50 shades of oxidative stress: A state-specific cysteine redox pattern hypothesis

Abstract

Oxidative stress is biochemically complex. Like primary colours, specific reactive oxygen species (ROS) and antioxidant inputs can be mixed to create unique "shades" of oxidative stress. Even a minimal redox module comprised of just 12 (ROS & antioxidant) inputs and 3 outputs (oxidative damage, cysteine-dependent redox-regulation, or both) yields over half a million "shades" of oxidative stress. The present paper proposes the novel hypothesis that: state-specific shades of oxidative stress, such as a discrete disease, are associated with distinct tell-tale cysteine oxidation patterns. The patterns are encoded by many parameters, from the identity of the oxidised proteins, the cysteine oxidation type, and magnitude. The hypothesis is conceptually grounded in distinct ROS and antioxidant inputs coalescing to produce unique cysteine oxidation outputs. And considers the potential biological significance of the holistic cysteine oxidation outputs. The literature supports the existence of state-specific cysteine oxidation patterns. Measuring and manipulating these patterns offer promising avenues for advancing oxidative stress research. The pattern inspired hypothesis provides a framework for understanding the complex biochemical nature of state-specific oxidative stress.

Keywords: Cysteine; Oxidation; Oxidative stress; Oxiform; Pattern; ROS; Redox-regulation; Technology.

Graphical abstract

Fig. 1

50 shades of oxidative stress. Like how mixing colours creates shades, the left side of the figure depicts how mixing discrete “ROS” and antioxidant (AOX) inputs can produce distinct “shades” of oxidative stress. The right side depicts how the elements of a simple 12 input and 3 output redox system can generate over half a million shades of oxidative stress. See the main text for specific details. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

Fig. 2

Painting different pictures in the oxidative stress box. The visual of the author's publicly available image, used with his permission, is represented in different ways that stress how subtly varying different inputs, in this case image saturation, contrast, and shading, can produce different outcomes. It is intended as a visual device to capture the essence of a hypothesis on distinct “shades” of oxidative stress. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

Fig. 3

A visual overview of the cysteine landscape. Redox states. A single-molecule with 3-cysteines can adopt one of 4 mathematically permitted by the residue integer percentage cysteine redox states. At the population level, such as the two single cells depicted, the total pool of the protein identity specified single molecule can fall anywhere on a 0–100% redox state spectrum. Redox space. The sulfur atom in cysteine can adopt a panoply of different chemotypes. They are grouped by their character, such as free radical chemotypes like thiyl radicals. The redox space presented is not exhaustive. Oxiforms. According to a quadratic nR law whereby n is the redox state (2, reduced or oxidised) and r is the residue integers, respectively, a single-molecule with 3-cysteines can adopt 8 unique oxiforms. They distribute unevenly by the cysteine redox state: 100 (1), 33 (3), 66 (3), 0 (1).

Fig. 4

The cysteine redox pattern hypothesis: a visual representation. In essence, the basic pattern elements, listed 1–4, can be combined in myriad of ways to translate unique redox inputs into specific patterns of oxidised proteins. Although the geometries portrayed here are purely arbitrary, the hypothesis predicts the existence of patterns that can be geometrically represented by the distance between individual elements and in, 3 and 4D, the magnitude of the connecting line, as encoded by percent cysteine oxidation, over time. At the bottom, panel A shows as individual dots a vast array of possibilities encoded by a defined subset of the cysteine proteome. Panel B uses a squiggled line to show the potential for a specific pattern associated with a unique form or shade of oxidative stress to be drawn onto the vast canvas. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

Fig. 5

A schematic illustrating the underlying conceptual model. In this model, a redox input comprising the intersection of the ROS and antioxidant (AOX) generates a specific cysteine output, in the form of a pattern. The pattern may link in a casually important way to a functional outcome, such as a disease state. This relationship being visually represented at the nexus of the Venn diagram.

Fig. 6

Visual overview of selected functional aspects. Single-molecule level. Left and right scheme show a residue-specific cysteine event, reduced to oxidised transition, having 0 and 1 functional weight on a defined parameter, such as enzyme activity, respectively. Population level. The panel shows the functional impact, even for a 1-weighted single-molecule effect, of a small number of oxidised molecules being buffered by the majority of reduced molecules. Pattern level. The panel shows a pattern and relates the nodes A and B to receptor-linked convergent biological pathway. In this case, the weighted effect of the pattern surpasses a functional threshold. As a result, there is a causal transition from state 1 to state 2.