Small molecule signaling agents: the integrated chemistry and biochemistry of nitrogen oxides, oxides of carbon, dioxygen, hydrogen sulfide, and their derived species

Abstract

Several small molecule species formally known primarily as toxic gases have, over the past 20 years, been shown to be endogenously generated signaling molecules. The biological signaling associated with the small molecules NO, CO, H₂S (and the nonendogenously generated O₂), and their derived species have become a topic of extreme interest. It has become increasingly clear that these small molecule signaling agents form an integrated signaling web that affects/regulates numerous physiological processes. The chemical interactions between these species and each other or biological targets is an important factor in their roles as signaling agents. Thus, a fundamental understanding of the chemistry of these molecules is essential to understanding their biological/physiological utility. This review focuses on this chemistry and attempts to establish the chemical basis for their signaling functions.

Figure 1

(a) Lewis and valence bond depiction of O₂. (b) Molecular orbital diagram for O₂.

Figure 2

Lipid peroxidation. Numerous oxidized products can be generated. Only the simplest alkylperoxide product is shown.

Figure 3

Bonding schemes for end-on O₂ binding to metals.

Figure 4

(a) Lewis structure/valence bond depiction of NO, (b) molecular orbital diagram for NO, (c) singly occupied molecular orbital (SOMO) of NO, and (d) NO spin density. Note: panels c and d were calculated at the CCSD(T)/6-311++G(3df,3pd)//MP2/ 6-311++G(3df,3pd) level (isovalues of 0.0004 and 0.02, respectively).

Figure 5

Attack of a nucleophile on a carbonyl versus attack on NO (note: electron in the NO π* orbital is not localized in the lobe shown but is distributed throughout the π* orbitals).

Figure 6

Valence bond depiction of NO₂ (note: only two of several resonance forms are shown).

Figure 7

Oxidation of substituted phenol by NO₂.

Figure 8

Nitro and nitrito coordination of NO₂ ⁻ to the iron center.

Figure 9

Possible mechanisms for the generation of NO via the reduction of ferrous-heme-bound nitrite. (a) Ferrous ion reduction of the nitro complex and (b) reduction of the nitrito complex.

Figure 10

Proximal ligand release via the coordination of NO to a ferrous heme.

Figure 11

Donation of electrons to the metal from the NO π* orbital in the bent geometry leading to a weakening of the trans-ligand bond (note: other bonding interactions are not shown).

Figure 12

Bonding in CO and CO−metal complexes.

Figure 13

Enhanced chemical properties of persulfides compared to thiols.

Figure 14

Binding geometries of O₂, NO, and CO to a ferrous heme protein. Preferred linear binding of CO causes steric crowding that is thought to inhibit binding.

Figure 15

Hydrogen bond stabilization of the heme Fe³⁺-O₂ ⁻ complex.

Figure 16

Simplistic scheme for HIF1a regulation by O₂ via PHD and FIH.

Figure 17

General mechanism for 2-oxoglutarate-dependent, nonheme iron hydroxylases.