# Expanding the Catalytic Repertoire of Heme-based Dioxygenases

> **NIH NIH R01** · ALBERT EINSTEIN COLLEGE OF MEDICINE · 2024 · $386,400

## Abstract

PROJECT SUMMARY
Human tryptophan dioxygenase (hTDO) and indoleamine 2, 3-dioxygenase 1 (hIDO1) are two hemeproteins
that catalyze the dioxygenation reaction of L-tryptophan (Trp) to N-formyl kynurenine. Although it is
generally believed that electrons and protons are crucial for oxygen activation by hemeproteins, the
dioxygenases are so unique that they catalyze the oxidative ring cleavage reaction of Trp without consuming
any electrons or protons. With time-resolved resonance Raman spectroscopy, combined with QM/MM
simulations, we have established a substrate-assisted mechanism accounting for the unusual chemistry
catalyzed by the dioxygenases. Recently, we discovered that, in addition to the Trp dioxygenation activity,
hTDO can bind NAD(P)H in the active site, thereby repurposing it for (i) a heme oxygenase (HO) reaction,
which converts the active holoprotein to the inactive apoprotein, (ii) an oxidase reaction, which reduces O2 to
superoxide, and (iii) a peroxidase reaction, which reduces H2O2 to water. Although hTDO and hIDO1 share
a common active site structure and catalyze the Trp dioxygenation reaction with the same mechanism, hIDO1
does not exhibit the HO activity, but it retains the oxidase and peroxidase activities. These exciting new
findings expand the substrate portfolio and the catalytic repertoire of the heme-based dioxygenases. The major
goal of this project is to decipher the structural determinants dictating the novel enzymatic activities of the two
dioxygenases. The scientific premise of this project is that the comprehension of the new enzymatic activities
of hTDO and hIDO1 will further our knowledge in heme oxygen chemistry and provide new insights into their
physiological functions, thereby offering guidelines for disease control and prevention.

## Key facts

- **NIH application ID:** 10901958
- **Project number:** 5R01GM151419-02
- **Recipient organization:** ALBERT EINSTEIN COLLEGE OF MEDICINE
- **Principal Investigator:** Syun-Ru Yeh
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $386,400
- **Award type:** 5
- **Project period:** 2023-08-15 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10901958

## Citation

> US National Institutes of Health, RePORTER application 10901958, Expanding the Catalytic Repertoire of Heme-based Dioxygenases (5R01GM151419-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10901958. Licensed CC0.

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