R.K., Christianson, D.W. (2013) Mechanistic Insights from the Binding of Substrate and Carbocation Intermediate Analogues to Aristolochene Synthase. Biochemistry 52, 5441-5453.

 

Hai, Y., Dugery, R.J., Healy, D., Christianson, D.W. (2013) Formiminoglutamase from Trypanosoma cruzi is an Arginase-Like Manganese Metalloenzyme. Biochemistry 52, 9294-9309.

 

Li, R., Chou, W.K.W., Himmelberger, J.A., Litwin, K.M., Harris, G.G., Cane, D.E., Christianson, D.W. (2014) Reprogramming the Chemodiversity of Terpenoid Cyclization by Remolding the Active Site Contour of epi-Isozizaene Synthase. Biochemistry 53, 1155-1168.

 

Kaiser, F.J., Ansari, M., Braunholz, D., Gil-Rodríguez, M.C., Decroos, C., Wilde, J.J., Fincher, C.T., Kaur, M., Bando, M., Bowman, C.M., Bradley, J., Clark, D., del Campo-Casanelles, M., Di Donato, N., Dubbs, H., Eckhold, J., Ernst, S., Ferreira, J.C., Francey, L., Gehlken, U., Guillén-Navarro, E., Gyftodimou, Y., Hall, B.D., Hennekam, R., Hullings, M., Hunter, J., Kline, A.D., Krumina, Z., Leppig, K., Lynch, S.A., Mallozzi, M.B., Mannini, L., McKee, S., Mehta, S., Micule, L., Mohammed, S., Moran, E., Mortier, G.R., Moser, J.-A.S., Nozaki, N., Nunes, L., Pappas, J., Pérez-Aytés, A., Petersen, M.B., Poffyn, A., Puisac, B., Revencu, N., Roeder, E., Saitta, S., Scheuerle, A., Siu, V.M., Thiese, H., Vater, I., Willems, P., Williamson, K., Wilson, L., Hakonarson, H., Wierzba, J., Musio, A., Gillessen-Kaesbach, G., Ramos, F.J., Jackson, L.G., Shirahige, K., Pié, J., Christianson, D.W., Krantz, I.D., FitzPatrick, D.R., Deardorff, M.A. (2014) HDAC8 Mutations Cause an X-Linked Clinically Recognizable Cornelia de Lange Syndrome-Like Disorder. Hum. Mol. Genet. 23, 2888-2900 (cover article).

 

Hai, Y., Edwards, J.E., Van Zandt, M.C., Hoffmann, K.F., Christianson, D.W. (2014) Crystal Structure of Schistosoma mansoni Arginase, a Potential Drug Target for the Treatment of Schistosomiasis. Biochemistry 53, 4671-4684.

 

Decroos, C., Bowman, C.M., Moser, J.-A.S., Christianson, K.E., Deardorff, M.A., Christianson, D.W. (2014) Compromised Structure and Function of HDAC8 Mutants in Cornelia de Lange Syndrome Spectrum Disorders. ACS Chem. Biol. 9, 2157-2164.

 

Hai, Y., Kerkhoven, E.J., Barrett, M.P., Christianson, D.W. (2015) Crystal Structure of an Arginase-Like Protein from Trypanosoma brucei that Evolved without a Binuclear Manganese Cluster. Biochemistry 54, 458-471.

 

Decroos, C., Clausen, D.J., Haines, B.E., Wiest, O., Williams, R.M., Christianson, D.W. (2015) Variable Active Site Loop Conformations Accommodate the Binding of Macrocyclic Largazole Analogues to HDAC8. Biochemistry 54, 2126-2135.

