Open AccessEndogenous Hemoprotein-Dependent Signaling Pathways of Nitric Oxide and Nitrite
Author(s) -
Matthew R. Dent,
Anthony W. DeMartino,
Jesús Tejero,
Mark T. Gladwin
Publication year - 2021
Publication title -
inorganic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.348
H-Index - 233
eISSN - 1520-510X
pISSN - 0020-1669
DOI - 10.1021/acs.inorgchem.1c01048
Subject(s) - chemistry , nitric oxide , heme , hemeprotein , signal transduction , biochemistry , nitrite , nitric oxide synthase , myoglobin , cell signaling , hemoglobin , microbiology and biotechnology , enzyme , biology , organic chemistry , nitrate
Interdisciplinary research at the interface of chemistry, physiology, and biomedicine have uncovered pivotal roles of nitric oxide (NO) as a signaling molecule that regulates vascular tone, platelet aggregation, and other pathways relevant to human health and disease. Heme is central to physiological NO signaling, serving as the active site for canonical NO biosynthesis in nitric oxide synthase (NOS) enzymes and as the highly selective NO binding site in the soluble guanylyl cyclase receptor. Outside of the primary NOS-dependent biosynthetic pathway, other hemoproteins, including hemoglobin and myoglobin, generate NO via the reduction of nitrite. This auxiliary hemoprotein reaction unlocks a "second axis" of NO signaling in which nitrite serves as a stable NO reservoir. In this Forum Article, we highlight these NO-dependent physiological pathways and examine complex chemical and biochemical reactions that govern NO and nitrite signaling in vivo. We focus on hemoprotein-dependent reaction pathways that generate and consume NO in the presence of nitrite and consider intermediate nitrogen oxides, including NO 2 , N 2 O 3 , and S -nitrosothiols, that may facilitate nitrite-based signaling in blood vessels and tissues. We also discuss emergent therapeutic strategies that leverage our understanding of these key reaction pathways to target NO signaling and treat a wide range of diseases.