Oxygen Activation by Mononuclear Mn, Co, and Ni Centers in Biology and Synthetic Complexes

The active sites of metalloenzymes that catalyze O2-dependent reactions generally contain iron or copper ions. However, several enzymes are capable of activating O2 at manganese or nickel centers instead, and a handful of dioxygenases exhibit activity when substituted with cobalt. This minireview summarizes the catalytic properties of oxygenases and oxidases with mononuclear Mn, Co, or Ni active sites, including oxalate-degrading oxidases, catechol dioxygenases, and quercetin dioxygenase. In addition, recent developments in the O2 reactivity of synthetic Mn, Co, or Ni complexes are described, with an emphasis on the nature of reactive intermediates featuring superoxo-, peroxo-, or oxo-ligands. Collectively, the biochemical and synthetic studies discussed herein reveal the possibilities and limitations of O2 activation at these three “overlooked” metals

A Synthetic Model of the Nonheme Iron–Superoxo Intermediate of Cysteine Dioxygenase

A nonheme Fe(II) complex (1) that models substrate-bound cysteine dioxygenase (CDO) reacts with O2 at −80 °C to yield a purple intermediate (2). Analysis with spectroscopic and computational methods determined that 2 features a thiolate-ligated Fe(III) center bound to a superoxide radical, mimicking the putative structure of a key CDO intermediate

A Domestic Geography of Money: How Mortgage Debt, Home Prices, and Toronto’s Condominiums “Prop up” the Canadian Economy

The most recent financialized redefinition of the home in Canada has arisen in response to the global financial crisis of 2008. The global financial crisis negatively impacted nations around the world, yet, in Canada the effects were lightly felt. In response to this crisis, Canadian banks received significant financial support from the government through the Insured Mortgage Purchase Program and the Canada Mortgage Bond program totaling roughly $137.55 billion. These two programs incentivized Canadian lenders to relax mortgage qualifying standards, to generate increased mortgage debt which could then be packaged into mortgage backed securities. Through discourse analysis of primarily government reports, this thesis contextualizes the inflation of house prices and household debt since the global financial crisis and considers how an “adverse economic event” may cause a downward spiral of unemployment, mortgage default, and a steep decline in house prices. It examines the significance of Toronto and its condominium market in “propping up” the economy through the increased generation of mortgage debt. It is through this urban, geographical analysis that we see the human and physical realization of Canada’s current economic milieu

Quantitative Analysis of Traffic Related Air Pollution Along the Atlanta BeltLine East Side Trail

INTRODUCTION: Air pollution in urban areas has been a growing concern in the public health sector, especially with regards to negative health effects from traffic-related air pollution. AIM: The aim of this study is to quantify air pollution levels along the Atlanta BeltLine Eastside Trail, a popular urban trail located in Downtown Atlanta, and compare the pollution levels to measurements taken along a nearby roadway. The goal is to ultimately determine if there are any significant differences between air quality along the BeltLine and air quality along nearby roadways. No statistical significance in the data would suggest that individuals utilizing the BeltLine are exposed to the same levels of traffic-related air pollutants that are present on nearby roadways. METHODS: Samples were collected along the Eastside Trail of the BeltLine and along neighboring roads over the course of 11 days using a mobile monitoring platform. Four parameters of air quality were measured- Optical Particle Counter (OPC) volume concentration, particle number concentration, median particle diameter, and black carbon levels. A paired t-test was conducted to assess any statistical significance between samples taken along the BeltLine versus samples taken along nearby roadways. RESULTS: While there was some statistical significance between recorded air pollution levels for individual days, the overall results showed no statistical significance for any of the air quality parameters that were examined. DISCUSSION: The findings of this study indicate that individuals utilizing the BeltLine have the potential to be exposed to the same levels of air pollutants found along roadways

Spectroscopic and Computational Studies of Reversible O\u3csub\u3e2\u3c/sub\u3e Binding by a Cobalt Complex of Relevance to Cysteine Dioxygenase

