Synthetic models of metalloenzymes

Metal ions play an important role in the enzymic catalysis of many metalloproteins. The molecular details of the catalytic cycle are often obscured by the complexity of the biological system. It has been the goal of our research for the past few years to elucidate the mechanisms of metalloenzymes through the synthesis of simple metal complexes that mimic the structure of the active sites. The reactivity of such metal complexes have provided insights into the enzyme mechanism. Further, successful enzyme models have provided a rational basis for the construction of synthetic, biomimetic catalysts. In this lecture, recent advances in the study of active site models of carboxypeptidase A, CPA, a zinc-containing protease, and cytochrome P-450, a heme-containing monooxygenase will be described.The role of zinc in the peptidase activity of CPA has been ascribed to coordination of the substrate amide carbonyl, coordination of a nucleophilic hydroxide or even to a less specific structural role. To choose among these possibilities we have synthesized a family of metal-complexing amides which does not allow a metal-carbonyl interaction. Large zinc- and copper-mediated rate enhancements (104---107) for amide hydrolysis are observed with these compounds. Kinetic and titrimetric measurements indicate that the deprotonation of a metal-bound water is a component of this catalysis. A mechanism for amide hydrolysis involving nucleophilic attack of a metal hydroxide is consistent with the observed results.The catalytic cycle of cytochrome P-450 has been suggested to involve a reactive oxo-iron intermediate which is responsible for oxygen transfer to the substrate. We have prepared the first synthetic example of an iron(IV)-porphyrin cation radical complex (1). This species has been shown to be extraordinarily reactive toward hydrocarbons. The physico-chemical characterization of 1 and the elucidation of the mechanism of olefin epoxidation and alkane hydroxylation will be described.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/25361/1/0000809.pd

Oxygen Activation and Radical Transformations in Heme Proteins and Metalloporphyrins

As a result of the adaptation of life to an aerobic environment, nature has evolved a panoply of metalloproteins for oxidative metabolism and protection against reactive oxygen species. Despite the diverse structures and functions of these proteins, they share common mechanistic grounds. An open-shell transition metal like iron or copper is employed to interact with O_2 and its derived intermediates such as hydrogen peroxide to afford a variety of metal–oxygen intermediates. These reactive intermediates, including metal-superoxo, -(hydro)peroxo, and high-valent metal–oxo species, are the basis for the various biological functions of O_2-utilizing metalloproteins. Collectively, these processes are called oxygen activation. Much of our understanding of the reactivity of these reactive intermediates has come from the study of heme-containing proteins and related metalloporphyrin compounds. These studies not only have deepened our understanding of various functions of heme proteins, such as O2 storage and transport, degradation of reactive oxygen species, redox signaling, and biological oxygenation, etc., but also have driven the development of bioinorganic chemistry and biomimetic catalysis. In this review, we survey the range of O_2 activation processes mediated by heme proteins and model compounds with a focus on recent progress in the characterization and reactivity of important iron–oxygen intermediates. Representative reactions initiated by these reactive intermediates as well as some context from prior decades will also be presented. We will discuss the fundamental mechanistic features of these transformations and delineate the underlying structural and electronic factors that contribute to the spectrum of reactivities that has been observed in nature as well as those that have been invented using these paradigms. Given the recent developments in biocatalysis for non-natural chemistries and the renaissance of radical chemistry in organic synthesis, we envision that new enzymatic and synthetic transformations will emerge based on the radical processes mediated by metalloproteins and their synthetic analogs

Stereospecific aliphatic hydroxylation upon photoreduction of iron (III)

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/22203/1/0000634.pd

Respiratory viral infection alters the gut microbiota by inducing inappetence

ABSTRACT Respiratory viral infections are extremely common, but their impacts on the composition and function of the gut microbiota are poorly understood. We previously observed a significant change in the gut microbiota after viral lung infection. Here, we show that weight loss during respiratory syncytial virus (RSV) or influenza virus infection was due to decreased food consumption, and that the fasting of mice altered gut microbiota composition independently of infection. While the acute phase tumor necrosis factor alpha (TNF-α) response drove early weight loss and inappetence during RSV infection, this was not sufficient to induce changes in the gut microbiota. However, the depletion of CD8+ cells increased food intake and prevented weight loss, resulting in a reversal of the gut microbiota changes normally observed during RSV infection. Viral infection also led to changes in the fecal gut metabolome, with a significant shift in lipid metabolism. Sphingolipids, polyunsaturated fatty acids (PUFAs), and the short-chain fatty acid (SCFA) valerate were all increased in abundance in the fecal metabolome following RSV infection. Whether this and the impact of infection-induced anorexia on the gut microbiota are part of a protective anti-inflammatory response during respiratory viral infections remains to be determined. IMPORTANCE The gut microbiota has an important role in health and disease: gut bacteria can generate metabolites that alter the function of immune cells systemically. Understanding the factors that can lead to changes in the gut microbiome may help to inform therapeutic interventions. This is the first study to systematically dissect the pathway of events from viral lung infection to changes in gut microbiota. We show that the cellular immune response to viral lung infection induces inappetence, which in turn alters the gut microbiome and metabolome. Strikingly, there was an increase in lipids that have been associated with the resolution of disease. This opens up new paths of investigation: first, what is the (presumably secreted) factor made by the T cells that can induce inappetence? Second, is inappetence an adaptation that accelerates recovery from infection, and if so, does the microbiome play a role in this

Tectonic influences on the preservation of marine terraces: Old and new evidence from Santa Catalina Island, California

