Carbon monoxide--physiology, detection and controlled release

Abstract

Carbon monoxide (CO) is increasingly recognized as a cell-signalling molecule akin to nitric oxide (NO). CO has attracted particular attention as a potential therapeutic agent because of its reported anti-hypertensive, anti-inflammatory and cell-protective effects. We discuss recent progress in identifying new effector systems and elucidating the mechanisms of action of CO on, e.g., ion channels, as well as the design of novel methods to monitor CO in cellular environments. We also report on recent developments in the area of CO-releasing molecules (CORMs) and materials for controlled CO application. Novel triggers for CO release, metal carbonyls and degradation mechanisms of CORMs are highlighted. In addition, potential formulations of CORMs for targeted CO release are discussed.

Fig. 1

Haem degradation. Haem (Fe²⁺-protoporphyrin IX), released from haemoglobin (left), is degraded by the aid of haem oxygenase to carbon monoxide (CO), ferrous ions (Fe²⁺) and biliverdin IX. A subsequent step, catalysed by biliverdin reductase, yields bilirubin IX.

Fig. 2

CO binding to soluble guanylyl cyclase. Haem coordination by soluble guanylyl cyclase (A, PDB ID 2O09) with unoccupied coordination site, in the presence of NO (B, PDB ID 2O0C), and in the presence of CO (C, PDB ID 2O0G). The images were rendered using MacPyMol v0.99.

Fig. 3

A model of the Slo1 BK channel function and the structure. (A) Allosteric model of the Slo1 BK channel function. The ion conduction gate can be closed or open as specified by the equilibrium constant L. Each of the four voltage sensor domains could be at rest or activated as specified by the equilibrium constant J. Each of the Ca²⁺ sensors could be unbound or bound as specified by the constant K. The model lumps the two Ca²⁺ sensors of each Slo1 subunit into one functional unit. The allosteric interactions are specified by the constants D, C and E. (B) Structural organization of each of the four Slo1 subunits in a functional Slo1 BK channel (not drawn to scale). Each polypeptide is about 1,100 residues long. (C) Probable structure of a functional Slo1 BK channel. The grey transmembrane domain is a homology model based on PDB ID 2R9R and the cytoplasmic domain is from PDB ID 3NAF. In the cytoplasmic domain, each subunit is shown using a different colour. The Ca²⁺ ligand residues are displayed using spheres. The images were rendered using MacPyMol v0.99.

Fig. 4

Colourimetric detection of CO via binuclear rhodium complexes. (A) Basic structure of the complexes (HAc = CH₃CO₂H). (B) The photograph shows ([Rh₂{(m-CH₃C₆H₃)P(m-CH₃C₆H₄)₂}₂(O₂CCH₃)₂]·(CH₃CO₂H)₂) adsorbed on silica gel in the absence (left) and presence of 8 ppm (middle) and 2000 ppm (right) of CO. Adapted and reprinted with permission from ref. Copyright 2011 American Chemical Society.

Fig. 5

Confocal microscopy images of the turn-on fluorescent probe for selective CO detection based on palladium-mediated carbonylation reactivity (COP-1). The organometallic probe is capable of detecting CO both in aqueous buffer and in living HEK293T cells with high selectivity. Left: Cells incubated with COP-1 for 30 min. Right: Cells incubated with 50 μM CORM-3 and 1 μM COP-1. Adapted and reprinted with permission from ref. Copyright 2012 American Chemical Society.

Fig. 6

The biosensor COSer is composed of yellow fluorescent protein (YFP) as the fluorescent reporter and CooA, a dimeric haem protein from Rhodospirillum rubrum as the CO recognition unit. (A) Left: Inactive monomer CooA. Right: Active CO binding to CooA induces a conformational change. (B) Upon CO binding, the C helix of CooA is broken into two parts (“C helix a” and “C helix b”) connected by residues 132 to 134. (C) COSer contains YFP inserted by two short linkers between residues 132 and 133 in each CooA monomer. The resulting structural change upon CO binding to CooA induces an increase in fluorescence of the probe. Reprinted with permission from ref. Copyright 2010 Wiley-VCH.

Fig. 7

Selection of metal-based CO-releasing molecules (CORMs).

Fig. 8

Degradation and CO liberation from acyloxycyclohexadiene tricarbonyliron complexes (enzyme-triggered CORMs, ET-CORMs).^,

Fig. 9

Structure of hen egg white lysozyme bound to Ru fragments derived from fac-[Ru(CO)₃Cl₂(1,3-thiazole)]. Four amino-acid residues (His15, Asp18, Asp101 and Asp119) interact with five ruthenium atoms. Adapted and reprinted with permission from ref. Copyright 2012 Elsevier.

Fig. 10

Proposed pH-dependent interaction of CORM-3 with bases. The attack of a hydroxide ion at a carbonyl ligand results in a hydroxycarbonyl moiety; at higher pH values the acyl group can be deprotonated or the chloride ion substituted by an OH group. The suggested final species combines both possible interaction pathways at alkaline conditions.

Fig. 11

Conceptual model for the development of pharmaceutical CORMs (adapted from Romao et al.).

Fig. 12

Schematic presentation of induced CO-release from CORM-functionalized iron oxide nanoparticles through an alternating magnetic (AC) field. Tri(carbonyl)-chlorido-dihydroxyphenylalaninato-ruthenium(II) displays an immobilised analogue of CORM-3. Adapted and reprinted with permission from ref. Copyright 2013 RSC Publishing.

Fig. 13

Metal-organic frameworks (MOFs) with iron for the loading and delivery of CO. (A, B) Scanning electron microscope (SEM) pictures of crystals of Fe MOF with terephthalic acid. (C) Structure of Fe MOF, as viewed along the c axis. Empty circles represent the coordination sites for CO, iron atoms: light-gray spheres, oxygen atoms: gray spheres, and carbon atoms: black spheres. Adapted and reprinted with permission from ref. Copyright 2013 Wiley-VCH.

Fig. 14

[Mn(CO)₃(tpm)]⁺ (tpm = tris(pyrazolyl)methane) complexes containing alkyne-functionalized tpm ligands covalently attached to dopable nanodiamonds and silica nanoparticles. The corresponding transmission electron microscope (TEM) pictures are also shown (bars indicate 50 nm). Adapted and reprinted with permission from ref.^, Copyright 2011 American Chemical Society and 2012 RSC Publishing.

Fig. 15

Concept of embedding water-insoluble, photoactive NO and CO metal complexes into fibrous polymer non-wovens and nanoparticles. The NORMAs and CORMAs are important for the development of safe NO and CO delivering devices for therapeutic purposes; toxic metabolites after gas release are retained in the biocompatible polymer matrix.^–