Protein thiol modification and apoptotic cell death as cGMP-independent nitric oxide (NO) signaling pathways.
Nitric oxide signaling is achieved through both cGMP-dependent and cGMP-independent mechanisms. The latter are exemplified by protein thiol modification followed by subsequent NAD(+)-dependent automodification of the glycolytic enzyme GAPDH, or by mechanisms inducing accumulation of the tumor suppressor gene p53 and causing apoptotic cell death. Both cGMP-independent actions are initiated using NO-releasing compounds and an active LPS/cytokine-inducible NO synthase. NO-synthase inhibitors block the release of NO and hinder downstream signaling mechanisms; they are therefore valuable pharmacological tools linking a defined cellular response to various NO actions. Signal transducing mechanisms elicited by NO can be studied using GAPDH as a representative example of NO-induced protein modification and are grouped as follows: --S-Nitrosylation reactions initiated by NO+ --NAD(+)-dependent, post-translational covalent automodification of GAPDH --Oxidative modification (thiol oxidation) and inhibition of GAPDH by NO-related agents, probably ONOO- GAPDH and several other protein targets may serve as molecular sensors of elevated NO concentrations and may transmit this message through posttranslational modification and oxidation-induced conformational changes as cGMP-independent NO signaling pathways. Toxicity of NO seems to be linked to both apoptosis and necrosis, depending on the chemistry of NO it undergoes in a given biological milieu. Toxicity manifests as a relative excess of NOx, metal-NO interactions, and ONOO- formation in relation to cellular defense systems. Although accumulation of the tumor-suppressor gene product p53 in response to NO opens a regulatory mechanism known to be involved in apoptotic cell death, cGMP-independent signaling pathways remain to be elucidated. As NO-dependent modification of GAPDH would imply down-regulation of glycolysis and concomitant energy production followed by cell death, our data so far do not support this assumption. In recent years, NO has proved to be a beneficial messenger with a potentially toxic activity. It will be challenging to investigate NO biochemistry in closer detail and to elucidate how NO targets biological systems, especially in relation to its pathophysiological role.
University of Konstanz, Faculty of Biology, Germany.
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B
Brüne
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Mohr
U K
UK
Messmer
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002248:Carbon Monoxide / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000378:metabolism; D006801:Humans; D009243:NAD / Q000378:metabolism; D009569:Nitric Oxide / Q000502:physiology* / Q000633:toxicity; D011506:Proteins / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013438:Sulfhydryl Compounds / Q000378:metabolism
D011506:Proteins; D013438:Sulfhydryl Compounds; D009243:NAD; D009569:Nitric Oxide; D002248:Carbon Monoxide; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D006152:Cyclic GMP