Person: Chang, Roger
Loading...
Email Address
AA Acceptance Date
Birth Date
Research Projects
Organizational Units
Job Title
Last Name
Chang
First Name
Roger
Name
Chang, Roger
5 results
Search Results
Now showing 1 - 5 of 5
Publication Antibacterial mechanisms identified through structural systems pharmacology(BioMed Central, 2013) Chang, Roger; Xie, Lei; Bourne, Philip E; Palsson, Bernhard OBackground: The growing discipline of structural systems pharmacology is applied prospectively in this study to predict pharmacological outcomes of antibacterial compounds in Escherichia coli K12. This work builds upon previously established methods for structural prediction of ligand binding pockets on protein molecules and utilizes and expands upon the previously developed genome scale model of metabolism integrated with protein structures (GEM-PRO) for E. coli, structurally accounting for protein complexes. Carefully selected case studies are demonstrated to display the potential for this structural systems pharmacology framework in discovery and development of antibacterial compounds. Results: The prediction framework for antibacterial activity of compounds was validated for a control set of well-studied compounds, recapitulating experimentally-determined protein binding interactions and deleterious growth phenotypes resulting from these interactions. The antibacterial activity of fosfomycin, sulfathiazole, and trimethoprim were accurately predicted, and as a negative control glucose was found to have no predicted antibacterial activity. Previously uncharacterized mechanisms of action were predicted for compounds with known antibacterial properties, including (1-hydroxyheptane-1,1-diyl)bis(phosphonic acid) and cholesteryl oleate. Five candidate inhibitors were predicted for a desirable target protein without any known inhibitors, tryptophan synthase β subunit (TrpB). In addition to the predictions presented, this effort also included significant expansion of the previously developed GEM-PRO to account for physiological assemblies of protein complex structures with activities included in the E. coli K12 metabolic network. Conclusions: The structural systems pharmacology framework presented in this study was shown to be effective in the prediction of molecular mechanisms of antibacterial compounds. The study provides a promising proof of principle for such an approach to antibacterial development and raises specific molecular and systemic hypotheses about antibacterials that are amenable to experimental testing. This framework, and perhaps also the specific predictions of antibacterials, is extensible to developing antibacterial treatments for pathogenic E. coli and other bacterial pathogens.Publication Transplantability of a circadian clock to a noncircadian organism(2015) Chen, Anna H.; Lubkowicz, David; Yeong, Vivian; Chang, Roger; Silver, PamelaCircadian oscillators are posttranslationally regulated and affect gene expression in autotrophic cyanobacteria. Oscillations are controlled by phosphorylation of the KaiC protein, which is modulated by the KaiA and KaiB proteins. However, it remains unclear how time information is transmitted to transcriptional output. We show reconstruction of the KaiABC oscillator in the noncircadian bacterium Escherichia coli. This orthogonal system shows circadian oscillations in KaiC phosphorylation and in a synthetic transcriptional reporter. Coexpression of KaiABC with additional native cyanobacterial components demonstrates a minimally sufficient set of proteins for transcriptional output from a native cyanobacterial promoter in E. coli. Together, these results demonstrate that a circadian oscillator is transplantable to a heterologous organism for reductive study as well as wide-ranging applications.Publication Streptomyces thermoautotrophicus does not fix nitrogen(Nature Publishing Group, 2016) MacKellar, Drew; Lieber, Lucas; Norman, Jeffrey S.; Bolger, Anthony; Tobin, Cory; Murray, James W.; Oksaksin, Mehtap; Chang, Roger; Ford, Tyler J.; Nguyen, Peter Q.; Woodward, Jimmy; Permingeat, Hugo R.; Joshi, Neel S.; Silver, Pamela; Usadel, Björn; Rutherford, Alfred W.; Friesen, Maren L.; Prell, JürgenStreptomyces thermoautotrophicus UBT1 has been described as a moderately thermophilic chemolithoautotroph with a novel nitrogenase enzyme that is oxygen-insensitive. We have cultured the UBT1 strain, and have isolated two new strains (H1 and P1-2) of very