Mapping the hydrolase-oxygenase boundaries and range of catalytic capabilities in the HD-domain dinuclear metalloenzyme superfamily

Project: Research project

Project Details


MIOX is the founding and, to date, only established member of the nascent mixed-valent di-iron oxygenase (MVDO) sub-family. It uses a Fe2(II/III) cofactor to activate O2 at the Fe(II) site and myo-inositol at the Fe(III) site for a C-C-bond-cleaving, four-electron oxidation. A recent paper and our preliminary data on the P-C-bond cleaving enzyme, PhnZ, strongly suggest it is the second example of an MVDO, and our analysis of available sequences and structures suggests that several other proteins belong to this class. The mapping of the phosphohydrolase-MVDO boundaries in the HD-domain superfamily and characterization of new MVDOs will facilitate proper functional assignment, expand the known catalytic repertoire of this new class of oxygenase, and shed light on Nature's evolution of radically divergent functions within a common protein scaffold. The project will likely uncover fundamentally new reactions that will expand the known catalytic repertoire of a novel class of oxygenase that at present consists of just a single documented member. It will yield insight into how Nature remodels a protein scaffold and its metallocofactor in seemingly subtle ways to create markedly different catalytic activities. Thus this project addresses two central challenges in molecular biosciences: (1) functional assignment of the huge number of proteins predicted within the terabases of available DNA sequence and (2) understanding the evolution of new functions within a 'superfamily' of proteins sharing a common architecture. It will also provide outstanding training in activities ranging from bioinformatic analysis, to analytical and protein biochemistry, to enzyme kinetics and mechanism, to protein crystallography, to biological spectroscopy. The scientific project will infuse the primary outreach activity, a ~120-participant, biennial training 'workshop' in modern metallobiochemistry, with new case studies illustrating important concepts, and efforts to extract such concepts and develop new case studies will sharpen the scientific focus of the trainees.

Effective start/end date9/1/138/31/17


  • National Science Foundation: $720,000.00


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