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
Bowman, Sarah E J; Bridwell-Rabb, Jennifer; Drennan, Catherine L (2016) Metalloprotein Crystallography: More than a Structure. Acc Chem Res 49:695-702
Wittenborn, Elizabeth C; Jost, Marco; Wei, Yifeng et al. (2016) Structure of the Catalytic Domain of the Class I Polyhydroxybutyrate Synthase from Cupriavidus necator. J Biol Chem 291:25264-25277
Meyer, Peter A; Socias, Stephanie; Key, Jason et al. (2016) Data publication with the structural biology data grid supports live analysis. Nat Commun 7:10882
Gibson, Marcus I; Chen, Percival Yang-Ting; Johnson, Aileen C et al. (2016) One-carbon chemistry of oxalate oxidoreductase captured by X-ray crystallography. Proc Natl Acad Sci U S A 113:320-5
Jost, Marco; Born, David A; Cracan, Valentin et al. (2015) Structural Basis for Substrate Specificity in Adenosylcobalamin-dependent Isobutyryl-CoA Mutase and Related Acyl-CoA Mutases. J Biol Chem 290:26882-98
Jost, Marco; Fernández-Zapata, Jésus; Polanco, María Carmen et al. (2015) Structural basis for gene regulation by a B12-dependent photoreceptor. Nature 526:536-41
Jost, Marco; Simpson, Jeffrey H; Drennan, Catherine L (2015) The Transcription Factor CarH Safeguards Use of Adenosylcobalamin as a Light Sensor by Altering the Photolysis Products. Biochemistry 54:3231-4
Chang, Shiou-chi; Fedeles, Bogdan I; Wu, Jie et al. (2015) Next-generation sequencing reveals the biological significance of the N(2),3-ethenoguanine lesion in vivo. Nucleic Acids Res 43:5489-500
Gagnon, Derek M; Brophy, Megan Brunjes; Bowman, Sarah E J et al. (2015) Manganese binding properties of human calprotectin under conditions of high and low calcium: X-ray crystallographic and advanced electron paramagnetic resonance spectroscopic analysis. J Am Chem Soc 137:3004-16
Jost, Marco; Cracan, Valentin; Hubbard, Paul A et al. (2015) Visualization of a radical B12 enzyme with its G-protein chaperone. Proc Natl Acad Sci U S A 112:2419-24

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