Gaseous signaling molecules

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Gaseous signaling molecules are gaseous molecules that are either synthesised internally (endogenously) in the organism, tissue or cell or are received by the organism, tissue or cell from outside (say, from the atmosphere or hydrosphere, as in the case of oxygen) and that are used to transmit chemical signals which induce certain physiological or biochemical changes in the organism, tissue or cell. The term is applied to, for example, oxygen, carbon dioxide, nitric oxide, carbon monoxide, hydrogen sulfide, sulfur dioxide, nitrous oxide, hydrogen cyanide, ammonia, methane, hydrogen, ethylene, etc.

 

Many, but not all, gaseous signaling molecules are called gasotransmitters.

Gaseous signaling molecules as gasotransmitters

Gasotransmitters is a subfamily of endogenous molecules of gases or gaseous signaling molecules, including NO, CO, H
₂S. These particular gases share many common features in their production and function but carry on their tasks in unique ways, which differ from classical signaling molecules, in the human body. In 1981, it was first suggested from clinical work with nitrous oxide that a gas had a direct action at pharmacological receptors and thereby acted as a neurotransmitter. In vitro experiments confirmed these observations which were replicated at NIDA later. 

The terminology and characterization criteria of “gasotransmitter” were firstly introduced in 2002. For one gas molecule to be categorized as a gasotransmitters, all of the following criteria should be met.

1. It is a small molecule of gas;
2. It is freely permeable to membranes. As such, its effects do not rely on the cognate membrane receptors. It can have endocrine, paracrine, and autocrine effects. In their endocrine mode of action, for example, gasotransmitters can enter the blood stream; be carried to remote targets by scavengers and released there, and modulate functions of remote target cells;
3. It is endogenously and enzymatically generated and its production is regulated;
4. It has well defined and specific functions at physiologically relevant concentrations. Thus, manipulating the endogenous levels of this gas evokes specific physiological changes;
5. Functions of this endogenous gas can be mimicked by its exogenously applied counterpart;
6. Its cellular effects may or may not be mediated by second messengers, but should have specific cellular and molecular targets.

In 2011, a European Network on Gasotransmitters (ENOG) was formed. The aim of the network is to promote research on NO, CO and H
₂S in order to better understand the biology of gasotransmitters and to unravel the role of each mediator in health and disease. Moreover, the network aims to contribute to the translation of basic science knowledge in this area of research into therapeutic or diagnostic tools.

Carbon dioxide

Carbon dioxide is one of the mediators of local autoregulation of blood supply. If its levels are high, the capillaries expand to allow a greater blood flow to that tissue. 

Bicarbonate ions are crucial for regulating blood pH. A person's breathing rate influences the level of CO₂ in their blood. Breathing that is too slow or shallow causes respiratory acidosis, while breathing that is too rapid leads to hyperventilation, which can cause respiratory alkalosis.

Although the body requires oxygen for metabolism, low oxygen levels normally do not stimulate breathing. Rather, breathing is stimulated by higher carbon dioxide levels.

The respiratory centers try to maintain an arterial CO₂ pressure of 40 mm Hg. With intentional hyperventilation, the CO₂ content of arterial blood may be lowered to 10–20 mm Hg (the oxygen content of the blood is little affected), and the respiratory drive is diminished. This is why one can hold one's breath longer after hyperventilating than without hyperventilating. This carries the risk that unconsciousness may result before the need to breathe becomes overwhelming, which is why hyperventilation is particularly dangerous before free diving.

Nitric oxide

NO is one of the few gaseous signalling molecules known and is additionally exceptional due to the fact that it is a radical gas. It is a key vertebrate biological messenger, playing a role in a variety of biological processes. It is a known bioproduct in almost all types of organisms, ranging from bacteria to plants, fungi, and animal cells.

Nitric oxide, known as the 'endothelium-derived relaxing factor', or 'EDRF', is biosynthesized endogenously from L-arginine, oxygen, and NADPH by various nitric oxide synthase (NOS) enzymes. Reduction of inorganic nitrate may also serve to make nitric oxide. The endothelium (inner lining) of blood vessels uses nitric oxide to signal the surrounding smooth muscle to relax, thus resulting in vasodilation and increasing blood flow. Nitric oxide is highly reactive (having a lifetime of a few seconds), yet diffuses freely across membranes. These attributes make nitric oxide ideal for a transient paracrine (between adjacent cells) and autocrine (within a single cell) signaling molecule.

