1997 — 1998 |
Hegg, Eric L. |
F32Activity Code Description: To provide postdoctoral research training to individuals to broaden their scientific background and extend their potential for research in specified health-related areas. |
Structure/Mechanism of Alpha-Keto Acid Dependent Enzymes @ University of Minnesota Twin Cities
oxygenases; enzyme structure; enzyme model; ketoacid; enzyme mechanism; thermodynamics; chemical kinetics; X ray crystallography; Raman spectrometry; nuclear magnetic resonance spectroscopy; electron spin resonance spectroscopy;
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0.94 |
2002 — 2006 |
Hegg, Eric L. |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Elucidating the Biosynthesis and Transport of Heme A @ Michigan State University
[unreadable] DESCRIPTION (provided by applicant): Cytochrome c oxidase is the terminal oxidase in all plants, animals, aerobic yeasts, and some bacteria. Catalyzing the reduction of molecular oxygen to water concomitant with the pumping of protons across the inner mitochondrial membrane, cytochrome c oxidase generates a proton gradient responsible for approximately 50 percent of the ATP formed during eukaryotic aerobic metabolism. Heme A is an obligatory cofactor in eukaryotic cytochrome c oxidase, present at both an electron transfer site and the site of oxygen reduction. Heme A differs from heme B (protoheme) in that a farnesyl moiety has been added to one of the vinyl groups, and a methyl substituent has been oxidized to an aldehyde. These conversions (both of which are required to obtain active cytochrome c oxidase) are catalyzed by heme 0 synthase and heme A synthase, respectively. Surprisingly, despite the obvious importance of heme A to both cytochrome c oxidase and the energy transduction pathway, very little is known about how heme A is synthesized, how it is transported, or how it is inserted into cytochrome c oxidase.The focus of this research is to elucidate the biosynthesis of heme A and its method of transport, including the formation of associated multi-component complexes. Preliminary data obtained in this lab demonstrates that heme A synthase alters the activity of heme 0 synthase, suggesting that the two enzymes are part of a larger protein complex. We have also obtained the first direct evidence indicating that heme A synthase represents a novel heme-containing oxygenase. To confirm these tantalizing results and to enhance our understanding of heme A biosynthesis and transport, an interdisciplinary research plan has been developed. Biochemical and molecular approaches will be used to define specific macromolecular complexes and protein-protein interactions involving heme A synthase. The proteins hypothesized to interact with heme A synthase are 1) heme 0 synthase, 2) two COX1 translation activators of the mitochondrial ribosome complex, and 3) subunit I of cytochrome c oxidase. In addition, a variety of chemical and spectroscopic techniques will be employed to 1) fully characterize the active site of heme A synthase, 2) determine the nature of the active oxidant, and 3) elucidate the mechanism of heme A biosynthesis. Combined, the proposed experiments represent a comprehensive attack on heme A synthase, thus providing fundamental information about the assembly of cytochrome c oxidase and further insight into biological 02 activation.
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1 |
2004 — 2010 |
Hegg, Eric |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Career: Modeling Acetyl-Coa Synthase - Novel Bioinorganic Chemistry At a Dinuclear Site @ Michigan State University
This CAREER award by the Inorganic, Bioinorganic, and Organometallic Chemistry program supports work by Professor Eric Hegg at the Michigan State University to model the active site of acetyl-CoA synthase. This unusual enzyme allows certain organisms to use carbon dioxide as their sole carbon source. Model complexes will be prepared that will lead to a better understanding of the active site and the reaction mechanism of acetyl-CoA synthase. Ultimately this work will provide important information concerning acetyl-CoA biosynthesis and enzymatic C1/C2 chemistry.
Integrated within this research is an educational component designed to improve undergraduate biochemistry courses. A major thrust of this plan is to develop and utilize computer-based laboratory modules that will allow students to apply the concepts learned in class, demonstrate real-world applications of the information covered in the course, and expose them to the many new technologies required in modern biochemical research.
