Nature has mastered the ability to use bioavailable metals to achieve spectacular transformations of chemistry, by combining them with diverse protein folds, and unique coordination environments. Through the assembly of metalloproteins and metalloenzymes, Nature has achieved remarkable diversity in chemical transformations and in tuning the nascent properties of metal ions such as iron, through generating yet-further-modifiable redox-active cofactors, like iron-sulfur clusters and iron bound in heme cofactors. To achieve that diversity, specific protein scaffolds and arrangements of iron-sulfur clusters, and/or heme groups have been elaborated upon extensively, giving us diverse chemistry ? much of which, the fields of enzymology and bioinorganic are still discovering today. Two NIGMS funded research areas ongoing in the Elliott Group at Boston University are (1) Query the structure-function relationships of the vast, ?AdoMet Radical Enzyme (ARE) superfamily?, where tens of thousands of reactions are thought to be catalyzed by hundres of thousands of distinct members of the ARE, through the study of the redox traits of the iron sulfur clusters found in the ARE superfamily; and (2) Test hypotheses about structural and chemical diversity found with heme containing enzymes of the so- called ?bacterial cytochrome c peroxidase (bCCP) superfamily? found within gram negative micro-organisms. Through these two related projects, which form the background of the current R35 proposal, the diversity of structures, function and redox chemistries of metalloproteins are examined through a combination of electrochemical, biophysical, bioinformatic, and structural approaches. The mechanistic details of the ARE superfamily are still forthcoming, where many novel states of iron-sulfur clusters have been proposed; here we will bring our electrochemical lens to bear upon the nature of those states, in order to understand the thermodynamics and kinetics of their generation and inter-conversion. With respect to the bCCP superfamily, we have recently demonstrated that novel forms of reactivity of enzymes of this superfamily can be found by looking beyond the canonical family members that have been examined for the past 20 years. Here we propose to examine other new family members that are suggested to engage in sulfur-conversions relevant to the microbiome and to human health. Together, these studies marry our interests in bioinformatics and biophysical chemistry, to probe the diversity of nature's redox enzymes, revealing not only what is possible in the chemistry of these remarkable catalysts, but how nature masters the desired reactivity with the correct metallocofactor.

Public Health Relevance

All organisms make use of redox-based processes for energetic transformations that span the fundamental chemistry of living, as well as the protection of the organism from highly reactive radical-based species. Often these transformations are catalyzed by metal-containing cofactors such as iron-sulfur clusters and heme units that are bound within proteins and enzymes. Understanding the diversity of the strategies that nature makes use of in the design and function of such redox-catalysis is critical to understanding the biological chemistry of ourselves and pathogens alike.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Unknown (R35)
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Special Emphasis Panel (ZRG1)
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Anderson, Vernon
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Boston University
Schools of Arts and Sciences
United States
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