David M. Chenoweth

Photo: 
First Name: 
David M.
Last Name: 
Chenoweth
Official Title: 
Associate Professor of Chemistry

Organic and Bioorganic Chemistry

Contact Information
Office Location: 
2002 IAST, lab: 2020,2080,2100 IAST
Email: 
dcheno@sas.upenn.edu
Phone: 
215-­573-­1953
Admin Support: 
Education: 
  • B.S. Indiana University-Purdue University Indianapolis (1999)
  • Organic Chemist, Eli Lilly & Co., Indianapolis, IN (2000 – 2004)
  • Ph.D. California Institute of Technology (2009)
  • Kanel Foundation Predoctoral Fellow (2007 – 2009)
  • Caltech Herbert Newby McCoy Award (2009)
  • NIH/NIGMS Postdoctoral Fellow, Massachusetts Institute of Technology (2009 – 2010)
Research Interests: 

Research in the Chenoweth laboratory is grounded in organic chemistry and molecular recognition with applications to biological and materials problems. We synthesize molecules and study their properties and interactions for a broad range of applications in bioorganic and materials chemistry. We are particularly interested in the design and synthesis of new molecules that can modulate nucleic acid and protein structure. Additionally, we are equally interested in the synthesis of new materials with sensing and self-assembly properties.

 

Undergraduate students, graduate students, and postdoctoral researchers are exposed to a diverse array of topics including organic chemistry, synthesis, bioorganic chemistry, macromolecular structure (nucleic acids and proteins), biochemistry, and polymer chemistry.

Selected Publications: 

Zhang, Yitao; Malamakal, Roy M.; Chenoweth, David M. “Aza-Glycine Induces Collagen Hyperstability” J. Am. Chem. Soc. 2015, ASAP. DOI: 10.1021/jacs.5b04590. See Chemical & Engineering News story by Stu Borman: “Chemical Modification Is Best Ever At Strengthening And Stabilizing Collagen” Chemical & Engineering News, Volume 93, Issue 38, p. 7, News of The Week.

 

Zhang, Yitao; Malamakal, Roy M.; Chenoweth, David M. “A Single Stereodynamic Center Modulates the Rate of Self-Assembly in a Biomolecular System” Angew. Chem. Int. Ed. 2015, 54, 10826-10832.

 

Suh, Sung-Eun; Barros, Stephanie A.; Chenoweth, David M. “Triple Aryne–Tetrazine Reaction Enabling Rapid Access to a New Class of Polyaromatic Heterocycles” Chemical Science 2015, 6, 5128-5132.

 

Tran, Mai N.; Chenoweth, David M. “Synthesis and Properties of Lysosome-Specific Photoactivatable Probes for Live-Cell Imaging” Chemical Science 2015, 6, 4508-4512.

 

Barros, Stephanie A.; Chenoweth, David M. “Triptycene-Based Small Molecules Modulate (CAG)·(CTG) Repeat Junctions" Chemical Science 2015, 6, 4752-4755.

 

Tran, Mai N.; Chenoweth, David M. “Photoelectrocyclization as an Activation Mechanism for Organelle Specific Live-Cell Imaging Probes” Angew. Chem. Int. Ed. 2015, 54, 6442-6446.

 

Ballister, Edward R.; Ayloo, Swathi; Chenoweth, David M.; Lampson, Michael A.; Holzbaur, Erika L.F. “Optogenetic Control of Organelle Transport Using a Photocaged Chemical Inducer of Dimerization” Current Biology 2015, 10, R407-R408.

 

Ballister, Edward R.; Aonbangkhen, Chanat; Mayo, Alyssa M.; Lampson, Michael A.; Chenoweth, David M. "Localized Light-Induced Protein Dimerization in Living Cells using a Photocaged Dimerizer” Nature Communications 2014, 5, 5475.

 

Barros, Stephanie A.; Chenoweth, David M. "Recognition of Nucleic Acid Junctions Using Triptycene-Based Molecules” Angew. Chem. Int. Ed. 2014, 53, 13746-13750.

 

Rarig, Robert-André F.; Tran, Mai N.; Chenoweth, David M. "Synthesis and Conformational Dynamics of the Reported Structure of Xylopyridine A” J. Am. Chem. Soc. 2013, 135, 9213–9219, ASAP.

 

Chenoweth, David M.; Meier, Jordan L.; Dervan, Peter B. "Pyrrole-Imidazole Polyamides Distinguish Between Double-Helical DNA and RNA” Angew. Chem. Int. Ed. 2013, 52, 415-418.

 

Weizmann, Yossi; Chenoweth, David M.; Swager, Timothy, M. "DNA−CNT Nanowire Networks for DNA Detection” J. Am. Chem. Soc. 2011, 133, 3238–3241.

