# Biological Transition Metals

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2021 · $537,038

## Abstract

PROJECT SUMMARY
 Our program is devoted to understanding the roles played by transition metals in biologically central
enzymatic transformations. We here focus on three key problems involving enzymatic transition-ion centers,
and have assembled outstanding multidisciplinary teams to attack them. The approach to one problem
incorporates a study of biomimetic inorganic complexes. The approaches to all incorporate a suite of advanced
paramagnetic resonance techniques, many of which we have developed, one of which will be enhanced by
further development. The Aims for the coming period build on remarkable advances during the current grant
period1-41 and represent both dramatic reinventions of ongoing projects and the initiation of major new ones.
(a) 'Radical-SAM (S-adenosyl methionine)' enzymes: This enzyme superfamily is Nature's most
widespread means of performing radical-based chemistry. We will explore profound insights into and
challenges for the accepted paradigm of radical initiation, reductive homolytic cleavage of SAM, raised by our
recent discoveries. (b) Enzymatic C-H Activation: This process has a central role in the emerging idea that
active-site dynamic compaction is of major importance in enzyme catalysis. Our new ENDOR structure-
determination protocol has provided a foundation for this picture, and will be used to develop a precise
understanding of how active-site architecture and enzyme dynamics control catalytic C-H bond cleavage. (c)
Mechanism of N2 activation: We recently revealed how the nitrogenase MoFe protein is activated to carry
out one of the most challenging chemical transformation in biology, cleavage of the N≡N triple bond. We will
test and extend this mechanism, while deepening and expanding our understanding of the nitrogenase catalytic
cycle by with an ultimate aim of characterizing the structures and mechanistic interconversions of the complete
set of enzyme intermediates. (d) Biomimetic Complexes: We strengthen our ability to characterize trapped
nitrogenase intermediates through ENDOR studies of the suite of biomimetic metal complexes, which exhibit
every proposed state of N2 binding and reduction, while in parallel supporting the efforts of synthetic inorganic
chemists' to generate catalytically competent biomimetic complexes. (e) Methods Development: For many
systems, the CW ENDOR protocol gives far better signal/noise than pulsed (Davies, Mims) ENDOR
techniques. However, `sweep artifacts' in CW ENDOR often distort the ENDOR response and lose information.
Our hybrid `stochastic ENDOR' protocol (CW EPR/pulsed RF) abolishes these artifacts, but at present its
application is `hit or miss'. Its proposed development will provide the option of choosing the optimum protocol
for each spin system studied. Synergy: Each of the enzyme systems addressed a problem of fundamental
importance, while the diversity of these Aims synergistically benefits each one.

## Key facts

- **NIH application ID:** 10093059
- **Project number:** 5R01GM111097-49
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** BRIAN M HOFFMAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $537,038
- **Award type:** 5
- **Project period:** 1979-01-01 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10093059

## Citation

> US National Institutes of Health, RePORTER application 10093059, Biological Transition Metals (5R01GM111097-49). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10093059. Licensed CC0.

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