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0.915 |
2011 — 2015 |
Ostrom, Nathaniel [⬀] Hegg, Eric Lennon, Jay Bhattacharya, Sourendra |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Do Biological Processes Result in the 17-O Mass Independent Anomaly in Atmospheric Nitrous Oxide? Resolution and Establishment of 17-O as a Tracer of Microbial Production @ Michigan State University
Nitrous oxide (N2O) is one of the three most important biogenic greenhouse gases contributing to the human induced global warming trend over the past 150 years. Consequently, N2O is also an integral component of greenhouse gas accounting practices and included in both European and U.S. carbon markets (i.e. the Chicago Climate Exchange). While recent efforts by the IPCC have balanced the global N2O budget, great uncertainty remains. Nearly all materials on Earth have a consistent relationship between the 17O and 18O isotopes of oxygen that is termed mass dependence. Tropospheric N2O, however, is enriched in 17O relative to oxygen in mass dependence by 0.9 ?. This 17O anomaly in N2O has long been considered to reflect incorporation of 17O from photochemical reactions in the stratosphere and exchange of N2O between the stratosphere and troposphere. Recently it has been proposed that the 17O anomaly in N2O is biologically produced and the result of incorporation of oxygen from water into N2O during its microbial production. If correct, this would be the first observation of a biologically produced 17O anomaly. In this proposal the PIs will test three mechanisms by which the 17O anomaly may be introduced into biologically produced N2O: (1) exchange with water, (2) differential incorporation of oxygen from O2 and water, and (3) denitrification of atmospheric nitrate that carries a 17O anomaly. Further, they will test for the presence of a 17O anomaly during production by inorganic UV photo-oxidation. The PIs will pursue a variety of approaches to evaluate the potential for biological N2O to generate a 17O anomaly that includes production of N2O from purified enzymes, pure microbial cultures and incubation of agricultural soils.
The presence of a 17O anomaly in biologically produced N2O has profound implications for understanding the origin of atmospheric N2O and the global budget of this important greenhouse gas by international organizations such as the IPCC. The instrumentation, methodologies, and knowledge of microbial N2O production that will be developed will become an integral component of a short course at MSU that involves graduate students, professors and professionals from across the country (Stable Isotope Biogeochemistry). The project will also involve a team undergraduate mechanical, electrical and computer engineering students who will develop and deploy an Eddy-covariance Trace Gas Trapping System that will enable collection of sufficient quantities of N2O in a plant canopy to constrain the iso-flux of N2O from soils to the atmosphere.
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0.915 |
2012 — 2015 |
Hegg, Eric L. |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Biosynthesis and Insertion of Heme a During Cytochrome C Oxidase Biogenesis @ Michigan State University
DESCRIPTION (provided by applicant): Heme A is an obligatory cofactor in eukaryotic cytochrome c oxidase (CcO), but little is known about how heme A is inserted into CcO, or how the flux of heme through the heme a biosynthetic pathway is coordinated to CcO assembly. Because CcO is indirectly responsible for ~50% of the ATP formed during aerobic metabolism, it is crucial that cells maintain a proper level of heme A, and deficiencies in heme a homeostasis lead to several clinical and fatal early-onset mitochondrial disorders. At the same time, however, excess heme a is toxic, and it is therefore critical for cells to regulate its production to ensure that there is sufficient, but not excess, heme A available. Our lack of understanding about the processes that affect heme a biosynthesis and its insertion into CcO represents a major knowledge gap in a fundamental aspect of aerobic metabolism. The objectives of this proposal are to reveal how the flux of heme through the heme a biosynthetic pathway is coupled to CcO biosynthesis and the key protein-protein interactions that assist and help regulate these processes. At least three different proteins are critical for the biosynthesis of heme A and its subsequent insertion into subunit 1 (Cox1) of CcO: heme O synthase (HOS), heme A synthase (HAS) and Surf1/Shy1. We hypothesize that HOS and HAS form distinct, large protein complexes that alter enzymatic activity. In our model, the HAS complex delivers heme A to Cox1 while Surf1/Shy1 aids in this process by stabilizing the newly inserted heme A and preventing its loss during assembly. We further hypothesize that the activity of HOS and HAS is coupled to Cox1 translation. These hypotheses will be tested by pursuing two specific aims: 1) characterize the relationship between heme A biosynthesis and CcO assembly, and 2) ascertain the significance of the HOS and HAS protein complexes. To accomplish these goals, we will employ both in vivo and in vitro studies using Rhodobacter sphaeroides and Saccharomyces cerevisiae as models. The proposed research is significant because it addresses two of the most central but also least understood aspects of CcO biogenesis. (1) How does the cell regulate the production of the vital yet toxic heme a cofactor? (2) How is heme A inserted into CcO? Our approach is innovative because we are simultaneously employing both R. sphaeroides and S. cerevisiae to capitalize on the stability and relative simplicity of bacterial oxidases while validating our results in a genetically tractable eukaryote. The synergy provided by employing both systems positions us to make rapid progress addressing these essential questions of CcO biogenesis. PUBLIC HEALTH RELEVANCE: Heme A is an obligatory cofactor in cytochrome c oxidase, the enzyme responsible for converting O2 to water and storing the energy as an electrochemical gradient during respiration. The proposed research on heme A homeostasis is relevant to public health because improper regulation of heme a levels leads to a variety of mitochondrial diseases including anemia, Leigh Syndrome, and infantile cardiomyopathy. We will reveal how heme a biosynthesis is regulated and how this critical cofactor is inserted during cytochrome c oxidase biogenesis.