 

Chenoweth, David M.; Dervan, Peter B. “Structural Basis for Cyclic Py-Im Polyamide Allosteric Inhibition of Nuclear Receptor Binding” J. Am. Chem. Soc. 2010, 132, 14521. Selected for the cover of JACS Oct. 20, 2010, Vol 132, Issue 41. Covered by Chemical and Engineering News Sept. 27, 2010 issue, “Putting DNA in a Bind”.

 

Weizmann, Yossi; Chenoweth, David M.; Swager, Timothy, M. “Addressable Terminally-Linked DNA-CNT Nanowires” J. Am. Chem. Soc. 2010, 132, 14009.

 

Weizmann, Yossi; Lim, Jeewoo; Chenoweth, David M.; Swager, Timothy, M. “Regiospecific Synthesis of Au-Nanorod/SWCNT/Au-Nanorod Heterojunctions” Nano Lett. 2010, 10, 2466.

 

Chenoweth, Kimberly; Chenoweth, David M.; Goddard III, William A. “Cyclooctyne-based Reagents for Uncatalyzed Click Chemistry: A Computational Survey” Org. Biomol. Chem. 2009, 7, 5255.

 

Chenoweth, David M.; Harki, Daniel A.; Dervan, Peter B. “Oligomerization Route to DNA Binding Py-Im Polyamide Macrocycles” Org. Lett. 2009, 11, 3590.

 

Chenoweth, David M.; Dervan, Peter B. “Allosteric Modulation of DNA by Small Molecules” Proc. Natl. Acad. Sci. U.S.A. 2009, 106, 13175. Covered by Nature News: "Get into the groove" Nature 2009, 460, 669. Also selected by the Stanford Synchrotron (SSRL) as a science highlight for November 2009.

 

Chenoweth, David M.; Harki, Daniel A.; Dervan, Peter B. “Solution-Phase Synthesis of Pyrrole-Imidazole Polyamides” J. Am. Chem. Soc. 2009, 131, 7175.

 

Chenoweth, David M.; Harki, Daniel A.; Phillips, John W.; Dose, Christian; Dervan, Peter B. “Cyclic Pyrrole-Imidazole Polyamides Targeted to the Androgen Response Element” J. Am. Chem. Soc. 2009, 131, 7182.

 

Chenoweth, David M.; Chenoweth, Kimberly; Goddard III, William A. “Lancifodilactone G: Insights about an Unusually Stable Enol” J. Org. Chem., 2008, 73, 6853.

 

Dose, Christian; Farkas, Michelle E.; Chenoweth, David M.; Dervan, Peter B. “Next Generation Hairpin Polyamides with (R)-3,4-Diaminobutyric Acid Turn Unit” J. Am. Chem. Soc., 2008, 130, 6859.

 

Chenoweth, David M.; Viger, Anne; Dervan, Peter B. “Fluorescent Sequence-Specific dsDNA Binding Oligomers” J. Am. Chem. Soc., 2007, 129, 2216. Covered by Chemical and Engineering News.

 

Chenoweth, David M.; Poposki, Julie A.; Marques, Michael A.; Dervan, Peter B. “Programmable oligomers targeting 5'-GGGG-3' in the minor groove of DNA and NF-k B binding inhibition” Bioorg. Med. Chem., 2007, 15, 759.

 

Doss, Raymond M.; Marques, Michael M.; Foister, Shane; Chenoweth, David M.; Dervan, Peter B. “Programmable Oligomers for Minor Groove DNA Recognition” J. Am. Chem. Soc., 2006, 128, 9074.

 

Nurok, D.; Frost, M. C.; Chenoweth, D. M. “Separation using planar chromatography with electroosmotic flow” J. Chromatogr., A, 2000, 903, 211. 

 

Nurok, David; Frost, Megan C.; Pritchard, Cary L.; Chenoweth, David M. “The performance of planar chromatography using electroosmotic flow” J. Planar Chromatogr.-Mod. TLC, 1998, 11, 244.

Department of Chemistry

231 S. 34 Street, Philadelphia, PA 19104-6323

215.898.8317 voice | 215.573.2112 fax | web@chem.upenn.edu

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