similar phenotypic and genetic characters. These strains show minimal growth on ammonium-free media, and fail to incorporate isotopically labeled N2 gas into biomass in multiple independent assays. The sdn genes previously published as the putative nitrogenase of S. thermoautotrophicus have little similarity to anything found in draft genome sequences, published here, for strains H1 and UBT1, but share >99% nucleotide identity with genes from Hydrogenibacillus schlegelii, a draft genome for which is also presented here. H. schlegelii similarly lacks nitrogenase genes and is a non-diazotroph. We propose reclassification of the species containing strains UBT1, H1, and P1-2 as a non-Streptomycete, non-diazotrophic, facultative chemolithoautotroph and conclude that the existence of the previously proposed oxygen-tolerant nitrogenase is extremely unlikely.Publication Do genome-scale models need exact solvers or clearer standards?(John Wiley & Sons, Ltd, 2015) Ebrahim, Ali; Almaas, Eivind; Bauer, Eugen; Bordbar, Aarash; Burgard, Anthony P; Chang, Roger; Dräger, Andreas; Famili, Iman; Feist, Adam M; Fleming, Ronan MT; Fong, Stephen S; Hatzimanikatis, Vassily; Herrgård, Markus J; Holder, Allen; Hucka, Michael; Hyduke, Daniel; Jamshidi, Neema; Lee, Sang Yup; Le Novère, Nicolas; Lerman, Joshua A; Lewis, Nathan E; Ma, Ding; Mahadevan, Radhakrishnan; Maranas, Costas; Nagarajan, Harish; Navid, Ali; Nielsen, Jens; Nielsen, Lars K; Nogales, Juan; Noronha, Alberto; Pal, Csaba; Palsson, Bernhard O; Papin, Jason A; Patil, Kiran R; Price, Nathan D; Reed, Jennifer L; Saunders, Michael; Senger, Ryan S; Sonnenschein, Nikolaus; Sun, Yuekai; Thiele, InesPublication Systems biology of the structural proteome(BioMed Central, 2016) Brunk, Elizabeth; Mih, Nathan; Monk, Jonathan; Zhang, Zhen; O’Brien, Edward J.; Bliven, Spencer E.; Chen, Ke; Chang, Roger; Bourne, Philip E.; Palsson, Bernhard O.Background: The success of genome-scale models (GEMs) can be attributed to the high-quality, bottom-up reconstructions of metabolic, protein synthesis, and transcriptional regulatory networks on an organism-specific basis. Such reconstructions are biochemically, genetically, and genomically structured knowledge bases that can be converted into a mathematical format to enable a myriad of computational biological studies. In recent years, genome-scale reconstructions have been extended to include protein structural information, which has opened up new vistas in systems biology research and empowered applications in structural systems biology and systems pharmacology. Results: Here, we present the generation, application, and dissemination of genome-scale models with protein structures (GEM-PRO) for Escherichia coli and Thermotoga maritima. We show the utility of integrating molecular scale analyses with systems biology approaches by discussing several comparative analyses on the temperature dependence of growth, the distribution of protein fold families, substrate specificity, and characteristic features of whole cell proteomes. Finally, to aid in the grand challenge of big data to knowledge, we provide several explicit tutorials of how protein-related information can be linked to genome-scale models in a public GitHub repository (https://github.com/SBRG/GEMPro/tree/master/GEMPro_recon/). Conclusions: Translating genome-scale, protein-related information to structured data in the format of a GEM provides a direct mapping of gene to gene-product to protein structure to biochemical reaction to network states to phenotypic function. Integration of molecular-level details of individual proteins, such as their physical, chemical, and structural properties, further expands the description of biochemical network-level properties, and can ultimately influence how to model and predict whole cell phenotypes as well as perform comparative systems biology approaches to study differences between organisms. GEM-PRO offers insight into the physical embodiment of an organism’s genotype, and its use in this comparative framework enables exploration of adaptive strategies for these organisms, opening the door to many new lines of research. With these provided tools, tutorials, and background, the reader will be in a position to run GEM-PRO for their own purposes. Electronic supplementary material The online version of this article (doi:10.1186/s12918-016-0271-6) contains supplementary material, which is available to authorized users.