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1 |
2020 — 2024 |
Hegg, Eric Anctil, Annick (co-PI) [⬀] Dorgan, John |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Efri E3p: Reincarnation of Polymers For the Circular Economy @ Michigan State University
The United States recycles less than 10% of generated plastic waste. Low recycling rates create problems including: 1) leakage of waste plastic into the natural environment and accompanying fragmentation into microplastic particulate pollution that negatively affects ecosystems and human health, 2) depletion of our oil and natural gas supplies - the need to use lots of energy to make new plastics, and 3) increased greenhouse gas emissions compared to using recycled materials. The microplastics pollution problem is particularly concerning because these small plastic particles are entering the human food chain, and the effects of microplastic consumption of these very small plastic particles is currently unknown. Furthermore, several analyses have shown enhanced recycling will lead to dramatic job growth; upwards of a million jobs could be created. In this Emerging Frontiers in Research and Innovation project an interdisciplinary and diverse team will work to transform the plastics industries to eliminate end-of-life waste. Revolutionary approaches to sorting, cleaning, and transforming waste plastics enables a transformational outcome; present ?end of life? thinking becomes holistic ?end of cycle? thinking as more plastics are repeatedly used rather than thrown into a dump. The knowledge and technologies developed through this research will enable greater rates of plastics recycling, more recycling creates jobs while helping to protect the environment and human health. Investing in improved recycling technologies will help the USA remain competitive in the ever-changing global economy. Participation in programmatic activities is inclusive and fostered by novel cross-disciplinary interaction with Community Sustainability programs and through delivery of outreach programs for K-12 and undergraduate college students. A Diversity Team will work in partnership with the tribal colleges of Michigan, which are Minority-serving institutions, to support meaningful participation in STEM research by the Native American community. A deep and culturally diverse awareness of sustainability issues will be fostered through incorporation of traditional learnings into program pedagogy.
The goal of the project is to develop and demonstrate new approaches to recycling plastics. The scope of the project includes novel ways to depolymerize polymers and repolymerize the products into valuable materials. Controlled experimentation complemented by chemical kinetic models, molecular-scale simulations, and machine learning are the primary methods used. Specialized expertise in life cycle analysis (LCA) will be used to assess and establish the utility of the new and innovative approaches. Chemical recycling through depolymerization is accomplished through cascading of chemically and biochemically catalyzed transformations. Consistent with a rapidly emerging innovation trend in the chemical sciences, synergistic combinations of chemically and enzymatically catalyzed transformations will be demonstrated through the case study of chemical oxidation followed by enzymatically catalyzed decarboxylation to create naptha (mixed alkanes). The resulting low-temperature cascaded approach will be compared to the present state-of-the-art of thermal pyrolysis; LCA will guide process improvements and be used to assess if this new cascading approach provides improved sustainability metrics. A direct comparison of a high-temperature pyrolysis process with a low-temperature cascading pathway can substantially advance knowledge in the plastic recycling field; to date, no such comprehensive evaluation is available. However, the implications regarding which of the two pathways deserves future emphasis are profound. The innovative use of combined reactor-separators will be demonstrated and is expected to be a superior approach to producing monomers from waste plastics. Repolymerization will be pursued as a means of ?reincarnating? end-of-life plastic into brand new, high-value, specialty polymers for use in their next life. Oxidation of waste polyethylene will be used to produce dicarboxylic acids, and the innovative use of ammonolysis on waste polyethylene terephthalate will provide aromatic diamines. Resulting monomers are to be incorporated into newly formed polymers including polyesters, polyamides, polyaramids, polyesteramides, and polyesteraramids. These resulting polymers are considerably more expensive (2-3x) than the reclaimed waste plastic, providing an economic incentive that can effectively increase recycling rates.
This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.
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0.915 |