Biological transition metals

The National Institute of General Medical Sciences awarded Northwestern University $569,685 on July 1, 2026, under the Biomedical Research and Research Training program (CFDA 93.859) to support a five-project program investigating the structure and function of biologically central transition-metal ions across 53 years of continuous NIH funding.

The funded research encompasses radical-SAM enzyme characterization, intra-cellular manganese speciation, and related metallobiochemistry projects employing advanced paramagnetic resonance techniques including electron-nuclear double resonance (ENDOR) and electron spin-echo envelope modulation (ESEEM). Investigators include biochemists, microbiologists, inorganic chemists, and theoreticians examining radical initiation mechanisms and enzymatic transformations in radical-SAM superfamily members, including ribosomally synthesized and post-translationally modified peptides with potential biotechnological and pharmaceutical applications. The research addresses novel targets including human RSAD1, a radical-SAM enzyme implicated in disease mechanisms.

Work is performed at Northwestern University's Evanston, Illinois campus. The period of performance extends from July 1, 2026, through March 31, 2031. The award is classified as a Project Grant, an assistance type supporting investigator-initiated biomedical research designed to advance fundamental understanding of human health and disease.

Abstract

Abstract our continually evolving program, now in its 53RD year of continuous NIH funding, is devoted to understanding the structure and function of biologically central transition-metal ions, and the properties that underlie their key roles in human health and disease. Our efforts begin with the identification of central unsolved problems in metallobiochemistry, and proceed through the assembly of a collaborative team of outstanding biochemists, microbiologists, inorganic chemists and theoreticians to attack them. In this proposal: studies of 'radical-SAM' enzymes (a) involve broderick, biochemist, suess, inorganic chemist, mosquera, theorist; studies of intra-cellular MN2+ speciation (b) involve daly, microbiologist, o'halloran, inorganic chemist, COX, biologist; these projects are accompanied by continued collaborations with rosenzweig (c, d) and ragsdale (e). We address these problems with advanced paramagnetic resonance techniques, electron-nuclear double resonance (endor) and electron spin-echo envelope modulation (eseem), which we likewise modify through development of new experimental protocols, analysis procedures, and instrumentation, as required. This proposal addresses five major projects (a-e) selected from our portfolio, as noted below. For each, we describe recent progress then present an overview of future research, repeating this pattern for large sub-projects, as well. (a) radical SAM (RS) enzymes form a vast superfamily of over 700,000 members from all forms of life, and catalyze a spectacular diversity of reactions. Among our research targets are characterization of the mechanism of radical initiation and of enzymatic transformations. These latter include (but are not limited to): enzymes that form ribosomally synthesized and post-translationally modified peptides (ripps), diverse natural products with potential biotechnological and pharmaceutical applications; human (HS) RSAD1, a novel RS enzyme implicated in alzheimer's disease (ad) and associated with neurons in ad. (b) we have developed the ability to determine MN2+ speciation in vivo using EPR/endor spectroscopy, and this provides: a potential to assess the radiation resistance of an individual tumor, which might well assist in optimizing a radiation/chemotherapeutic regime; a means of using drosophila as whole-animal experimental vehicle to help develop prophylactic medical countermeasures to protect radiological emergency responders, radiotherapy patients, and astronauts; and will contribute to the search for prophylactics that reduce MN toxicity, which has long been linked to parkinson's and alzheimer diseases. (c) continuation of our study of membrane-bound particulate methane monooxygenase (pmmo), nature's primary methane-oxidizing enzyme. (d) studies of the enzyme hvfb, which is involved in biosynthesis of a ripp virulence factor, and which contains a novel triiron factor of undetermined structure. (e) characterization of newly accessible catalytic intermediates of CO dehydrogenase (codh), an enzyme that catalyzes oxidation of CO to CO2, and of NI-methyl-scom reductase (MCR), a NI-tetrapyrrole (F430)-containing enzyme responsible for most of the methane biosynthesis on earth.