The substitution of non-native metal ions into metalloenzyme active sites is a common strategy for gaining insights into enzymatic structure and function. For some nonheme iron dioxygenases, replacement of the Fe(II) center with a redox-active, divalent transition metal (e.g., Mn, Co, Ni, Cu) gives rise to an enzyme with equal or greater activity than the wild-type enzyme. In this manuscript, we apply this metal-substitution approach to synthetic models of the enzyme cysteine dioxygenase (CDO). CDO is a nonheme iron dioxygenase that initiates the catabolism of L-cysteine by converting this amino acid to the corresponding sulfinic acid. Two mononuclear Co(II) complexes (3 and 4) have been prepared with the general formula [Co2+(TpR2)(CysOEt)] (R = Ph (3) or Me (4); TpR2 = hydrotris(pyrazol-1-yl)borate substituted with R-groups at the 3- and 5-positions, and CysOEt is the anion of L-cysteine ethyl ester). These Co(II) complexes mimic the active-site structure of substrate-bound CDO and are analogous to functional iron-based CDO models previously reported in the literature. Characterization with X-ray crystallography and/or 1H NMR spectroscopy revealed that 3 and 4 possess five-coordinate structures featuring facially-coordinating TpR2 and S,N-bidentate CysOEt ligands. The electronic properties of these high-spin (S = 3/2) complexes were interrogated with UV-visible absorption and X-band electron paramagnetic resonance (EPR) spectroscopies. The air-stable nature of complex 3 replicates the inactivity of cobalt-substituted CDO. In contrast, complex 4 reversibly binds O2 at reduced temperatures to yield an orange chromophore (4-O2). Spectroscopic (EPR, resonance Raman) and computational (density functional theory, DFT) analyses indicate that 4-O2 is a S = 1/2 species featuring a low-spin Co(III) center bound to an end-on (η1) superoxo ligand. DFT calculations were used to evaluate the energetics of key steps in the reaction mechanism. Collectively, these results have elucidated the role of electronic factors (e.g., spin-state, d-electron count, metal–ligand covalency) in facilitating O2 activation and S-dioxygenation in CDO and related models

Modeling Water Age and Disinfection Byproduct Formation in Drinking Water Distribution Systems in East Tennessee

Chlorine disinfection of drinking waters is responsible for the standard of health we enjoy today and the eradication of waterborne disease. Chlorine also reacts with natural organic matter (NOM) to form disinfection byproducts (DBPs) which have been linked to cancer as well as reproductive and developmental issues. The exact mechanism for formation of regulated DBPs, trihalomethanes (THMs) and haloacetic acids (HAAs), is unknown. The literature has identified relationships between DBP formation and, most notably, characteristics of NOM, chlorine contact time, temperature, pH [negative log of hydrogen ion concentration], and chlorine dose. This study develops models both specific to individual utilities, and general to utilities with surface water sources using NaClO [sodium hypochlorite] for disinfection within the geographic region of East Tennessee. The study utilizes existing data from four utilities collected for compliance with regulations. Calibrated hydraulic models of the four distribution systems are employed to accurately determine water age (chlorine contact time) in the distribution system, often a limitation of field scale models. Multivariate power functions predict THMs and HAAs for individual utilities and across utilities with similar raw water characteristics and treatment processes. R2 [coefficient of determination] ranges from 0.52 to 0.80. Developed models account for actual distribution system conditions, including water age, and predict THM and HAA levels for the four utilities with a higher R2 value than applicable existing lab scale and field scale models. Results arm utilities with strategies to develop specific DBP models using existing data, control DBP levels, improve quality of drinking water, and achieve compliance with regulations

Employing the enzyme cofactor function of ascorbic acid to affect oncogenic pathways in human melanoma: modulating Hypoxia Inducible Factor-1α and DNA demethylation to reduce malignant potential

Dioxygenase enzymes such as the HIF hydroxylases (PHD1-3, FIH) and the Ten-eleven translocation (TET1-3) enzymes regulate the activity of the hypoxia inducible factor-1a (HIF1a) transcription factor and the DNA methylation status of cells, respectively. Aberrant accumulation and activation of HIF-1a can allow malignant cells to acquire attributes that promote progression, chemotherapy resistance, and survival, while aberrant hypermethylation of gene promoters can silence the expression of tumor suppressor genes essential to preventing tumorigenesis. Inadequate levels of intracellular ascorbic acid (AA), a necessary cofactor for optimal dioxygenase enzyme function, could potentiate these tumorigenic conditions. In fact, plasma levels of AA have been found to be below normal physiological levels in individuals with melanoma, as well as other cancer types. Interestingly, melanoma tumors frequently demonstrate both high expression of HIF-1a and increased promoter methylation. AA therefore may present a valuable adjuvant therapy option for melanoma patients by regulating the HIF-1 and DNA demethylation pathways. In these studies, we investigated the ability of AA supplementation to decrease aberrant HIF-1a accumulation and activity in melanoma cell lines and to increase global 5-hydroxymethylcytosine (5hmC) content of DNA in metastatic melanoma to ultimately reduce the malignant potential. Our studies showed that treatment with AA (reduced vitamin C) significantly increased intracellular vitamin C content of cultured melanoma cells and significantly decreased the stability, accumulation, and transcriptional activity of HIF-1α. Supplementation with AA also significantly increased global 5hmC content and ultimately resulted in the significant decrease of malignant potential of metastatic melanoma cells. Additionally, we discovered novel evidence that HIF-1α may regulate the DNA methylation status of melanoma cells by influencing the expression of TET2. Taken together, these results suggest that deficiencies in AA levels, commonly observed in malignant tissue and blood plasma of cancer patients, may be a contributing factor to the deregulation of the HIF-1α and DNA demethylation pathways. Deregulation of these pathways is likely due to the loss of its cofactor function for the dioxygenase enzymes that tightly regulate various oncogenic factors. Furthermore, AA has the potential to be a powerful adjuvant therapy for metastatic melanoma, and further investigations in multiple cancer types are warranted to advance the use of AA to the clinical setting

