Metal Ions in biology allow for an expanded chemical repertoire with the local protein environment and metal coordination sphere acting synergistically to impart unusual capabilities. It is therefore not surprising that the reactions catalyzed by metalloenzymes are chemically challenging and essential for life. This proposal focuses the complex metalloenzymes involved in anaerobic CO2 fixation. With greenhouse gases and climate change receiving renewed attention due to Superstorm Sandy and the recent droughts in the Midwest, we seek to understand the chemistry by which microbes convert the greenhouse gas CO2 into a metabolic carbon source. Our approach involves a variety of biophysical methods, which will allow us to visualize the hand-off of one-carbon units between enzymes in this pathway, as well as to probe the structural basis for enzymatic generation of low-potential electrons, which drive the chemistry of the pathway. By combining X-ray crystallography, small-angle X-ray scattering, analytical ultracentrifugation, isothermal titration calorimetry, and electron microscopy, we will explore the mechanism of action of the complex metalloenzymes in anaerobic CO2 fixation.

Public Health Relevance

Our structure/function studies of the enzymes of the Wood-Ljungdahl pathway of anaerobic carbon dioxide fixation provide insight into how microbes can convert a greenhouse gas into a metabolic carbon source. Our findings have applications in the synthesis of biomimetic catalysts for environmental remediation, in the engineering of biosynthetic pathways for the conversion of carbon dioxide into biofuels, and in the design of antiparasitic medicines. With climate change emerging as a major health concern, these studies are timely.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM069857-09
Application #
8628533
Study Section
Macromolecular Structure and Function E Study Section (MSFE)
Program Officer
Smith, Ward
Project Start
2004-01-02
Project End
2018-05-31
Budget Start
2014-06-02
Budget End
2015-05-31
Support Year
9
Fiscal Year
2014
Total Cost
$264,440
Indirect Cost
$72,231
Name
Massachusetts Institute of Technology
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
001425594
City
Cambridge
State
MA
Country
United States
Zip Code
02139
Kung, Yan; Ando, Nozomi; Doukov, Tzanko I et al. (2012) Visualizing molecular juggling within a B12-dependent methyltransferase complex. Nature 484:265-9
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Phillips, Christine M; Stultz, Collin M; Drennan, Catherine L (2010) Searching for the Nik operon: how a ligand-responsive transcription factor hunts for its DNA binding site. Biochemistry 49:7757-63
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Kung, Yan; Doukov, Tzanko I; Seravalli, Javier et al. (2009) Crystallographic snapshots of cyanide- and water-bound C-clusters from bifunctional carbon monoxide dehydrogenase/acetyl-CoA synthase. Biochemistry 48:7432-40
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Phillips, Christine M; Schreiter, Eric R; Guo, Yayi et al. (2008) Structural basis of the metal specificity for nickel regulatory protein NikR. Biochemistry 47:1938-46
Doukov, Tzanko I; Blasiak, Leah C; Seravalli, Javier et al. (2008) Xenon in and at the end of the tunnel of bifunctional carbon monoxide dehydrogenase/acetyl-CoA synthase. Biochemistry 47:3474-83
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Schreiter, Eric R; Drennan, Catherine L (2007) Ribbon-helix-helix transcription factors: variations on a theme. Nat Rev Microbiol 5:710-20

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