Carbon Monoxide Signaling: Examining Its Engagement with Various Molecular Targets in the Context of Binding Affinity, Concentration, and Biologic Response

Abstract

Carbon monoxide (CO) has been firmly established as an endogenous signaling molecule with a variety of pathophysiological and pharmacological functions, including immunomodulation, organ protection, and circadian clock regulation, among many others. In terms of its molecular mechanism(s) of action, CO is known to bind to a large number of hemoproteins with at least 25 identified targets, including hemoglobin, myoglobin, neuroglobin, cytochrome c oxidase, cytochrome P450, soluble guanylyl cyclase, myeloperoxidase, and some ion channels with dissociation constant values spanning the range of sub-nM to high lM. Although CO's binding affinity with a large number of targets has been extensively studied and firmly established, there is a pressing need to incorporate such binding information into the analysis of CO's biologic response in the context of affinity and dosage. Especially important is to understand the reservoir role of hemoglobin in CO storage, transport, distribution, and transfer. We critically review the literature and inject a sense of quantitative assessment into our analyses of the various relationships among binding affinity, CO concentration, target occupancy level, and anticipated pharmacological actions. We hope that this review presents a picture of the overall landscape of CO's engagement with various targets, stimulates additional research, and helps to move the CO field in the direction of examining individual targets in the context of all of the targets and the concentration of available CO. We believe that such work will help the further understanding of the relationship of CO concentration and its pathophysiological functions and the eventual development of CO-based therapeutics.-Significance Statement--The further development of carbon monoxide (CO) as a therapeutic agent will significantly rely on the understanding of CO's engagement with therapeutically relevant targets of varying affinity. This review critically examines the literature by quantitatively analyzing the intricate relationships among targets, target affinity for CO, CO level, and the affinity state of carboxyhemoglobin and provide a holistic approach to examining the molecular mechanism(s) of action for CO.

The importance of and difficulties involved in creating molecular probes for a carbon monoxide gasotransmitter

“…Gaseous signaling molecules refer to gaseous molecules that are synthesized within organs, tissues, or cells, or received from the environment, and are utilized to transmit chemical signals. 3 These molecules are capable of inducing particular physiological or biochemical changes, and encompass, but are not restricted to, oxygen, 4 carbon dioxide, 5 nitric oxide, 6 carbon monoxide, 7 hydrogen sulfide, 8 sulfur dioxide, 9 hydrogen cyanide, 10 ammonia, 11 and hydrogen. 12 Not all gaseous signaling molecules can be classified as gasotransmitter molecules; they need to fulfill the following prerequisites: (1) the capacity to diffuse freely through membranes, thereby making their biological effects independent of membrane receptors.…”

Strategies toward Metal‐Free Carbon Monoxide Prodrugs: An Update

“…[2] Ample studies indicate that CO is more than just a metabolic waste, and it is highly involved in the modulation of signaling pathways in mammals. [3][4][5][6][7][8][9] For example, CO was reported to reversibly bind to core transcriptional factors, NPAS2 and CLOCK in the transcription-translation feedback loops to regulate circadian rhythms, and the selective removal of endogenous CO significantly disrupts rhythmic expression of the clock genes. [7] In addition to its physiological roles, ample studies have demonstrated that CO also plays indispensable roles under pathological conditions, and the delivery of exogenous CO conveyed a wide range of pharmacological effects both in vitro and in vivo, including anti-tumor, [10][11] anti-inflammatory, [12][13] antimicrobial, [14][15] and cytoprotective effects, [16][17][18][19] among others.…”

“…Interestingly, CO is also generated endogenously at a rate of 16 μmol/hour in humans via the catabolism of heme in the presence of heme oxygenase (HO‐1/2) [2] . Ample studies indicate that CO is more than just a metabolic waste, and it is highly involved in the modulation of signaling pathways in mammals [3–9] . For example, CO was reported to reversibly bind to core transcriptional factors, NPAS2 and CLOCK in the transcription‐translation feedback loops to regulate circadian rhythms, and the selective removal of endogenous CO significantly disrupts rhythmic expression of the clock genes [7] .…”

Toward “CO in a Pill”: Silica-Immobilized Organic CO Prodrugs for Studying the Feasibility of Systemic Delivery of CO via In Situ Gastrointestinal CO Release

“…Carbon monoxide (CO) is well-known as a “silent killer” among the general population due to its lethal toxicity at high concentrations. However, the past two decades have witnessed intensive studies in revealing the physiological roles, therapeutic activities, mechanism(s) of action, and innovative delivery approaches of CO. − The prospect of developing CO into a therapeutic agent for treating various diseases is on the horizon . Compared to conventional small-molecule drugs, delivering such a gaseous molecule for therapeutic use poses unique challenges.…”