Independent of nitric oxide synthase, an alternative pathway, coined the nitrate-nitrite-nitric oxide pathway, elevates nitric oxide through the sequential reduction of dietary nitrate derived from plant-based foods. Nitrate-rich vegetables, in particular leafy greens, such as spinach and arugula, and beetroot, have been shown to increase cardioprotective levels of nitric oxide with a corresponding reduction in blood pressure in pre-hypertensive persons. For the body to generate nitric oxide through the nitrate-nitrite-nitric oxide pathway, the reduction of nitrate to nitrite occurs in the mouth, by commensal bacteria, an obligatory and necessary step. Monitoring nitric oxide status by saliva testing detects the bioconversion of plant-derived nitrate into nitric oxide. A rise in salivary levels is indicative of diets rich in leafy vegetables which are often abundant in anti-hypertensive diets such as the DASH diet.

The production of nitric oxide is elevated in populations living at high altitudes, which helps these people avoid hypoxia by aiding in pulmonary vasculature vasodilation. Effects include vasodilatation, neurotransmission, modulation of the hair cycle, production of reactive nitrogen intermediates and penile erections (through its ability to vasodilate). Nitroglycerin and amyl nitrite serve as vasodilators because they are converted to nitric oxide in the body. The vasodilating antihypertensive drug minoxidil contains an NO moiety and may act as an NO agonist. Likewise, Sildenafil citrate, popularly known by the trade name Viagra, stimulates erections primarily by enhancing signaling through the nitric oxide pathway in the penis. 

Nitric oxide (NO) contributes to vessel homeostasis by inhibiting vascular smooth muscle contraction and growth, platelet aggregation, and leukocyte adhesion to the endothelium. Humans with atherosclerosis, diabetes, or hypertension often show impaired NO pathways. A high salt intake was demonstrated to attenuate NO production in patients with essential hypertension, although bioavailability remains unregulated.

Nitric oxide is also generated by phagocytes (monocytes, macrophages, and neutrophils) as part of the human immune response. Phagocytes are armed with inducible nitric oxide synthase (iNOS), which is activated by interferon-gamma (IFN-γ) as a single signal or by tumor necrosis factor (TNF) along with a second signal. On the other hand, transforming growth factor-beta (TGF-β) provides a strong inhibitory signal to iNOS, whereas interleukin-4 (IL-4) and IL-10 provide weak inhibitory signals. In this way, the immune system may regulate the resources of phagocytes that play a role in inflammation and immune responses. Nitric oxide is secreted as free radicals in an immune response and is toxic to bacteria and intracellular parasites, including Leishmania and malaria; the mechanism for this includes DNA damage and degradation of iron sulfur centers into iron ions and iron-nitrosyl compounds.

In response, many bacterial pathogens have evolved mechanisms for nitric oxide resistance. Because nitric oxide might have proinflammatory actions in conditions like asthma, there has been increasing interest in the use of exhaled nitric oxide as a breath test in diseases with airway inflammation. Reduced levels of exhaled NO have been associated with exposure to air pollution in cyclists and smokers, but, in general, increased levels of exhaled NO are associated with exposure to air pollution.

Nitric oxide can contribute to reperfusion injury when an excessive amount produced during reperfusion (following a period of ischemia) reacts with superoxide to produce the damaging oxidant peroxynitrite. In contrast, inhaled nitric oxide has been shown to help survival and recovery from paraquat poisoning, which produces lung tissue-damaging superoxide and hinders NOS metabolism.

In plants, nitric oxide can be produced by any of four routes: (i) L-arginine-dependent nitric oxide synthase, (although the existence of animal NOS homologs in plants is debated), (ii) plasma membrane-bound nitrate reductase, (iii) mitochondrial electron transport chain, or (iv) non-enzymatic reactions. It is a signaling molecule, acts mainly against oxidative stress and also plays a role in plant pathogen interactions. Treating cut flowers and other plants with nitric oxide has been shown to lengthen the time before wilting.

Two important biological reaction mechanisms of nitric oxide are S-nitrosation of thiols, and nitrosylation of transition metal ions. S-nitrosation involves the (reversible) conversion of thiol groups, including cysteine residues in proteins, to form S-nitrosothiols (RSNOs). S-Nitrosation is a mechanism for dynamic, post-translational regulation of most or all major classes of protein. The second mechanism, nitrosylation, involves the binding of NO to a transition metal ion like iron or copper. In this function, NO is referred to as a nitrosyl ligand. Typical cases involve the nitrosylation of heme proteins like cytochromes, thereby disabling the normal enzymatic activity of the enzyme. Nitrosylated ferrous iron is particularly stable, as the binding of the nitrosyl ligand to ferrous iron (Fe(II)) is very strong. Hemoglobin is a prominent example of a heme protein that may be modified by NO by both pathways: NO may attach directly to the heme in the nitrosylation reaction, and independently form S-nitrosothiols by S-nitrosation of the thiol moieties.

