Reactive oxygen species and alpha,beta-unsaturated aldehydes as second messengers in signal transduction

Abstract

Signaling by H(2)O(2), alpha,beta-unsaturated aldehydes, such as 4-hydroxy-2-nonenal (HNE) and related chemical species, is thought to differ from signaling by other second messengers because the oxidants and other electrophiles can readily undergo nonenzymatic reactions and are therefore classified as "reactive." This brief review will describe how and when the chemistry of signaling is similar or differs from classic second messengers, such as cyclic AMP, or posttranslational signaling, such as farnesylation or ubiquitination. The chemistry of cysteine provides a common factor that underlies signaling by H(2)O(2) and HNE. Nonetheless, as H(2)O(2) and HNE are rapidly metabolized in vivo, spatial considerations are extremely important in their actions. Therefore, the locations of sources of H(2)O(2) and alpha,beta-unsaturated aldehydes, the NADPH oxidases, mitochondria, membrane lipids, and redox cycling toxicants, as well as their targets, are key factors. The activation of the JNK pathway by HNE and endogenously generated H(2)O(2) illustrates these principles.

Figure 1

Locations of superoxide and hydrogen peroxide production and degradation relevant to signaling. (1) Superoxide produced on the outside of the cell by NADPH oxidase in the plasma membrane, (2) dismutes to H₂O₂, (3) that can enter the cytosol through an aquaporin. (4) Superoxide can enter cells through an anion channel where (5) it will be dismuted to H₂O₂ and O₂. In the cytosol, (6) Prdx and (7) Gpx will rapidly eliminate H₂O₂. (8) Catalase present in the peroxisomes will eliminate H₂O₂ that either enters. (9) Superoxide is generated in the mitochondria from ubiquisemiquinone oxidation in a reaction that is pulled forward by (10) Mn superoxide dismutase to generate H₂O₂. If O₂^•− were produced on the outside of the inner membrane, (11) Cu/Zn SOD present there would dismute it to H₂O₂ and O₂. (12) NADPH oxidase 4 present on the nuclear and/or endoplasmic reticulum generates O₂^•− that would also be dismuted. Oxidoreductases in other compartments are potential sources of O₂^•− and H₂O₂ but are not clearly implicated in physiological signaling.

Figure 2

Nonenzymatic reactions of 4-hydroxynonenal. HNE can react with an amine (1) to form either a Schiff base (bottom) or a Michael addition product (top). Michael addition products can form with (2) the imidazole moiety of histidine or (3) the thiol moiety of cysteine. (4) A hemiacetal can form with an alcohol. (5) Tetrahydropyrimidoguanine products can form from the reaction of guanine with both the α,β-unsaturated bond and aldehyde functional group.

Figure 3

Enzymatic metabolism of 4-hydroxynonenal. HNE can be reduced by aldose reductase, oxidized by aldehyde dehydrogenase, and conjugated to GSH by a glutathione S-transferase.