Chemistry & Biochemistry
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The Department of Chemistry and Biochemistry offers research-oriented programs culminating in the Doctor of Philosophy degree. The faculty in the department have expertise over a broad range of specialty areas including synthesis, structure, spectroscopy, and mechanism. In each of these fields, the strength of the department has been recognized at the international level.
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Item Antimicrobial activity of naturally occurring phenols and derivatives against biofilm and planktonic bacteria(2019-10) Walsh, Danica J.; Livinghouse, Tom; Goeres, Darla M.; Mettler, Madelyn; Stewart, Philip S.Biofilm-forming bacteria present formidable challenges across diverse settings, and there is a need for new antimicrobial agents that are both environmentally acceptable and relatively potent against microorganisms in the biofilm state. The antimicrobial activity of three naturally occurring, low molecular weight, phenols, and their derivatives were evaluated against planktonic and biofilm Staphylococcus epidermidis and Pseudomonas aeruginosa. The structure activity relationships of eugenol, thymol, carvacrol, and their corresponding 2- and 4-allyl, 2-methallyl, and 2- and 4-n-propyl derivatives were evaluated. Allyl derivatives showed a consistent increased potency with both killing and inhibiting planktonic cells but they exhibited a decrease in potency against biofilms. This result underscores the importance of using biofilm assays to develop structure-activity relationships when the end target is biofilm.Item Reaction centers of the thermophilic microaerophile, Chloracidobacterium thermophilum (Acidobacteria) I: biochemical and biophysical characterization(Springer Science and Business Media LLC, 2019-06) He, Zhihui; Ferlez, Bryan; Kurashov, Vasily; Tank, Marcus; Golbeck, John H.; Bryant, Donald A.Chloracidobacterium thermophilum is a microaerophilic, anoxygenic member of the green chlorophototrophic bacteria. This bacterium is the first characterized oxygen-requiring chlorophototroph with chlorosomes, the FMO protein, and homodimeric type-1 reaction centers (RCs). The RCs of C. thermophilum are also unique because they contain three types of chlorophylls, bacteriochlorophyll aP esterified with phytol, Chl aPD esterified with D2,6- phytadienol, and Zn-BChl aP¢ esterified with phytol, in the approximate molar ratio 32:24:4. The light-induced difference spectrum of these RCs had a bleaching maximum at 839 nm and also revealed an electrochromic bandshift that is probably derived from a BChl a molecule near P840+. The FX [4Fe-4S] cluster had a midpoint potential of ca. –581 mV, and the spectroscopic properties of the P+ FX– spin-polarized radical-pair were very similar to those of reaction centers of heliobacteria and green sulfur bacteria. The data further indicate that electron transfer occurs directly from A0– to FX, as occurs in other homodimeric Type-1 RCs. Washing experiments with isolated membranes suggested that the PscB subunit of these reaction centers is more tightly bound than PshB in heliobacteria. Thus, the reaction centers of C. thermophilum have some properties that resemble other homodimeric reaction centers but also have specific properties that are more similar to those of Photosystem I. These differences probably contribute to protection of the electron transfer chain from oxygen, contributing to the oxygen tolerance of this microaerophile.Item Enabling microbial syringol conversion through structure-guided protein engineering(2019-07-19) Machovina, Melodie M.; Mallinson, Sam J. B.; Knott, Brandon C.; Meyers, Alexander W.; Garcia-Borras, Marc; Bu, Lintao; Gado, Japheth E.; Oliver, April; Schmidt, Graham P.; Hinchen, Daniel J.; Crowley, Michael F.; Johnson, Christopher W.; Neidle, Ellen L.; Payne, Christina M.; Houk, Kendall N.; Beckham, Gregg T.; McGeehan, John E.; DuBois, Jennifer L.Microbial conversion of aromatic compounds is an emerging and promising strategy for valorization of the plant biopolymer lignin. A critical and often rate-limiting reaction in aromatic catabolism is O-aryl-demethylation of the abundant aromatic methoxy groups in lignin to form diols, which enables subsequent oxidative aromatic ring-opening. Recently, a cytochrome P450 system, GcoAB, was discovered to demethylate guaiacol (2-methoxyphenol), which can be produced from coniferyl alcohol-derived lignin, to form catechol. However, native GcoAB has minimal ability to demethylate syringol (2,6-dimethoxyphenol), the analogous compound that can be produced from sinapyl alcohol-derived lignin. Despite the abundance of sinapyl alcohol-based lignin in plants, no pathway for syringol catabolism has been reported to date. Here we used structure-guided protein engineering to