# Heme and Nonheme Transition Metal Complexes, Reactivity, and Mechanism

> **NIH NIH R35** · JOHNS HOPKINS UNIVERSITY · 2024 · $577,001

## Abstract

Project Summary
This proposal focuses on the activation and utilization of dioxygen by heme and nonheme transition metal centers
in metalloenzymes and in related synthetic systems. A subset of nonheme iron enzymes utilize a single iron
center to activate dioxygen and mediate the oxidation of various substrates, including sulfur substrates as seen
in thiol dioxygenases (TDOs) (e.g. cysteine dioxygenase (CDO)), persulfide dioxygenases (PDOs) (e.g.
ethylmalonic encephalopathy protein (ETHE1)), sulfoxide synthases (e.g. EgtB, OvoA), and isopenicillin N
synthase (IPNS). The related nonheme iron hydroxylases (e.g. TauD) and halogenases (e.g. SyrB2) also
activate O2 with a single iron center to transform C-H bonds into C-X (X = OH, Cl) groups. Many questions remain
regarding the mechanisms of action of these proteins, although the proposed pathways for these different
enzymes include several common iron/oxygen intermediates. Heme enzymes also activate O2 for similar
oxidative chemistry, such as C-H hydroxylation carried out by the monooxygenase cytochrome P450 (CYP), or
the C-C bond cleavage and dioxygenation of indoles carried out by tryptophan and indoleamine dioxygenase
(TDO/IDO). The proposed efforts involve the synthesis of biomimetic heme and nonheme iron complexes that
will be used to examine how the first and second coordination spheres influence O2 activation and substrate
oxidations. Efforts will be made to characterize metastable transition metal/O2 species (e.g. M-O2, M-OOH, M=O,
M-OH) that are proposed as key intermediates in heme and nonheme O2 activation. Characterization of these
species in structurally well-defined complexes will provide support for the analogous, putative intermediates in
the enzymatic systems. The feasibility of key bond-making and bond-breaking events will be established by
examining the reactivity of these metal/oxygen adducts with various substrates. Mechanistic questions will be
addressed through comprehensive thermodynamic and kinetic studies. Systematic modifications will be made
to these low molecular weight complexes through established synthetic methodologies, providing atomic-level
control over their geometric/electronic structures. This approach provides a means to establish structure-function
relationships that can be challenging or impossible to obtain when studying the enzymes alone. Questions to be
addressed include what are the key intermediates during heme and nonheme iron activation of O2? What are
the key spectroscopic features of these intermediates? Which of these species are capable of oxidizing which
substrates? How does the structural and electronic properties of the ligands holding the metal center influence
the O2 activation process? What controls the selectivity of substrate oxidations? Addressing these questions
should lead to new knowledge regarding how heme and nonheme iron enzymes activate O2 and selectively
oxidize substrates. These enzymes participate in biological processes that are e...

## Key facts

- **NIH application ID:** 10907410
- **Project number:** 5R35GM149233-02
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** David P Goldberg
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $577,001
- **Award type:** 5
- **Project period:** 2023-09-01 → 2028-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10907410

## Citation

> US National Institutes of Health, RePORTER application 10907410, Heme and Nonheme Transition Metal Complexes, Reactivity, and Mechanism (5R35GM149233-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10907410. Licensed CC0.

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