There are several mechanisms by which NO has been demonstrated to affect the biology of living cells. These include oxidation of iron-containing proteins such as ribonucleotide reductase and aconitase, activation of the soluble guanylate cyclase, ADP ribosylation of proteins, protein sulfhydryl group nitrosylation, and iron regulatory factor activation. NO has been demonstrated to activate NF-κB in peripheral blood mononuclear cells, an important transcription factor in iNOS gene expression in response to inflammation.

It was found that NO acts through the stimulation of the soluble guanylate cyclase, which is a heterodimeric enzyme with subsequent formation of cyclic-GMP. Cyclic-GMP activates protein kinase G, which causes reuptake of Ca²⁺ and the opening of calcium-activated potassium channels. The fall in concentration of Ca²⁺ ensures that the myosin light-chain kinase (MLCK) can no longer phosphorylate the myosin molecule, thereby stopping the crossbridge cycle and leading to relaxation of the smooth muscle cell.

Nitrous oxide

Nitrous oxide in biological systems can be formed by an enzymatic or non-enzymatic reduction of nitric oxide. In vitro studies have shown that endogenous nitrous oxide can be formed by the reaction between nitric oxide and thiol. Some authors have shown that this process of NO reduction to N₂O takes place in hepatocytes, specifically in their cytoplasm and mitochondria, and suggested that the N₂O can possibly be produced in mammalian cells. It is well known that N₂O is produced by some bacteria during process called denitrification. 

Apart from its direct and indirect actions at opioid receptors, it was also shown that N₂O inhibits NMDA receptor-mediated activity and ionic currents and diminishes NMDA receptor-mediated excitotoxicity and neurodegeneration. Nitrous oxide also inhibits methionine synthase and slows the conversion of homocysteine to methionine, increases homocysteine concentration and decreases methionine concentration. This effect was shown in lymphocyte cell cultures and in human liver biopsy samples.

Nitrous oxide does not bind as a ligand to the heme and does not react with thiol-containing proteins. Nevertheless, studies have shown that nitrous oxide can reversibly and non-covalently "insert" itself into the inner structures of some heme-containing proteins such as hemoglobin, myoglobin, cytochrome oxidase and alter their structure and function. The ability of nitrous oxide to alter the structure and function of these proteins was demonstrated by shifts in infrared spectra of cysteine thiols of hemoglobin and by partial and reversible inhibition of cytochrome oxidase.

Endogenous nitrous oxide can possibly play a role in modulating endogenous opioid and NMDA systems.

Carbon monoxide

Carbon monoxide is produced naturally by the human body as a signaling molecule. Thus, carbon monoxide may have a physiological role in the body, such as a neurotransmitter or a blood vessel relaxant. Because of carbon monoxide's role in the body, abnormalities in its metabolism have been linked to a variety of diseases, including neurodegenerations, hypertension, heart failure, and inflammation.

Summary of function:

• CO functions as an endogenous signaling molecule.
• CO modulates functions of the cardiovascular system.
• CO inhibits blood platelet aggregation and adhesion.
• CO may play a role as potential therapeutic agent.

In mammals, carbon monoxide is naturally produced by the action of heme oxygenase 1 and 2 on the heme from hemoglobin breakdown. This process produces a certain amount of carboxyhemoglobin in normal persons, even if they do not breathe any carbon monoxide. 

Following the first report that carbon monoxide is a normal neurotransmitter in 1993, as well as one of three gases that naturally modulate inflammatory responses in the body (the other two being nitric oxide and hydrogen sulfide), carbon monoxide has received a great deal of clinical attention as a biological regulator. In many tissues, all three gases are known to act as anti-inflammatories, vasodilators, and encouragers of neovascular growth. However, the issues are complex, as neovascular growth is not always beneficial, since it plays a role in tumor growth, and also the damage from wet macular degeneration, a disease for which smoking (a major source of carbon monoxide in the blood, several times more than natural production) increases the risk from 4 to 6 times. 

There is a theory that, in some nerve cell synapses, when long-term memories are being laid down, the receiving cell makes carbon monoxide, which back-transmits to the transmitting cell, telling it to transmit more readily in future. Some such nerve cells have been shown to contain guanylate cyclase, an enzyme that is activated by carbon monoxide.

Studies involving carbon monoxide have been conducted in many laboratories throughout the world for its anti-inflammatory and cytoprotective properties. These properties have potential to be used to prevent the development of a series of pathological conditions including ischemia reperfusion injury, transplant rejection, atherosclerosis, severe sepsis, severe malaria, or autoimmunity. Clinical tests involving humans have been performed, however the results have not yet been released.