enable microbial syringol utilization with GcoAB. Specifically, a phenylalanine residue (GcoA-F169) interferes with the binding of syringol in the active site, and on mutation to smaller amino acids, efficient syringol O-demethylation is achieved. Crystallography indicates that syringol adopts a productive binding pose in the variant, which molecular dynamics simulations trace to the elimination of steric clash between the highly flexible side chain of GcoA-F169 and the additional methoxy group of syringol. Finally, we demonstrate in vivo syringol turnover in Pseudomonas putida KT2440 with the GcoA-F169A variant. Taken together, our findings highlight the significant potential and plasticity of cytochrome P450 aromatic O-demethylases in the biological conversion of lignin-derived aromatic compounds.Item Zeolite-Templated Carbon as the Cathode for a High Energy Density Dual-Ion Battery(2019-04) Dubey, Romain J. -C.; Nussli, Jasmin; Piveteau, Laura; Kravchyk, Kostiantyn V.; Rossell, Marta D.; Campanini, Marco; Erni, Rolf; Kovalenko, Maksym V.; Stadie, Nicholas P.Dual-ion batteries (DIBs) are electrochemical energy storage devices that operate by the simultaneous participation of two different ion species at the anode and cathode and rely on the use of an electrolyte that can withstand the high operation potential of the cathode. Under such conditions at the cathode, issues associated with the irreversible capacity loss and the formation of solid-electrolyte interphase at the surface of highly porous electrode materials are far less significant than at lower potentials, permitting the exploration of high surface area, permanently porous framework materials as effective charge storage media. This concept is investigated herein by employing zeolite-templated carbon (ZTC) as a cathode in a dual-ion battery based on a potassium bis(fluorosulfonyl)imide (KFSI) electrolyte. Anion (FSI-) insertion within the pore network during electrochemical cycling is confirmed by NMR spectroscopy, and the maximum charge capacity is found to be proportional to surface area and micropore volume by comparison to other microporous carbon materials. Full cells based on ZTC as the cathode exhibit both high specific energy (up to 176 Wh kg-1, 79.8 Wh L-1) and high specific power (up to 3945 W kg-1, 1095 W L-1), stable cycling performance over hundreds of cycles, and reversibility within the potential range of 2.65-4.7 V versus K/K+.Item Characterization of synovial fluid metabolomic phenotypes of cartilage morphological changes associated with osteoarthritis(2019-08) Carlson, Alyssa K.; Rawle, Rachel A.; Wallace, Cameron W.; Brooks, Ellen G.; Adams, Erik; Greenwood, Mark C.; Olmer, Merissa; Lotz, Martin K.; Bothner, Brian; June, Ronald K."Objective Osteoarthritis (OA) is a multifactorial disease with etiological heterogeneity. The objective of this study was to classify OA subgroups by generating metabolomic phenotypes from human synovial fluid. Design: Post mortem synovial fluids (n = 75) were analyzed by high performance-liquid chromatography mass spectrometry (LC-MS) to measure changes in the global metabolome. Comparisons of healthy (grade 0), early OA (grades I-II), and late OA (grades III-IV) donor populations were considered to reveal phenotypes throughout disease progression. Results: Global metabolomic profiles in synovial fluid were distinct between healthy, early OA, and late OA donors. Pathways differentially activated among these groups included structural deterioration, glycerophospholipid metabolism, inflammation, central energy metabolism, oxidative stress, and vitamin metabolism. Within disease states (early and late OA), subgroups of donors revealed distinct phenotypes. Synovial fluid metabolomic phenotypes exhibited increased inflammation (early and late OA), oxidative stress (late OA), or structural deterioration (early and late OA) in the synovial fluid. Conclusion: These results revealed distinct metabolic phenotypes in human synovial fluid, provide insight into pathogenesis, represent novel biomarkers, and can move toward developing personalized interventions for subgroups of OA patients.Item Ligation state of nickel during C-O bond activation with monodentate phosphines(2018-11) Hooker, Leidy V.; Neufeldt, Sharon R.The oxidative addition of phenolic electrophiles at Ni(0) in the presence of monodentate phosphine ligands was studied with both dispersion-free and dispersion-containing DFT methods. With the popular bulky ligand PCy3, consideration of dispersion has a striking effect on the predicted ligation state of nickel during oxidative addition of aryl sulfamates. Dispersion-containing methods such as M06L indicate a clear preference for a bis-phosphine ligated transition state (TS), while dispersion free methods like B3LYP strongly favor a mono-phosphine ligated TS. This