The California Channel Islands contain some of the best geologic records of past climate and sea-level changes, recorded in uplifted, fossil-bearing marine terrace deposits. Among the eight California Channel Islands and the nearby Palos Verdes Hills, only Santa Catalina Island does not exhibit prominent emergent marine terraces, though the same terrace-forming processes that acted on the other Channel Islands must also have occurred on Santa Catalina. We re-evaluated previous researchers\u27 field evidence and examined new topographic, bathymetric, and stream-profile data in order to find possible explanations for the lack of obvious marine terrace landforms or deposits on the island today. The most likely explanation is associated with the island\u27s unresolved tectonic history, with evidence for both recent uplift and subsidence being offered by different researchers. Bathymetric and seismic reflection data indicate the presence of submerged terrace-like landforms from a few meters below present sea level to depths far exceeding that of the lowest glacial lowstand, suggesting that the Catalina Island block may have subsided, submerging marine terraces that would have formed in the late Quaternary. Similar submerged marine terrace landforms exist offshore of all of the other California Channel Islands, including some at anomalously great depths, but late Quaternary uplift is well documented on those islands. Therefore, such submarine features must be more thoroughly investigated and adequately explained before they can be accepted as definitive evidence of subsidence. Nevertheless, the striking similarity of the terrace-like features around Santa Catalina Island to those surrounding the other, uplifting, Channel Islands prompted us to investigate other lines of evidence of tectonic activity, such as stream profile data. Recent uplift is suggested by disequilibrium stream profiles on the western side of the island, including nickpoints and profile convexities. Rapid uplift is also indicated by the island\u27s highly dissected, steep topography and abundant landslides. A likely cause of uplift is a restraining bend in the offshore Catalina strike-slip fault. Our analysis suggests that Santa Catalina Island has recently experienced, and may still be experiencing, relatively rapid uplift, causing intense landscape rejuvenation that removed nearly all traces of marine terraces by erosion. A similar research approach, incorporating submarine as well as subaerial geomorphic data, could be applied to many tectonically active coastlines in which a marine terrace record appears to be missing

Oxidative Aliphatic C-H Fluorination with Fluoride Ion Catalyzed by a Manganese Porphyrin

Despite the growing importance of fluorinated organic compounds in drug development, there are no direct protocols for the fluorination of aliphatic C-H bonds using conveniently handled fluoride salts. We have discovered that a manganese porphyrin complex catalyzes alkyl fluorination by fluoride ion under mild conditions in conjunction with stoichiometric oxidation by iodosylbenzene. Simple alkanes, terpenoids, and even steroids were selectively fluorinated at otherwise inaccessible sites in 50 to 60% yield. Decalin was fluorinated predominantly at the C2 and C3 methylene positions. Bornyl acetate was converted to exo-5-fluoro-bornyl acetate, and 5α-androstan-17-one was fluorinated selectively in the A ring. Mechanistic analysis suggests that the regioselectivity for C-H bond cleavage is directed by an oxomanganese(V) catalytic intermediate followed by F delivery via an unusual manganese(IV) fluoride that has been isolated and structurally characterized

Late Quaternary sea-level history and the antiquity of mammoths (\u3ci\u3eMammuthus exilis\u3c/i\u3e and \u3ci\u3eMammuthus columbi\u3c/i\u3e), Channel Islands National Park, California, USA

Fossils of Columbian mammoths (Mammuthus columbi) and pygmymammoths (Mammuthus exilis) have been reported from Channel Islands National Park, California. Most date to the last glacial period (Marine Isotope Stage [MIS] 2), but a tusk of M. exilis (or immature M. columbi) was found in the lowest marine terrace of Santa Rosa Island. Uranium-series dating of corals yielded ages from 83.8 ± 0.6 ka to 78.6 ± 0.5 ka, correlating the terrace withMIS 5.1, a time of relatively high sea level.Mammoths likely immigrated to the islands by swimming during the glacial periodsMIS 6 (~150 ka) orMIS 8 (~250 ka),when sea levelwas lowand the island–mainland distance was minimal, as during MIS 2. Earliest mammoth immigration to the islands likely occurred late enough in the Quaternary that uplift of the islands and the mainland decreased the swimming distance to a range that could be accomplished by mammoths. Results challenge the hypothesis that climate change, vegetation change, and decreased land area from sea-level rise were the causes of mammoth extinction at the Pleistocene/ Holocene boundary on the Channel Islands. Pre-MIS 2 mammoth populations would have experienced similar or even more dramatic changes at the MIS 6/5.5 transition

A stereochemical probe of the fate of carbon radicals oxidized by metals

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/22205/1/0000636.pd

Care of patients with pulmonary arterial hypertension during the coronavirus (COVID-19) pandemic

The COVID-19 pandemic presents many unique challenges when caring for patients with pulmonary hypertension. The COVID-19 pandemic has altered routine standard of care practice and the acute management particularly for those patients with pulmonary arterial hypertension, where pulmonary arterial hypertension-specific treatments are used. It is important to balance the ongoing care and evaluation of pulmonary arterial hypertension patients with exposure risk to COVID-19 for patients coming to clinic or the hospital. If there is a morbidity and mortality benefit from starting pulmonary arterial hypertension therapies, for example in a patient with high-likelihood of pulmonary arterial hypertension, then it remains important to complete the thorough evaluation. However, the COVID-19 outbreak may also represent a unique time when pulmonary hypertension experts have to weigh the risks and benefits of the diagnostic work-up including potential exposure to COVID-19 versus initiating targeted pulmonary arterial hypertension therapy in a select high-risk, high likelihood World Symposium Pulmonary Hypertension Group 1 pulmonary arterial hypertension patients. This document will highlight some of the issues facing providers, patients, and the pulmonary arterial hypertension community in real-time as the COVID-19 pandemic is evolving and is intended to share expected common clinical scenarios and best clinical practices to help the community at-large