Carbon suboxide

Those are 6- or 8-ring macrocyclic polymers of carbon suboxide that were found in living organisms. They are acting as an endogenous digoxin-like Na+/K+-ATP-ase and Ca-dependent ATP-ase inhibitors, endogenous natriuretics, antioxidants and antihypertensives

 

Carbon suboxide, C₃O₂, can be produced in small amounts in any biochemical process that normally produces carbon monoxide, CO, for example, during heme oxidation by heme oxygenase-1. It can also be formed from malonic acid. It has been shown that carbon suboxide in an organism can quickly polymerize into macrocyclic polycarbon structures with the common formula (C₃O₂)_n (mostly (C₃O₂)₆ and (C₃O₂)₈), and that those macrocyclic compounds are potent inhibitors of Na⁺/K⁺-ATP-ase and Ca-dependent ATP-ase, and have digoxin-like physiological properties and natriuretic and antihypertensive actions. Those macrocyclic carbon suboxide polymer compounds are thought to be endogenous digoxin-like regulators of Na⁺/K⁺-ATP-ases and Ca-dependent ATP-ases, and endogenous natriuretics and antihypertensives. Other than that, some authors think also that those macrocyclic compounds of carbon suboxide can possibly diminish free radical formation and oxidative stress and play a role in endogenous anticancer protective mechanisms, for example in the retina.

Hydrogen sulfide

Hydrogen sulfide is produced in small amounts by some cells of the mammalian body and has a number of biological signaling functions. (Only two other such gases are currently known: nitric oxide (NO) and carbon monoxide (CO).) 

The gas is produced from cysteine by the enzymes cystathionine beta-synthase and cystathionine gamma-lyase. It acts as a relaxant of smooth muscle and as a vasodilator and is also active in the brain, where it increases the response of the NMDA receptor and facilitates long term potentiation, which is involved in the formation of memory.

Eventually the gas is converted to sulfite in the mitochondria by thiosulfate reductase, and the sulfite is further oxidized to thiosulfate and sulfate by sulfite oxidase. The sulfates are excreted in the urine.

Due to its effects similar to nitric oxide (without its potential to form peroxides by interacting with superoxide), hydrogen sulfide is now recognized as potentially protecting against cardiovascular disease. The cardioprotective role effect of garlic is caused by catabolism of the polysulfide group in allicin to H
₂S, a reaction that could depend on reduction mediated by glutathione.

Though both nitric oxide (NO) and hydrogen sulfide have been shown to relax blood vessels, their mechanisms of action are different: while NO activates the enzyme guanylyl cyclase, H
₂S activates ATP-sensitive potassium channels in smooth muscle cells. Researchers are not clear how the vessel-relaxing responsibilities are shared between nitric oxide and hydrogen sulfide. However, there exists some evidence to suggest that nitric oxide does most of the vessel-relaxing work in large vessels and hydrogen sulfide is responsible for similar action in smaller blood vessels.

Recent findings suggest strong cellular crosstalk of NO and H
₂S, demonstrating that the vasodilatatory effects of these two gases are mutually dependent. Additionally, H
₂S reacts with intracellular S-nitrosothiols to form the smallest S-nitrosothiol (HSNO), and a role of hydrogen sulfide in controlling the intracellular S-nitrosothiol pool has been suggested.

Like nitric oxide, hydrogen sulfide is involved in the relaxation of smooth muscle that causes erection of the penis, presenting possible new therapy opportunities for erectile dysfunction.

Hydrogen sulfide (H
₂S) deficiency can be detrimental to the vascular function after an acute myocardial infarction (AMI). AMIs can lead to cardiac dysfunction through two distinct changes; increased oxidative stress via free radical accumulation and decreased NO bioavailability. Free radical accumulation occurs due to increased electron transport uncoupling at the active site of endothelial nitric oxide synthase (eNOS), an enzyme involved in converting L-arginine to NO. During an AMI, oxidative degradation of tetrahydrobiopterin (BH4), a cofactor in NO production, limits BH4 availability and limits NO productionby eNOS. Instead, eNOS reacts with oxygen, another cosubstrates involved in NO production. The products of eNOS are reduced to superoxides, increasing free radical production and oxidative stress within the cells. A H
₂S deficiency impairs eNOS activity by limiting Akt activation and inhibiting Akt phosphorylation of the eNOSS1177 activation site. Instead, Akt activity is increased to phosphorylate the eNOST495 inhibition site, downregulating eNOS production of NO.

