# Materials Approaches for Understanding Biological Energy Transduction and Bifurcation

> **NIH NIH F32** · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · 2020 · $57,142

## Abstract

PROJECT SUMMARY/ABSTRACT
 Metalloenzymes orchestrate complex multiproton/multielectron reactions critical to human life, such as
the 6H+/6e- reduction of dinitrogen to ammonia by nitrogenase and the 4H+/4e- reduction of dioxygen to water by
monooxygenase enzymes. To accomplish these reactions with minimal loss of partially reduced species (PRS),
many metalloenzymes have redox-active cofactors located in close proximity to the active site. These cofactors
are often loaded with several electron and proton equivalents prior to substrate binding, enabling selective
conversion of the substrate to product with minimal PRS loss. Often, PRSs are highly reactive and lead to cellular
damage. For enzymes such as Cytochrome P450 (CYP) and Cytochrome c Oxidase (CcO), loss of PRSs, such
as H2O2, is linked to various diseases such as down syndrome, multiple sclerosis and cancer. Therefore,
understanding the influence that local electron reservoirs have on the selectivity of multiproton/multielectron
transformations may aid the treatment of the aforementioned diseases.
 In order to fundamentally understand the influence that local electron reservoirs have on the selectivity
of multielectron/multiproton transformations, we propose to study the activity and selectivity for O2 reduction
using iron porphyrins covalently attached to conductive electrodes as artificial models of O2 reducing enzymes.
Rather than using a molecular electron reservoir, we will covalently attach metalloporphyrins to carbon and metal
oxide electrode surfaces. We hypothesize that metalloenzymes utilize these redox-loaded cofactors to provide
the active site with a highly coupled source of electrons, and that changes to the electron coupling between the
donor (electrode) and acceptor (metalloporphyrin) will influence the kinetics of the bifurcating steps leading to
the desired product (H2O) or the undesired PRS (H2O2). By using an electrode as a tunable surrogate for a
redox cofactor, these interfacial constructs will allow a multidimensional control of the distance, coupling and
electron transfer driving force between the electrode and iron porphyrin active site, enabling a fundamental study
of the steps that lead to bifurcation and loss of PRS in enzymes such as CcO and CYP. These studies will
provide insights into how redox-active cofactors influence product bifurcation in metalloenzymes, which may lead
to new methods of treatment or prevention of diseases induced by H2O2 loss in biological systems.

## Key facts

- **NIH application ID:** 9997977
- **Project number:** 5F32GM130071-03
- **Recipient organization:** MASSACHUSETTS INSTITUTE OF TECHNOLOGY
- **Principal Investigator:** Michael Pegis
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $57,142
- **Award type:** 5
- **Project period:** 2018-09-10 → 2021-07-14

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9997977

## Citation

> US National Institutes of Health, RePORTER application 9997977, Materials Approaches for Understanding Biological Energy Transduction and Bifurcation (5F32GM130071-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9997977. Licensed CC0.

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