# Leveraging host-imposed metal starvation to elucidate the molecular and environmental factors that dictate metal utilization by the iron/manganese superoxide dismutase superfamily

> **NIH NIH R01** · UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN · 2021 · $587,712

## Abstract

Project Summary/Abstract:
Superoxide is a toxic molecule that all organisms exposed to oxygen must cope with. This is particularly true for
pathogenic microbes, as the host harnesses the toxic properties of superoxide to combat invaders via the
oxidative burst. To detoxify superoxide, nearly all forms of life, including strict anaerobes, produce superoxide
dismutase (SOD). Convergent evolution has led to the development of three independent SOD families, all of
which are dependent on metals for function. The most widely distributed family of SODs are those which depend
on iron (Fe) or manganese (Mn) for function. Members of the Fe/Mn superfamily are present in eukaryotes,
archaea, and bacteria. Despite over forty years of study, it is not possible to predict accurately the metal utilized
by members of the Fe/Mn superfamily of SODs. Difficulties in predicting metalloprotein metal utilization are not
confined to the Fe/Mn SOD superfamily but also occur with other classes of metalloenzymes. This deficiency is
driven by relatively low levels of protein sequence identity amongst SODs from different organisms that utilize
the same metal cofactor. Additionally, the environmental and molecular factors that dictate the metal used by
members of this protein superfamily are also unknown. Members of the Fe/Mn SOD superfamily are canonically
thought to use either Fe or Mn, but not both, as a cofactor. This idea arose despite early investigations that
identified Fe/Mn SOD family members that are active with both Fe and Mn. The ability of these “cambialistic”
SODs (able to use either Fe or Mn as a catalytic cofactor) was dismissed as a quirk of chemistry. At the time, it
was thought that intracellular metal concentrations did not change enough to alter the metal bound by a SOD.
S. aureus possesses two superoxide dismutases, SodA and SodM, which are ~75% identical. Initially, both
SODs were reported to be Mn-dependent. During infection, the host restricts the availability of Mn and inactivates
Mn-dependent SODs via the Mn-binding immune protein calprotectin. Recent work discovered that SodM
critically contributes to the ability of S. aureus to maintain a defense against oxidative stress when Mn-starved,
both in culture and during infection, while SodA is important when Mn is freely available. Biochemical analyses
revealed that SodM is not strictly Mn-dependent but is instead cambialistic, and the ability to use Fe enables it
to promote resistance to oxidative stress when S. aureus is Mn-limited by the host. These observations support
a physiological role for cambialism and the hypothesis that metal availability shapes the repertoire of SODs
possessed by an organism. The experiments in this proposal will evaluate this hypothesis and elucidate the
molecular features that dictate metal utilization in the Fe/Mn SOD superfamily. Aim I: Elucidate the molecular
features that dictate metal utilization of Fe/Mn SOD superfamily members. Aim II: Determine if environmental
...

## Key facts

- **NIH application ID:** 10294718
- **Project number:** 1R01AI155611-01A1
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
- **Principal Investigator:** Thomas Everett Kehl-Fie
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $587,712
- **Award type:** 1
- **Project period:** 2021-05-19 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10294718

## Citation

> US National Institutes of Health, RePORTER application 10294718, Leveraging host-imposed metal starvation to elucidate the molecular and environmental factors that dictate metal utilization by the iron/manganese superoxide dismutase superfamily (1R01AI155611-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10294718. Licensed CC0.

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