Mechanisms of nitrite bioactivation

Abstract

It is now accepted that the anion nitrite, once considered an inert oxidation product of nitric oxide (NO), contributes to hypoxic vasodilation, physiological blood pressure control, and redox signaling. As such, its application in therapeutics is being actively testing in pre-clinical models and in human phase I–II clinical trials. Major pathways for nitrite bioactivation involve its reduction to NO by members of the hemoglobin or molybdopterin family of proteins, or catalyzed dysproportionation. These conversions occur preferentially under hypoxic and acidic conditions. A number of enzymatic systems reduce nitrite to NO and their activity and importance are defined by oxygen tension, specific organ system and allosteric and redox effectors. In this work, we review different proposed mechanisms of nitrite bioactivation, focusing on analysis of kinetics and experimental evidence for the relevance of each mechanism under different conditions.

Examining the reaction of NO and H 2 S and the possible cross-talk between the two signaling pathways

“…Therefore, because of its extended lifetime, its ability to resist nucleophilic attack, and its ability to release NO, ONSS − (in comparison with HSNO) seems to be a candidate as a NO transporter or extended NOreleasing species. The idea that biological NO sources exist (besides direct NOS generation) with targeted release at distant sites or extended kinetics is not new (8,9), but ONSS − appears to be a viable candidate for this role.…”

Endothelial Monocyteactivating Factor Ii Cancels Oxidative Stress, Сonstitutive Nos Uncoupling and Induced Violations of Cardiac Hemodynamics in Hypertension (Part Ii)

“…Аналогічно реверсному спряженому (de novo синтез NO)/ неспряженому(генерація • О 2 -) стану сNOS, працює ще один потужний генератор як синтезу NO так і • О 2 --реверсний фермент ксантиноксидаза, він же одночасно нітрат-і нітритредуктаза. Давно відкритий цей феномен ксантиноксидази останнім часом став широко досліджуватися саме в цьому аспекті [18][19][20][21]. Неважко припустити, що і реверсний процес неспряження cNOS, за якого також дуже швидко можна підвищити вміст NO і, навпаки, зменшити утворення • О 2 -, теж має бути доступним для багатьох фізіологічних біорегуляторів.…”

Pharmacology and therapeutic role of inorganic nitrite and nitrate in vasodilatation

“…A surprisingly large number of different proteins have been identified that can reduce nitrite to NO in vitro, and detailed recent reviews on this topic are available (van Faassen et al, 2009;Kapil et al, 2010b;Lundberg & Weitzberg, 2010;Kim-Shapiro & Gladwin, 2013). However, there is neither agreement in the literature as to which of these potential nitrite bioactivation processes are the most relevant for vasodilatation (or any other biological process), nor do we understand the reason for this particularly high degree of redundancy.…”

“…According to this principle, the proteins involved in nitrite reduction can be divided into two broad groups: heme-based proteins and molybdopterin-based oxidoreductases. The two best studied examples of the former are Hb and Mb, and both have been claimed to play major roles in nitrite bioactivation (Shiva et al, 2007a;Totzeck et al, 2012b;Kim-Shapiro & Gladwin, 2013), in particular under hypoxic conditions (Crawford et al, 2006;Hendgen-Cotta et al, 2014). Less well studied members of this group include neuroglobin and cytoglobin, cytochrome C and cytochrome C reductase, cytochrome P450, and the endothelial NOS isoform.…”