# Structure and Function of Heme-based Dioxygenases

> **NIH NIH R01** · ALBERT EINSTEIN COLLEGE OF MEDICINE · 2021 · $420,000

## Abstract

SUMMARY
Tryptophan (Trp) is the least abundant essential amino acid. The majority of our dietary Trp is metabolized
through the kynurenine (KYN) pathway. The first and rate-limiting step of the KYN pathway is catalyzed by
three heme-based dioxygenases, tryptophan dioxygenase (hTDO), indoleamine 2,3-dioxygenase 1 (hIDO1), and
indoleamine 2,3-dioxygenase 2 (hIDO2). Recently it was found that the three dioxygenases are expressed in
cancer cells to promote cancer immune escape. Consequently they have been considered as key drug targets for
cancer immunotherapy. Despite their importance, the structural and functional properties of these enzymes remain
elusive, which has hindered the progress of the field. The central hypothesis of this project, as supported by our
preliminary data, is (i) the functional properties of the three dioxygenases are regulated by cellular metabolites
and (ii) each dioxygenase exhibits distinct structural features and possesses unique drug binding sites. We will
test our hypothesis by addressing two specific aims: (i) identify cellular metabolites that interact with each
dioxygenase and define the related regulatory mechanisms, and (ii) define structural differences between the three
dioxygenases and determine new small molecule binding sites in each dioxygenase. We will use a new high-
throughput mass spectrometry-based screening technology to identify metabolites that interact with each
dioxygenase and use X-ray crystallography and spectroscopic techniques to define their specific molecular
interactions and functional consequences. These studies will reveal previously unknown cellular players in
dioxygenase-related human physiology that may impact the specific functions of these enzymes in cancer and
other diseases, thereby offering novel information enabling innovative molecular approaches for disease
prevention and control. In parallel, we will use an integrated approach, involving a wide spectrum of biochemical
and biophysical techniques, and a group of structurally diverse inhibitors as probes to define unique structural
features and new small molecule binding sites in each dioxygenase. The outcome of these studies will offer
important knowledge enabling better understanding of structure-and-function relationships of the three heme-
based dioxygenases and expanding our toolkit for rational design of enzyme-selective inhibitors. We have
assembled a team of experts to carry out this innovative project with the multifaceted approach. These studies
will address significant gaps in our knowledge of molecular mechanisms underlying the biological functions of
the three dioxygenases and provide important new insights into related drug development and disease treatment.

## Key facts

- **NIH application ID:** 10136611
- **Project number:** 5R01GM115773-07
- **Recipient organization:** ALBERT EINSTEIN COLLEGE OF MEDICINE
- **Principal Investigator:** Syun-Ru Yeh
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $420,000
- **Award type:** 5
- **Project period:** 2016-06-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10136611

## Citation

> US National Institutes of Health, RePORTER application 10136611, Structure and Function of Heme-based Dioxygenases (5R01GM115773-07). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10136611. Licensed CC0.

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