# Nitric Oxide Signaling Chemistry at Non-Heme Sites

> **NIH NIH R01** · GEORGETOWN UNIVERSITY · 2020 · $294,114

## Abstract

Project Summary
Nitric Oxide Signaling Chemistry at Non-Heme Sites
 Nitric oxide (NO) is a powerful signaling molecule with far reaching effects. It plays numerous roles in
many disparate areas of human biology, from vasodilation in the cardiovascular system to host defense
against microbial pathogens. Although NO donor drugs have long served as therapeutic agents for
cardiovascular disease, the discrete molecular mechanisms connected to NO signaling are not well
understood. Adding to the complexity of NO biology, molecular relatives of NO such as S-nitrosothiols
(RSNOs), nitrite (NO2-) and nitroxyl (HNO) can also exhibit NO-like behavior. Thus, an understanding of the
discrete mechanistic pathways by which these species form, interconvert, and react with biologically relevant
molecular sites is crucial for the rational development of therapeutics to target NO signaling pathways. For
instance, several neurodegenerative diseases are linked to aberrant protein S-nitrosylation, underscoring the
need to understand the connection between free NO and protein RSNOs.
 Copper enzymes are integral to the interconversion of NO and its redox congeners in biological
systems. Multicopper oxidases such as ceruloplasmin can serve as NO oxidases, storing NO for later use as
S-nitrosothiols (RSNOs) and nitrite (NO2-). On the other hand, CuZnSOD catalyzes the loss of NO from
RSNOs and plays a role in vasodilation, antiplatelet aggregation, and regulation of intracellular RSNO levels.
RSNOs induce the release of Zn2+ ions from metallothioneins (MTs), reversibly inhibit DNA transcription by
some zinc fingers, and can S-nitrosate protein thiols. At high concentrations, however, NO is toxic leading to
highly reactive NxOy species responsible for nitrosative stress.
 Employing models inspired by coordination environments typically experienced by Cu and Zn ions in
biology, along with simple Lewis acids, we will carefully outline a variety of pathways for the interconversion
molecules that participate in NO signaling. We will develop and examine models that take advantage of the
CuII/I redox couple to convert NO into long lived, mobile species such as RSNOs and NO2- (Aim 1). We will
outline factors that control S-transnitrosation reactions at zinc and as well as at free thiols employing simple
Lewis acids (Aim 2). Through careful study of highly reactive, oxidizing [CuIII](?2-O2N2) and [CuII](?2-O2N)
species derived from the interaction of NO and NO2- at copper sites, we will demonstrate a wide range of
reactivity patterns that may participate in nitrosative stress under hypoxic conditions (Aim 3).

## Key facts

- **NIH application ID:** 9999003
- **Project number:** 5R01GM126205-04
- **Recipient organization:** GEORGETOWN UNIVERSITY
- **Principal Investigator:** TIMOTHY H WARREN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $294,114
- **Award type:** 5
- **Project period:** 2017-09-16 → 2021-08-04

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9999003

## Citation

> US National Institutes of Health, RePORTER application 9999003, Nitric Oxide Signaling Chemistry at Non-Heme Sites (5R01GM126205-04). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9999003. Licensed CC0.

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