| NSF Org: |
CHE Division Of Chemistry |
| Recipient: |
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| Initial Amendment Date: | February 10, 2016 |
| Latest Amendment Date: | February 10, 2016 |
| Award Number: | 1623856 |
| Award Instrument: | Continuing Grant |
| Program Manager: |
Catalina Achim
cachim@nsf.gov (703)292-2048 CHE Division Of Chemistry MPS Direct For Mathematical & Physical Scien |
| Start Date: | January 15, 2016 |
| End Date: | July 31, 2018(Estimated) |
| Total Intended Award Amount: | $270,272.00 |
| Total Awarded Amount to Date: | $270,272.00 |
| Funds Obligated to Date: |
FY 2015 = $150,000.00 |
| History of Investigator: |
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| Recipient Sponsored Research Office: |
1 UTSA CIR SAN ANTONIO TX US 78249-1644 (210)458-4340 |
| Sponsor Congressional District: |
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| Primary Place of Performance: |
TX US 78249-3209 |
| Primary Place of
Performance Congressional District: |
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| Unique Entity Identifier (UEI): |
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| Parent UEI: |
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| NSF Program(s): |
Molecular Biophysics, Chemistry of Life Processes |
| Primary Program Source: |
01001516DBNSF RESEARCH & RELATED ACTIVIT |
| Program Reference Code(s): |
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| Program Element Code(s): |
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| Award Agency Code: | 4900 |
| Fund Agency Code: | 4900 |
| Assistance Listing Number(s): | 47.049 |
ABSTRACT
With this award, the Chemistry of Life Processes Program in the Chemistry Division and the Molecular Biophysics Cluster in the Molecular and Cellular Biology Division are funding Dr. Aimin Liu from Georgia State University to characterize 3-hydroxyanthranilate-3,4-dioxygenase (HAO). This enzyme performs oxidative ring-cleavage at the meta position of six-membered aromatic rings in a reaction known as extradiol dioxygenation. HAO is a prototypic member of extradiol dioxygenases built upon a cupin structural fold (known as type III extradiol dioxygenases). The goal of this project is to study the substrate recognition, oxygen binding, activation, selective targeting, and to identify the intermediates of the reactions catalyzed by HAO. Furthermore, the Liu lab seeks to identify the role of an additional rubredoxin-like Fe(Cys)4 center of the enzyme, which is not required for catalysis but is conserved in bacterial enzymes. The research aims to build a framework for understanding the mechanism of these enzymes and common steps shared by extradiol dioxygenases. The chemical, structural, and spectroscopic properties of iron-bound oxygenated intermediates will help illuminate iron-dependent oxygen activation and oxidation mechanisms.
The incorporation of molecular oxygen into organic molecules is one of the most important metabolic processes in nature and its ultimate purpose is energy extraction. The Liu laboratory studies the mechanism by which a particular enzyme accomplishes this task. Knowledge created by the lab advances the understanding of oxygen activation and its specific incorporation into metabolites. The scientific questions are answered by using biochemical methods, spectroscopic tools, X-ray crystallography, and computational modeling. This multidisciplinary pursuit creates substantial opportunities to engage science students, including members of groups underrepresented in science, in research at the frontier of chemistry and biology. The knowledge gleaned from the research are incorporated in the biochemistry and bioinorganic chemistry curriculum.
PUBLICATIONS PRODUCED AS A RESULT OF THIS RESEARCH
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PROJECT OUTCOMES REPORT
Disclaimer
This Project Outcomes Report for the General Public is displayed verbatim as submitted by the Principal Investigator (PI) for this award. Any opinions, findings, and conclusions or recommendations expressed in this Report are those of the PI and do not necessarily reflect the views of the National Science Foundation; NSF has not approved or endorsed its content.
In the past funding period (2017-2018), we published a paper entitled "Adapting to oxygen: 3-Hydroxyanthrinilate 3,4-dioxygenase employs loop dynamics to accommodate two substrates with disparate polarities" in J. Biol. Chem. 2018, 293(27), 293, 10415-10424 (DOI: 10.1074/jbc.RA118.002698). This product was derived from our studies of Aim #2 for discerning the driving force of the catalytic loop motions and diagram the relationship between the loop motions and substrate recognition. The published manuscript of this work was chosen as the cover story of the journal (see http://www.jbc.org/content/293/27.cover-expansion).
In our pursuit of the catalytic mechanism of how molecular oxygen is activated by HAO and what directs the enzyme-bound dioxygen to target the substrate C3-C4 (meta) position, we have made several significant findings. These include the discovery of a hidden isomerase activity and successfully trapping and structurally characterizing several catalytic intermediates. With the aid of the single-crystal spectroscopic data, we were able to fully interpret the structural data. In this funding period, a long-sought monooxygenated key intermediate was captured from the in-crystallo chemical reaction with the wild-type enzyme and its native substrates. The capture of this intermediate and solved its structure at a high resolution filled the most critical piece of the catalytic cycle. It finally enables us to understand all the questions of the mechanistic pathway raised in the proposal (mostly in Aim #1). This exciting development will be combined with five other intermediate structures for a heavy-duty paper to be published soon in a leading journal.
An African-American student, Kednerlin Dornevil, graduated with a Ph.D. degree in Chemistry and Biochemistry under the support of this award in the past year. One significant chapter of his dissertation is placed on his discoveries on the identification of the role of the active site residues of HAO. With the support of this NSF award, Three undergraduate students (two are female) were also trained in our lab on the non-heme iron extradiol dioxygenase project, including one female undergraduate student from Muhlenberg College for a summer research.
Last Modified: 10/09/2018
Modified by: Aimin Liu
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A long-sought monooxygenated intermediate in the catalytic cycle of the extradiol dioxygenase has been captured.Yifang Wang, Fange Liu, Ana Gonzalez, and Aimin LiuCopyrightedAimin LiuThe structure of a monooxygenated intermediate
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