# A Biomimetic Approach to Elucidating the Role in Disease of the Oxygenase Enzyme Acireductone Dioxygenase (ARD)

> **NIH NIH SC2** · ST. EDWARD'S UNIVERSITY · 2021 · $119,971

## Abstract

Project Summary/Abstract
Acireductone dioxygenase (ARD) is found in the ubiquitous methionine salvage pathway (MSP) in animals,
plants, and bacteria. Enzymatically it is implicated in the regulation of SAM and MTA; the latter is a result of
polyamine synthesis and a regulator of cell growth in animals. The enzyme can bind to iron and nickel giving
two distinct products. The nickel reaction (“off-pathway”) catalyzes the transformation of acireductone into 3-
(methylthio)propionate, formate and carbon monoxide, a known anti-apoptotic signaling molecule. ARD is the
only known example of a metalloenzyme whose function differs only by the identity of the metal ion. Recent
mammalian studies have characterized mouse (MmARD) and human analogues (HsARD) of the enzyme. In
mammalian systems it has been shown that ARD is capable of binding manganese and cobalt to perform “off-
pathway” type chemistry. Recent work with these analogues in in-vitro studies has shown that HsARD might
play an intracellular regulatory role in brain tumors. Furthermore, it has been shown that the gene coding for
HsARD, ADI1, is downregulated in human and rat prostate cancer cells as well as gastrocarcinoma and
fibrosarcoma cells. These moonlighting functions, as well as the enzymatic roles of ARD beg the question
about the connection between ARD in disease. To date there is still debate about the exact mechanism of the
regiospecific substrate oxidation, and little is known about the role that metal identity plays in this reactivity.
This project uses synthetic biomimetic modeling to contribute to answering these questions. The proposed
work aims at greatly expanding the availability of models of ARD using nickel and mammalian relevant metals
with two specific aims: 1. Expand the limited availability of biomimetic structural and functional models of Ni-
ARD. These will be used to test the structural and mechanistic reasons for the observed “off-pathway”
oxidative regioselective reactivity in ARD. Mechanistic and kinetic studies will follow to provide valuable
information to explain the mechanism of regioselective substrate activation in Ni-ARD. 2. Synthesize and begin
to study the biomimetic reactivity of model complexes using metals relevant to mammalian systems (cobalt and
manganese specifically). These new compounds will contribute to the understanding of the “off-pathway”
reactions and the role of metal identity in promoting disease in human cells.

## Key facts

- **NIH application ID:** 10150868
- **Project number:** 5SC2GM130438-02
- **Recipient organization:** ST. EDWARD'S UNIVERSITY
- **Principal Investigator:** Santiago Andres Toledo Carrion
- **Activity code:** SC2 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $119,971
- **Award type:** 5
- **Project period:** 2020-05-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10150868

## Citation

> US National Institutes of Health, RePORTER application 10150868, A Biomimetic Approach to Elucidating the Role in Disease of the Oxygenase Enzyme Acireductone Dioxygenase (ARD) (5SC2GM130438-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10150868. Licensed CC0.

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