H
₂S therapy uses a H
₂S donor, such as diallyl trisulfide (DATS), to increase the supply of H
₂S to an AMI patient. H
₂S donors reduce myocardial injury and reperfusion complications. Increased H
₂S levels within the body will react with oxygen to produce sulfane sulfur, a storage intermediate for H
₂S. H
₂S pools in the body attracts oxygen to react with excess H
₂S and eNOS to increase NO production. With increased use of oxygen to produce more NO, less oxygen is available to react with eNOS to produce superoxides during an AMI, ultimately lowering the accumulation of reactive oxygen species (ROS). Furthermore, decreased accumulation of ROS lowers oxidative stress in vascular smooth muscle cells, decreasing oxidative degeneration of BH4. Increased BH4 cofactor contributes to increased production of NO within the body. Higher concentrations of H
₂S directly increase eNOS activity through Akt activation to increase phosphorylation of the eNOSS1177 activation site, and decrease phosphorylation of the eNOST495 inhibition site. This phosphorylation process upregulates eNOS activity, catalyzing more conversion of L-arginine to NO. Increased NO production enables soluble guanylyl cyclase (sGC) activity, leading to an increased conversion of guanosine triphosphate (GTP) to 3’,5’-cyclic guanosine monophosphate (cGMP). In H
₂S therapy immediately following an AMI, increased cGMP triggers an increase in protein kinase G (PKG) activity. PKG reduces intracellular Ca2+ in vascular smooth muscle to increase smooth muscle relaxation and promote blood flow. PKG also limits smooth muscle cell proliferation, reducing intima thickening following AMI injury, ultimately decreasing myocardial infarct size.

In Alzheimer's disease the brain's hydrogen sulfide concentration is severely decreased. In a certain rat model of Parkinson's disease, the brain's hydrogen sulfide concentration was found to be reduced, and administering hydrogen sulfide alleviated the condition. In trisomy 21 (Down syndrome) the body produces an excess of hydrogen sulfide. Hydrogen sulfide is also involved in the disease process of type 1 diabetes. The beta cells of the pancreas in type 1 diabetes produce an excess of the gas, leading to the death of these cells and to a reduced production of insulin by those that remain.

In 2005, it was shown that mice can be put into a state of suspended animation-like hypothermia by applying a low dosage of hydrogen sulfide (81 ppm H
₂S) in the air. The breathing rate of the animals sank from 120 to 10 breaths per minute and their temperature fell from 37 °C to just 2 °C above ambient temperature (in effect, they had become cold-blooded). The mice survived this procedure for 6 hours and afterwards showed no negative health consequences. In 2006 it was shown that the blood pressure of mice treated in this fashion with hydrogen sulfide did not significantly decrease.

A similar process known as hibernation occurs naturally in many mammals and also in toads, but not in mice. (Mice can fall into a state called clinical torpor when food shortage occurs). If the H
₂S-induced hibernation can be made to work in humans, it could be useful in the emergency management of severely injured patients, and in the conservation of donated organs. In 2008, hypothermia induced by hydrogen sulfide for 48 hours was shown to reduce the extent of brain damage caused by experimental stroke in rats.

As mentioned above, hydrogen sulfide binds to cytochrome oxidase and thereby prevents oxygen from binding, which leads to the dramatic slowdown of metabolism. Animals and humans naturally produce some hydrogen sulfide in their body; researchers have proposed that the gas is used to regulate metabolic activity and body temperature, which would explain the above findings.

Two recent studies cast doubt that the effect can be achieved in larger mammals. A 2008 study failed to reproduce the effect in pigs, concluding that the effects seen in mice were not present in larger mammals. Likewise a paper by Haouzi et al. noted that there is no induction of hypometabolism in sheep, either.

At the February 2010 TED conference, Mark Roth announced that hydrogen sulfide induced hypothermia in humans had completed Phase I clinical trials. The clinical trials commissioned by the company he helped found, Ikaria, were however withdrawn or terminated by August 2011.

Sulfur dioxide

The role of sulfur dioxide in mammalian biology is not yet well understood. Sulfur dioxide blocks nerve signals from the pulmonary stretch receptors and abolishes the Hering–Breuer inflation reflex.

It was shown that endogenous sulfur dioxide plays a role in diminishing an experimental lung damage caused by oleic acid. Endogenous sulfur dioxide lowered lipid peroxidation, free radical formation, oxidative stress and inflammation during an experimental lung damage. Conversely, a successful lung damage caused a significant lowering of endogenous sulfur dioxide production, and an increase in lipid peroxidation, free radical formation, oxidative stress and inflammation. Moreover, blockade of an enzyme that produces endogenous SO₂ significantly increased the amount of lung tissue damage in the experiment. Conversely, adding acetylcysteine or glutathione to the rat diet increased the amount of endogenous SO₂ produced and decreased the lung damage, the free radical formation, oxidative stress, inflammation and apoptosis.

It is considered that endogenous sulfur dioxide plays a significant physiological role in regulating cardiac and blood vessel function, and aberrant or deficient sulfur dioxide metabolism can contribute to several different cardiovascular diseases, such as arterial hypertension, atherosclerosis, pulmonary arterial hypertension, stenocardia.

