Protein carbonylation and metabolic control systems

Abstract

Oxidative stress is linked to the production of reactive lipid aldehydes that non-enzymatically alkylate cysteine, histidine, or lysine residues in a reaction termed protein carbonylation. Reactive lipid aldehydes and their derivatives are detoxified via a variety of phase I and phase II systems, and when antioxidant defenses are compromised or oxidative conditions are increased, protein carbonylation is increased. The resulting modification has been implicated as causative in a variety of metabolic states including neurodegeneration, muscle wasting, insulin resistance, and aging. Although such modifications usually result in loss of protein function, protein carbonylation may be regulatory and activate signaling pathways involved in antioxidant biology and cellular homeostasis.

Figure 1. Metabolism of reactive lipid aldehydes via detoxification or carbonylation

Schematic depiction of Phase I and Phase II metabolism of reactive lipid aldehydes is shown. For illustration purposes, the metabolism if 4-HNE (as shown in the bracket) is presented in detail but the reactions apply broadly to each of the indicated aldehydes. In addition, carbonylation the protein side chains (Cys, Lys or His) is shown in detail for 4-HNE but may occur for any of the other reactive lipids shown. MDA; malondialdehyde, 4-HHE; 4-hydroxy 2,3 hexenal. For other abbreviations, see text.

Figure 2. Protein carbonylation targets in metabolic disease

Protein carbonylation targets in a variety of metabolic diseases and their impact on cellular biology are listed. The list is not meant to be inclusive but exemplary of the breadth of biological targets affected by protein carbonylation.

Figure 3. Activation of cell signaling by protein carbonylation

Carbonylation of proteins results not only in enzyme inactivation, but also activation of several signaling pathways. (L) 4-HNE modification of KEAP1 at critical cysteine residues releases NRF2 that translocates to the nucleus. Activated NRF2 heterodimerizes with other factors and activates the transcription of a variety of antioxidant gene targets. (R) 4-HNE modification of thioredoxin releases ASK1 kinase that becomes phosphorylated and initiates a signaling cascade via SEK and JNK. Activation/phosphorylation of JNK leads to phosphorylation of IκBα and translocation/activation of p50/p65 to the nucleus and expression of pro-inflammatory gene targets.