Perspective on Recent Developments on Sulfur-Containing Agents and Hydrogen Sulfide Signaling

Abstract

The last couple of years have witnessed the coming together of several initially unconnected lines of investigation which now link natural sulfur products to hydrogen sulfide release and wide ranging cardiovascular protection. It has become apparent that sulfur compounds contained within garlic, onions, mushrooms and various edible beans and fruits may be transformed chemically or enzymatically in the human body with subsequent formation of hydrogen sulfide. The latter has emerged during the last decade from a shadowy existence as toxic gas to be recognized as the third gaseous transmitter besides nitric oxide (^˙NO) and carbon monoxide (CO). Hydrogen sulfide is formed endogenously in the human body by enzymes such as cystathionine β-synthase (CBS) in the brain and cystathionine γ-lyase (CSE) in liver, vascular and non-vascular smooth muscle. Although its exact chemical and biochemical modes of action are still not fully understood, levels of hydrogen sulfide in the brain and vasculature have unambiguously been associated with human health and disease. Not surprisingly, agents releasing hydrogen sulfide, as well as inhibitors of hydrogen sulfide synthesis (CBS and CSE inhibitors) have been investigated. Apart from linking our daily diet to a healthy brain and cardiovasculature, these findings may also provide new leads for drug design. Future studies will therefore need to focus on how such compounds are formed and transformed in the relevant plants, how food processing affects their chemical constitution, and how they release hydrogen sulfide (or control its levels) in the human body. Such multidisciplinary research should ultimately answer the all-important question if a hearty diet is also good for the heart.

Abbreviations

AAT:aspartate aminotransferase

AM:allyl mercaptan

APS:adenosine 5′-phosphosulfate

BCA:β-cyanoalanine

cAMP:3′,5′-cyclic adenosine monophosphate

CBS:cystathionine β-synthase

CSE:cystathionine γ-lyase

DADS:diallyl disulfide

DAS:diallyl sulfide

DATS:diallyl trisulfide

DATTS:diallyl tetrasulfide

GSH:glutathione (reduced)

GSSG:glutathione disulfide

MPST:3-mercaptopyruvate sulfur transferase

RSS:reactive sulfur species

SAC:S-allylcysteine

SAM:S-adenosylmethionine

SIR:sulfur-induced resistance

SO:sulfur oxidase

TSMT:thiol S-methyl transferase

natural sulfur products - garlic - polysulfides - hydrogen sulfide - vascular homeostasis

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1 These challenges include the search for agents able to tackle multi-drug resistant bacteria, selective anticancer agents, chemopreventive agents suitable to deal with diseases characteristic of an ageing society and readily available ‘green pesticides’ which kill pests but do not contaminate the food chain or ruin the eco-system. Natural sulfur agents have been considered as part of all of these challenges.

2 We will use the term ‘polysulfide’ to denote organic and inorganic sulfur species which contain sulfur-sulfur chains with chain lengths of three or more sulfur atoms. This is due to the fact that most natural, organic compounds discussed here are commonly known as ‘sulfides’, such as diallyl trisulfide. Please note, however, that strictly speaking organic molecules containing such groups (RS_xR, x ≥ 3, R ≠ H) should be referred to as ‘polysulfanes’, while inorganic species of the type S_x ²⁻ (x ≥ 3) should be called ‘polysulfides’.

3 Within this context, one should also point out that unlike most anticancer drugs of natural origin, diallyl trisulfide and related agents occur in edible plants, are considered non-toxic to humans and have formed part of the human diet for centuries.

4 Without wanting to spoil the recent excitement, from a chemist’s point of view, hydrogen sulfide is not really just a ‘gas’ at pH 7.4, but is mostly deprotonated to HS⁻ (see below). It would therefore rather qualify as an ‘anionic transmitter’.