It was shown that in children with pulmonary arterial hypertension due to congenital heart diseases the level of homocysteine is higher and the level of endogenous sulfur dioxide is lower than in normal control children. Moreover, these biochemical parameters strongly correlated to the severity of pulmonary arterial hypertension. Authors considered homocysteine to be one of useful biochemical markers of disease severity and sulfur dioxide metabolism to be one of potential therapeutic targets in those patients.

Endogenous sulfur dioxide also has been shown to lower the proliferation rate of endothelial smooth muscle cells in blood vessels, via lowering the MAPK activity and activating adenylyl cyclase and protein kinase A. Smooth muscle cell proliferation is one of important mechanisms of hypertensive remodeling of blood vessels and their stenosis, so it is an important pathogenetic mechanism in arterial hypertension and atherosclerosis. 

Endogenous sulfur dioxide in low concentrations causes endothelium-dependent vasodilation. In higher concentrations it causes endothelium-independent vasodilation and has a negative inotropic effect on cardiac output function, thus effectively lowering blood pressure and myocardial oxygen consumption. The vasodilating effects of sulfur dioxide are mediated via ATP-dependent calcium channels and L-type ("dihydropyridine") calcium channels. Endogenous sulfur dioxide is also a potent antiinflammatory, antioxidant and cytoprotective agent. It lowers blood pressure and slows hypertensive remodeling of blood vessels, especially thickening of their intima. It also regulates lipid metabolism.

Endogenous sulfur dioxide also diminishes myocardial damage, caused by isoproterenol adrenergic hyperstimulation, and strengthens the myocardial antioxidant defense reserve.

Sulfur dioxide expelled from the gastrointestinal tract (through the process of flatulence) is thought to be one of the main constituents to the unpleasant smell colloquially referred to as a "fart".

Hydrogen cyanide

Some authors have shown that neurons can produce hydrogen cyanide upon activation of their opioid receptors by endogenous or exogenous opioids. They have also shown that neuronal production of HCN activates NMDA receptors and plays a role in signal transduction between neuronal cells (neurotransmission). Moreover, increased endogenous neuronal HCN production under opioids was seemingly needed for adequate opioid analgesia, as analgesic action of opioids was attenuated by HCN scavengers. They considered endogenous HCN to be a neuromodulator.

It was also shown that, while stimulating muscarinic cholinergic receptors in cultured pheochromocytoma cells increases HCN production, in a living organism (in vivo) muscarinic cholinergic stimulation actually decreases HCN production.

Leukocytes generate HCN during phagocytosis.

The vasodilatation, caused by sodium nitroprusside, has been shown to be mediated not only by NO generation, but also by endogenous cyanide generation, which adds not only toxicity, but also some additional antihypertensive efficacy compared to nitroglycerine and other non-cyanogenic nitrates which do not cause blood cyanide levels to rise.

Ammonia

Ammonia also plays a role in both normal and abnormal animal physiology. It is biosynthesised through normal amino acid metabolism and is toxic in high concentrations. The liver converts ammonia to urea through a series of reactions known as the urea cycle. Liver dysfunction, such as that seen in cirrhosis, may lead to elevated amounts of ammonia in the blood (hyperammonemia). Likewise, defects in the enzymes responsible for the urea cycle, such as ornithine transcarbamylase, lead to hyperammonemia. Hyperammonemia contributes to the confusion and coma of hepatic encephalopathy, as well as the neurologic disease common in people with urea cycle defects and organic acidurias.

Ammonia is important for normal animal acid/base balance. After formation of ammonium from glutamine, α-ketoglutarate may be degraded to produce two molecules of bicarbonate, which are then available as buffers for dietary acids. Ammonium is excreted in the urine, resulting in net acid loss. Ammonia may itself diffuse across the renal tubules, combine with a hydrogen ion, and thus allow for further acid excretion.

Methane

Some authors have shown that endogenous methane is produced not only by the intestinal flora and then absorbed into the blood, but also is produced - in small amounts - by eukaryotic cells (during process of lipid peroxidation). And they have also shown that the endogenous methane production rises during an experimental mitochondrial hypoxia, for example, sodium azide intoxication. They thought that methane could be one of intercellular signals of hypoxia and stress.

Other authors have shown that cellular methane production also rises during sepsis or bacterial endotoxemia, including an experimental imitation of endotoxemia by lipopolysaccharide (LPS) administration.

Some other researchers have shown that methane, produced by the intestinal flora, is not fully "biologically neutral" to the intestine, and it participates in the normal physiologic regulation of peristalsis. And its excess causes not only belching, flatulence and belly pain, but also functional constipation.

Ethylene

An ethylene signal transduction pathway. Ethylene permeates the membrane and binds to a receptor on the endoplasmic reticulum. The receptor releases the repressed EIN2. This then activates a signal transduction pathway which activates a regulatory genes that eventually trigger an Ethylene response. The activated DNA is transcribed into mRNA which is then translated into a functional enzyme that is used for ethylene biosynthesis.