discrepancy in predicted ligation state is also found with small phosphines (PMe3) in combination with some aryl electrophiles (carbamates, acetates, pivalates, chlorides), but a bis-PMe3-ligated TS is predicted regardless of dispersion for other electrophiles (sulfamates, mesylates, tosylates). DFT calculations that include dispersion also offer a possible explanation for the observed poor efficacy of PtBu3 as a ligand in Ni-catalyzed cross-coupling reactions.Item N-Heterocyclic Carbene Ligand-Controlled Chemodivergent Suzuki–Miyaura Cross Coupling(2019-09) Reeves, Emily K.; Humke, Jenna N.; Neufeldt, Sharon R.Two N-heterocyclic carbene ligands provide orthogonal chemoselectivity during the Pd-catalyzed Suzuki–Miyaura (SM) cross-coupling of chloroaryl triflates. The use of SIPr [SIPr = 1,3-bis(2,6-diisopropylphenyl)-4,5-dihydroimidazol-2-ylidene] leads to selective cross-coupling at chloride, while the use of SIMes [SIMes = 1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene] provides selective coupling at triflate. With most chloroaryl triflates and arylboronic acids, ligand-controlled selectivity is high (≥10:1). The scope of this methodology is significantly more general than previously reported methods for selective SM coupling of chloroaryl triflates using phosphine ligands. Density functional theory studies suggest that palladium’s ligation state during oxidative addition is different with SIMes compared to SIPr.Item Carbon metabolism modulates the efficacy of drugs targeting the cytochrome bc1:aa3 in Mycobacterium tuberculosis(2019-06) Kalia, Nitin P.; Shi Lee, Bei; Ab Rahman, Nurlilah B.; Moraski, Garrett C.; Miller, Marvin J.; Pethe, KevinThe influence of carbon metabolism on oxidative phosphorylation is poorly understood in mycobacteria. M. tuberculosis expresses two respiratory terminal oxidases, the cytochrome bc1:aa3 and the cytochrome bd oxidase, which are jointly required for oxidative phosphorylation and mycobacterial viability. The essentiality of the cytochrome bc1:aa3 for optimum growth is illustrated by its vulnerability to chemical inhibition by the clinical drug candidate Q203 and several other chemical series. The cytochrome bd oxidase is not strictly essential for growth but is required to maintain bioenergetics when the function of the cytochrome bc1:aa3 is compromised. In this study, we observed that the potency of drugs targeting the cytochrome bc1:aa3 is influenced by carbon metabolism. The efficacy of Q203 and related derivatives was alleviated by glycerol supplementation. The negative effect of glycerol supplementation on Q203 potency correlated with an upregulation of the cytochrome bd oxidase-encoding cydABDC operon. Upon deletion of cydAB, the detrimental effect of glycerol on the potency of Q203 was abrogated. The same phenomenon was also observed in recent clinical isolates, but to a lesser extent compared to the laboratory-adapted strain H37Rv. This study reinforces the importance of optimizing in vitro culture conditions for drug evaluation in mycobacteria, a factor which appeared to be particularly essential for drugs targeting the cytochrome bc1:aa3 terminal oxidase.Item Nickel-Catalyzed Stille Cross Coupling of C-O Electrophiles(2019-04) Russell, John E.; Entz, Emily D.; Joyce, Ian M.; Neufeldt, Sharon R.Aryl sulfamates, tosylates, and mesylates undergo efficient Ni-catalyzed cross coupling with diverse organostannanes in the presence of relatively unhindered alkylphosphine ligands and KF. The coupling is valuable for difficult bond constructions, such as aryl-heteroaryl, aryl-alkenyl, and aryl-alkynyl, using nontriflate phenol derivatives. A combination of experimental and computational studies implicates an unusual mechanism for transmetalation involving an 8-centered cyclic transition state. This reaction is inhibited by chloride sources due to slow transmetalation of organostannanes at a Ni(II)-chloride intermediate. These studies help to explain why prior efforts to achieve Ni-catalyzed Stille coupling of phenol derivatives were unsuccessful.Item Langmuir's Theory of Adsorption: A Centennial Review(2019-04) Swenson, Hans; Stadie, Nicholas P.The 100th anniversary of Langmuir's theory of adsorption is a significant landmark for the physical chemistry and chemical engineering communities. Despite its simplicity, the Langmuir adsorption model captures the key physics of molecular interactions at interfaces and laid the foundation for further progress in understanding interfacial phenomena, developing new adsorbent materials, and designing engineering processes. The Langmuir model has had an exceptional impact on diverse fields within the chemical sciences (ranging from chemical biology to materials science), an impact that became clearer with the development of modified adsorption theories and continues to be relevant today.