Synthesis, X-ray Structures, Electronic Properties, and O\u3csub\u3e2\u3c/sub\u3e/NO Reactivities of Thiol Dioxygenase Active-Site Models

Mononuclear non-heme iron complexes that serve as structural and functional mimics of the thiol dioxygenases (TDOs), cysteine dioxygenase (CDO) and cysteamine dioxygenase (ADO), have been prepared and characterized with crystallographic, spectroscopic, kinetic, and computational methods. The high-spin Fe(II) complexes feature the facially coordinating tris(4,5-diphenyl-1-methylimidazol-2-yl)phosphine (Ph2TIP) ligand that replicates the three histidine (3His) triad of the TDO active sites. Further coordination with bidentate l-cysteine ethyl ester (CysOEt) or cysteamine (CysAm) anions yielded five-coordinate (5C) complexes that resemble the substrate-bound forms of CDO and ADO, respectively. Detailed electronic-structure descriptions of the [Fe(Ph2TIP)(LS,N)]BPh4 complexes, where LS,N = CysOEt (1) or CysAm (2), were generated through a combination of spectroscopic techniques [electronic absorption, magnetic circular dichroism (MCD)] and density functional theory (DFT). Complexes 1 and 2 decompose in the presence of O2 to yield the corresponding sulfinic acid (RSO2H) products, thereby emulating the reactivity of the TDO enzymes and related complexes. Rate constants and activation parameters for the dioxygenation reactions were measured and interpreted with the aid of DFT calculations for O2-bound intermediates. Treatment of the TDO models with nitric oxide (NO)—a well-established surrogate of O2—led to a mixture of high-spin and low-spin {FeNO}7 species at low temperature (−70 °C), as indicated by electron paramagnetic resonance (EPR) spectroscopy. At room temperature, these Fe/NO adducts convert to a common species with EPR and infrared (IR) features typical of cationic dinitrosyl iron complexes (DNICs). To complement these results, parallel spectroscopic, computational, and O2/NO reactivity studies were carried out using previously reported TDO models that feature an anionic hydrotris(3-phenyl-5-methyl-pyrazolyl)borate (Ph,MeTp–) ligand. Though the O2 reactivities of the Ph2TIP- and Ph,MeTp-based complexes are quite similar, the supporting ligand perturbs the energies of Fe 3d-based molecular orbitals and modulates Fe–S bond covalency, suggesting possible rationales for the presence of neutral 3His coordination in CDO and ADO

Deterministic 3SUM-Hardness

As one of the three main pillars of fine-grained complexity theory, the 3SUM problem explains the hardness of many diverse polynomial-time problems via fine-grained reductions. Many of these reductions are either directly based on or heavily inspired by P\u{a}tra\c{s}cu's framework involving additive hashing and are thus randomized. Some selected reductions were derandomized in previous work [Chan, He; SOSA'20], but the current techniques are limited and a major fraction of the reductions remains randomized. In this work we gather a toolkit aimed to derandomize reductions based on additive hashing. Using this toolkit, we manage to derandomize almost all known 3SUM-hardness reductions. As technical highlights we derandomize the hardness reductions to (offline) Set Disjointness, (offline) Set Intersection and Triangle Listing -- these questions were explicitly left open in previous work [Kopelowitz, Pettie, Porat; SODA'16]. The few exceptions to our work fall into a special category of recent reductions based on structure-versus-randomness dichotomies. We expect that our toolkit can be readily applied to derandomize future reductions as well. As a conceptual innovation, our work thereby promotes the theory of deterministic 3SUM-hardness. As our second contribution, we prove that there is a deterministic universe reduction for 3SUM. Specifically, using additive hashing it is a standard trick to assume that the numbers in 3SUM have size at most $n^3$. We prove that this assumption is similarly valid for deterministic algorithms.Comment: To appear at ITCS 202