The Reactive Sulfur Species Concept: 15 Years On

Abstract

Fifteen years ago, in 2001, the concept of "Reactive Sulfur Species" or RSS was advocated as a working hypothesis. Since then various organic as well as inorganic RSS have attracted considerable interest and stimulated many new and often unexpected avenues in research and product development. During this time, it has become apparent that molecules with sulfur-containing functional groups are not just the passive "victims" of oxidative stress or simple conveyors of signals in cells, but can also be stressors in their own right, with pivotal roles in cellular function and homeostasis. Many "exotic" sulfur-based compounds, often of natural origin, have entered the fray in the context of nutrition, ageing, chemoprevention and therapy. In parallel, the field of inorganic RSS has come to the forefront of research, with short-lived yet metabolically important intermediates, such as various sulfur-nitrogen species and polysulfides (S_x^2-), playing important roles. Between 2003 and 2005 several breath-taking discoveries emerged characterising unusual sulfur redox states in biology, and since then the truly unique role of sulfur-dependent redox systems has become apparent. Following these discoveries, over the last decade a "hunt" and, more recently, mining for such modifications has begun-and still continues-often in conjunction with new, innovative and complex labelling and analytical methods to capture the (entire) sulfur "redoxome". A key distinction for RSS is that, unlike oxygen or nitrogen, sulfur not only forms a plethora of specific reactive species, but sulfur also targets itself, as sulfur containing molecules, i.e., peptides, proteins and enzymes, preferentially react with RSS. Not surprisingly, today this sulfur-centred redox signalling and control inside the living cell is a burning issue, which has moved on from the predominantly thiol/disulfide biochemistry of the past to a complex labyrinth of interacting signalling and control pathways which involve various sulfur oxidation states, sulfur species and reactions. RSS are omnipresent and, in some instances, are even considered as the true bearers of redox control, perhaps being more important than the Reactive Oxygen Species (ROS) or Reactive Nitrogen Species (RNS) which for decades have dominated the redox field. In other(s) words, in 2017, sulfur redox is "on the rise", and the idea of RSS resonates throughout the Life Sciences. Still, the RSS story isn't over yet. Many RSS are at the heart of "mistaken identities" which urgently require clarification and may even provide the foundations for further scientific revolutions in the years to come. In light of these developments, it is therefore the perfect time to revisit the original hypotheses, to select highlights in the field and to question and eventually update our concept of "Reactive Sulfur Species".

Keywords: cellular thiolstat; reactive sulfur species; redox signalling; redoxome.; sulfur radicals.

Figure 1

A selection of RSS derived by simple analogy with ROS and RNS. This kind of “isosteric replacement” of sulfur atoms for oxygen, and on occasion for nitrogen, is a theoretical exercise on paper. It leads to a range of rather exotic RSS which only recently have been discovered in the context of human biology and often are still controversial.

Figure 2

Schematic illustration of the Gestalt switch which occurred in the field of sulfur redox biology during the first decade of this century. This conceptual switch has been a prerequisite to bring sulfur redox systems to the forefront of widely accepted redox research, and to stimulate new projects, concepts, and even the emergence of new or upsurge of existing journals in this field.

Figure 3

The diversification of the concept of RSS into different directions, from “Regulatory Sulfur Species” and inorganic “Reactive Sulfide Species” to “Recreational Sulfur Substances” used in various remedies. This diversification often depends on the scientific communities involved and is not necessarily mutually exclusive. The signpost contains real, published and simply by us invented malapropisms of the original RSS abbreviation, and is superimposed on a real signpost of the town of Thionville in Lorraine (France).

Figure 4

Despite the unassuming chemical composition of inorganic polysulfide S_x²⁻ species, the reactivity underlying their various biological activities is facet-rich and highly complex. This figure has been adapted from one of our publications on this inorganic matter in 2007 and has been updated to account for the most recent developments in this field, such as HSNO formation [95].

Figure 5

Overview of selected sulfur containing natural products found in edible plants, mushrooms and some lower organisms. These reactive sulfur secondary metabolites have been associated with all kinds of health benefits and play a major role in so-called functional foods, especially for the elderly. In most cases, these claims are controversial because of concentrations, bioavailability and stability. Still, a specific interaction with the enzymes and microbiota of the gut and subsequent formation of “reprocessed sulfur species” may be relevant. If and how these substances act as RSS in a more narrow biological sense is a matter of ongoing research. See text for details on the origin and potential uses of these suspected nutraceuticals.

Figure 6

Several organic, sulfur-containing compounds are used as food supplements or medical drugs. In some instances, such as disulfiram, the nature of a RSS is immediately apparent. Other compounds, such as omeprazole or clopidogrel, become activated and react via a reactive sulfur intermediate, yet their classification as RSS drug is less apparent. The same applies to releasing agents, for instance GYY4137, which harbour certain RSS, such as H₂S. Still others, such as the 1,2-dithiole-3-thiones, are under investigation or controversial with regard to their medical or recreational uses.