5 We will use the term ‘hydrogen sulfide’ to denote H₂S gas, the hydrogen sulfide anion (HS⁻) and the sulfide anion (S²⁻), bearing in mind that the first pKa of H₂S, i. e., pKa₁, is 6.96 and therefore H₂S is to roughly two-thirds deprotonated (to HS⁻) at physiological pH. The second pKa value describing the dissociation of HS⁻ to H⁺ and S²⁻ has been estimated to be around 17 to 21, i. e., this dissociation process plays no direct role in vivo, although (bound) S²⁻ may be formed due to interactions with ‘third parties’, such as S²⁻ ions bound to metal ions. We will use the appropriate chemical formulas, i. e., H₂S, HS⁻ and S²⁻ when referring to a particular (de)-protonation state of hydrogen sulfide.

6 We refer here generally to L-cysteine. Where relevant, we will explicitly distinguish between the two isomers.

7 For instance, a reduction in rat arterial blood pressure of 12 to 30 mm Hg has been reported after bolus injection of 2.8 to 14 μmol hydrogen sulfide per kg body weight [28].

8 The pro- and antioxidant properties of hydrogen sulfide, and their manifestation in human health, disease and therapy are complicated and have led to a range of recent investigations, some of which even appear to contradict each other. In 2007, several reviews and perspectives have been published on this matter, in part with a firm sight on drug development (hydrogen sulfide releasing agents, inhibitors of hydrogen sulfide-generating enzymes). This literature may be considered for more in depth information on this topic.

9 One may mention that the inorganic salt sodium hydrogen sulfide (NaHS) is widely used in research as a source of (exogenous) hydrogen sulfide (i. e., HS⁻ ions which rapidly enter into equilibrium with H₂S in buffered solution). Neither NaHS, nor simple hydrogen sulfide-releasing organic molecules, however, are suitable (yet) for medical applications. Most of the organic compounds release hydrogen sulfide too fast and in an uncontrolled manner.

10  The presence of hydrogen sulfide in two distinct forms distinguishes this gaseous modulator from ^˙NO and CO, both of which only occur in one, uncharged form in vivo.

11  ^˙NO is synthesized from L-arginine by (several isoforms) of NOS, a process also resulting in the formation of L-citrulline; CO is formed together with biliverdin and iron ions from protoheme IX by one of the heme oxygenases [18], [31].

12  Sulfite reductases often work hand in hand with enzymes reducing readily available sulfate (SO₄ ²⁻) to sulfite (SO₃ ²⁻) [34]. This process involves the initial formation of adenosine 5′-phosphosulfate (APS) from sulfate, an adenylation reaction catalyzed by ATP sulfurylase (ATPS) enzymes. APS is then reduced to sulfite by APS reductase enzymes, consuming GSH and also releasing adenosine 5′-phosphate in the process. Please note that the overall reduction of SO₄ ²⁻ to hydrogen sulfide formally consumes a total of eight electrons.

13  In a series of rather delicate experiments, hydrogen sulfide formation in the gut and in faeces has recently been investigated [38], [39]. Within this context, one needs to bear in mind that hydrogen sulfide formed in the gut may not simply diffuse into the (human) body. It may also be passed or end up as (inert) sulfide anions bound to metal ions in the faeces. Indeed, the use of zinc, iron and bismuth ions has been suggested to reduce the amounts of H₂S in flatus.

14  The precise outcome of these thiol/disulfide exchange reactions depends on the redox potentials of RSH and GSH, the potentials of their oxidized forms, and the concentrations of reaction partners involved.

15  In comparison, the carbon-carbon bond is considerably more stable (around 348 kJ mol⁻¹).

16  We have used GSH here as a representative example of intracellular thiol-based nucleophiles. This does not imply, of course, that this chemistry is limited to GSH. In fact, any thiol with appropriate nucleophilicity may participate in this chemistry, including thiols present in proteins and enzymes.

17  Here, we are somewhat cautious not to refer too bluntly to a second nucleophilic attack of GSH at one of the two relevant carbons of RSH (e. g. allyl mercaptan). Such a reaction in theory could indeed result in the formation of RSG and the release of hydrogen sulfide – although chemists may have some reservations with regard to such a process.