# Heme Oxygenases: chemically complex enzymes found in diverse biological pathways

> **NIH NIH R35** · UNIVERSITY OF VERMONT & ST AGRIC COLLEGE · 2022 · $300,182

## Abstract

Project Summary
 This research program will develop accurate, detailed models of enzymatic heme degradation. In
biological systems, heme oxygenases degrade heme to non-heme iron and oxygenated organic products, such
as: biliverdin, staphylobilin, and mycobilin. In eukaryotes, the liberated non-heme iron is ultimately recycled into
iron-dependent proteins. In prokaryotes, heme oxygenases are often part of iron acquisition pathways whereby
pathogenic organisms acquire iron from host-derived heme. Despite a general understanding of the overall
reactions catalyzed by heme oxygenases, the mechanistic details of how these enzymes catalyze the insertion
of two to three oxygen atoms into a heme substrate remain poorly understood. This mechanistic knowledge is
needed to selectively target heme oxygenase without disrupting other heme-dependent proteins. Recently, we
developed new optical assays to accurately measure heme binding constants and elucidate the partitioning of
heme between heme oxygenases and other heme-dependent proteins. We have also discovered an
unprecedented, dynamic out-of-plane distortion of heme within some heme oxygenase active sites, which is
correlated with enzymatic activity. Finally, we have revealed that an active site hydrogen bond promotes heme
degradation in staphylobilin-producing heme oxygenases by stabilizing a resonance structure with a cationic
radical at the carbon site of oxygenation. In the next five years, we will employ a combined spectroscopic and
computational approach to elucidate the mechanism of heme monooxygenation to meso-hydroxyheme by
mycobilin-producing heme oxygenases, and the mechanisms of meso-hydroxyheme oxygenation by biliverdin-
and staphylobilin-producing heme oxygenases. In general, we will employ a variety of spectroscopic
techniques to characterize analogues of key enzymatic intermediates. These experimental data will be used to
develop accurate computational models of the enzymatic reactions. Ultimately, this program will provide
detailed insight into a fascinating chapter of heme biochemistry, namely, self-oxygenation.

## Key facts

- **NIH application ID:** 10356808
- **Project number:** 5R35GM139516-02
- **Recipient organization:** UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
- **Principal Investigator:** Matthew D Liptak
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $300,182
- **Award type:** 5
- **Project period:** 2021-03-01 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10356808

## Citation

> US National Institutes of Health, RePORTER application 10356808, Heme Oxygenases: chemically complex enzymes found in diverse biological pathways (5R35GM139516-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10356808. Licensed CC0.

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