 

Ethylene serves as a hormone in plants. It acts at trace levels throughout the life of the plant by stimulating or regulating the ripening of fruit, the opening of flowers, and the abscission (or shedding) of leaves. Commercial ripening rooms use "catalytic generators" to make ethylene gas from a liquid supply of ethanol. Typically, a gassing level of 500 to 2,000 ppm is used, for 24 to 48 hours. Care must be taken to control carbon dioxide levels in ripening rooms when gassing, as high temperature ripening (20 °C;68 °F) has been seen to produce CO₂ levels of 10% in 24 hours.

Ethylene has been used since the ancient Egyptians, who would gash figs in order to stimulate ripening (wounding stimulates ethylene production by plant tissues). The ancient Chinese would burn incense in closed rooms to enhance the ripening of pears. In 1864, it was discovered that gas leaks from street lights led to stunting of growth, twisting of plants, and abnormal thickening of stems. In 1901, a Russian scientist named Dimitry Neljubow showed that the active component was ethylene. Sarah Doubt discovered that ethylene stimulated abscission in 1917. It wasn't until 1934 that Gane reported that plants synthesize ethylene. In 1935, Crocker proposed that ethylene was the plant hormone responsible for fruit ripening as well as senescence of vegetative tissues.

The Yang cycle

 

Ethylene is produced from essentially all parts of higher plants, including leaves, stems, roots, flowers, fruits, tubers, and seeds. Ethylene production is regulated by a variety of developmental and environmental factors. During the life of the plant, ethylene production is induced during certain stages of growth such as germination, ripening of fruits, abscission of leaves, and senescence of flowers. Ethylene production can also be induced by a variety of external aspects such as mechanical wounding, environmental stresses, and certain chemicals including auxin and other regulators.

Ethylene is biosynthesized from the amino acid methionine to S-adenosyl-L-methionine (SAM, also called Adomet) by the enzyme Met Adenosyltransferase. SAM is then converted to 1-aminocyclopropane-1-carboxylic acid (ACC) by the enzyme ACC synthase (ACS). The activity of ACS determines the rate of ethylene production, therefore regulation of this enzyme is key for the ethylene biosynthesis. The final step requires oxygen and involves the action of the enzyme ACC-oxidase (ACO), formerly known as the ethylene forming enzyme (EFE). Ethylene biosynthesis can be induced by endogenous or exogenous ethylene. ACC synthesis increases with high levels of auxins, especially indole acetic acid (IAA) and cytokinins.

Ethylene is perceived by a family of five transmembrane protein dimers such as the ETR₁ protein in Arabidopsis. The gene encoding an ethylene receptor has been cloned in Arabidopsis thaliana and then in tomato. Ethylene receptors are encoded by multiple genes in the Arabidopsis and tomato genomes. Mutations in any of the gene family, which comprises five receptors in Arabidopsis and at least six in tomato, can lead to insensitivity to ethylene. DNA sequences for ethylene receptors have also been identified in many other plant species and an ethylene binding protein has even been identified in Cyanobacteria.

Environmental cues such as flooding, drought, chilling, wounding, and pathogen attack can induce ethylene formation in plants. In flooding, roots suffer from lack of oxygen, or anoxia, which leads to the synthesis of 1-aminocyclopropane-1-carboxylic acid (ACC). ACC is transported upwards in the plant and then oxidized in leaves. The ethylene produced causes nastic movements (epinasty) of the leaves, perhaps helping the plant to lose water.

 

Ethylene in plant induces such responses:

• Seedling triple response, thickening and shortening of hypocotyl with pronounced apical hook.
• In pollination, when the pollen reaches the stigma, the precursor of the ethene, ACC, is secreted to the petal, the ACC releases ethylene with ACC oxidase.
• Stimulates leaf and flower senescence
• Stimulates senescence of mature xylem cells in preparation for plant use
• Induces leaf abscission
• Induces seed germination
• Induces root hair growth — increasing the efficiency of water and mineral absorption
• Induces the growth of adventitious roots during flooding
• Stimulates epinasty — leaf petiole grows out, leaf hangs down and curls into itself
• Stimulates fruit ripening
• Induces a climacteric rise in respiration in some fruit which causes a release of additional ethylene.
• Affects gravitropism
• Stimulates nutational bending
• Inhibits stem growth and stimulates stem and cell broadening and lateral branch growth outside of seedling stage (see Hyponastic response)
• Interference with auxin transport (with high auxin concentrations)
• Inhibits shoot growth and stomatal closing except in some water plants or habitually flooded ones such as some rice varieties, where the opposite occurs (conserving CO
  ₂ and O
  ₂)
• Induces flowering in pineapples
• Inhibits short day induced flower initiation in Pharbitus nil and Chrysanthemum morifolium

Small amounts of endogenous ethylene are also produced in mammals, including humans, due to lipid peroxidation. Some of endogenous ethylene is then oxidized to ethylene oxide, which is able to alkylate DNA and proteins, including hemoglobin (forming a specific adduct with its N-terminal valine, N-hydroxyethyl-valine). Endogenous ethylene oxide, just as like environmental (exogenous) one, can alkylate guanine in DNA, forming an adduct 7-(2-hydroxyethyl)-guanine, and this poses an intrinsic carcinogenic risk. It is also mutagenic.

