# Deciphering the Mechanisms of Pathogenic Ferrous Iron Acquisition and Eukaryotic Post-Translational Arginylation

> **NIH NIH R35** · UNIVERSITY OF MARYLAND BALTIMORE COUNTY · 2021 · $287,352

## Abstract

Project Summary
 This MIRA proposal aims to solve critical gaps in knowledge of two poorly understood protein systems
that are linked to health and human disease. To accomplish this proposal, the designed studies combine
structural, inorganic, and biochemical approaches with an innovative metallocentric point of view that is
essential yet has remained chiefly unexplored for these proteins. The first proposed system of study is the
ferrous (Fe2+) iron uptake (Feo) system, which is present in nearly all bacteria and is used by pathogens to
establish infection in mammalian hosts. Previous studies on Feo have either been too large or too small in
scope, leading to a fragmented and inconclusive understanding with little insight into mechanism. This
proposal outlines a comprehensive approach to study the Feo system at the protein level. Leveraging
structural, spectroscopic, and biochemical analyses, this proposal aims to delineate the mechanism of
prokaryotic Fe2+ transport, which will position future researchers to explore the urgent but broadly impactful
possibility that Feo may be exploited to combat bacterial virulence. The second proposed system of study
focuses on the arginine transferases (known as ATE1s), which are enzymes that arginylate the N-terminus of
peptides or proteins, subsequently triggering their degradation via the ubiquitin-proteasome system. Normal
ATE1 function is critical for neurogenesis and cardiovascular development, but structural and mechanistic
details of ATE1-mediated arginylation are sorely lacking, prohibiting the targeting of this system for therapeutic
intervention. Exciting results indicate ATE1s may be iron-containing enzymes, but the function of iron in this
system remains unknown. This proposal aims to delineate the structure and mechanism of ATE1s, including
the potential regulatory role of iron in these enzymes. To achieve this goal, this proposal combines protein-
level structural, biochemical, and spectroscopic methods to elucidate the arginylation mechanism of ATE1s,
and to resolve how iron controls this process. Once determined, this molecular-level detail will be invaluable to
design small molecules that target ATE1 for intervention. Combined, the results from this proposal hold the
promise to aid in the development of therapeutics to abrogate bacterial virulence and to treat neurological and
cardiovascular diseases.

## Key facts

- **NIH application ID:** 10176540
- **Project number:** 5R35GM133497-03
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE COUNTY
- **Principal Investigator:** Aaron T Smith
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $287,352
- **Award type:** 5
- **Project period:** 2019-08-15 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10176540

## Citation

> US National Institutes of Health, RePORTER application 10176540, Deciphering the Mechanisms of Pathogenic Ferrous Iron Acquisition and Eukaryotic Post-Translational Arginylation (5R35GM133497-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10176540. Licensed CC0.

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