Sulfur cycle

From Wikipedia, the free encyclopedia

The sulfur cycle is the collection of processes by which sulfur moves between rocks, waterways and living systems. Such biogeochemical cycles are important in geology because they affect many minerals. Biochemical cycles are also important for life because sulfur is an essential element, being a constituent of many proteins and cofactors, and sulfur compounds can be used as oxidants or reductants in microbial respiration. The global sulfur cycle involves the transformations of sulfur species through different oxidation states, which play an important role in both geological and biological processes. 

 

The Sulfur cycle (in general)

 

Sulfur cycle

Steps of the sulfur cycle are:

• Mineralization of organic sulfur into inorganic forms, such as hydrogen sulfide (H₂S), elemental sulfur, as well as sulfide minerals.
• Oxidation of hydrogen sulfide, sulfide, and elemental sulfur (S) to sulfate (SO₄²⁻).
• Reduction of sulfate to sulfide.
• Incorporation of sulfide into organic compounds (including metal-containing derivatives).

Structure of 3'-phosphoadenosine-5'-phosphosulfate, a key intermediate in the sulfur cycle.

 

These are often termed as follows:

Assimilative sulfate reduction in which sulfate (SO₄²⁻) is reduced by plants, fungi and various prokaryotes. The oxidation states of sulfur are +6 in sulfate and –2 in R–SH.

Desulfurization in which organic molecules containing sulfur can be desulfurized, producing hydrogen sulfide gas (H₂S, oxidation state = –2). An analogous process for organic nitrogen compounds is deamination.

Oxidation of hydrogen sulfide produces elemental sulfur (S₈), oxidation state = 0. This reaction occurs in the photosynthetic green and purple sulfur bacteria and some chemolithotrophs. Often the elemental sulfur is stored as polysulfides.

Oxidation in elemental sulfur by sulfur oxidizers produces sulfate.

Dissimilative sulfur reduction in which elemental sulfur can be reduced to hydrogen sulfide.

Dissimilative sulfate reduction in which sulfate reducers generate hydrogen sulfide from sulfate.

Sulfur oxidation state

Sulfur has four main oxidation states in nature, which are -2, +2, +4, and +6. The common sulfur species of each oxidation state are listed as follows: 

• S^2-: H₂S, FeS, FeS₂, CuS
• S₀: native, or elemental, sulfur
• S²⁺: SO
• S⁴⁺: SO₂, sulfite (SO₃^2-)
• S⁶⁺: SO₄^2- (H₂SO₄, CaSO₄), SF₆

Sulfur sources and sinks

Sulfur is found in oxidation states ranging from +6 in SO₄²⁻ to -2 in sulfides. Thus, elemental sulfur can either give or receive electrons depending on its environment. On the anoxic early Earth, most sulfur was present in minerals such as pyrite (FeS₂). Over Earth history, the amount of mobile sulfur increased through volcanic activity as well as weathering of the crust in an oxygenated atmosphere. Earth's main sulfur sink is the oceans SO₄²⁻, where it is the major oxidizing agent.

When SO₄²⁻ is assimilated by organisms, it is reduced and converted to organic sulfur, which is an essential component of proteins. However, the biosphere does not act as a major sink for sulfur, instead the majority of sulfur is found in seawater or sedimentary rocks including: pyrite rich shales, evaporite rocks (anhydrite and baryte), and calcium and magnesium carbonates (i.e. carbonate-associated sulfate). The amount of sulfate in the oceans is controlled by three major processes:

1. input from rivers

2. sulfate reduction and sulfide re-oxidation on continental shelves and slopes

3. burial of anhydrite and pyrite in the oceanic crust.

The primary natural source of sulfur to the atmosphere is sea spray or windblown sulfur rich dust, neither of which is long lived in the atmosphere. In recent times, the large annual input of sulfur from the burning of coal and other fossil fuels has added a substantial amount SO₂ which acts as an air pollutant. In the geologic past, igneous intrusions into coal measures have caused large scale burning of these measures, and consequential release of sulfur to the atmosphere. This has led to substantial disruption to the climate system, and is one of the proposed causes of the Permian–Triassic extinction event.

Dimethylsulfide [(CH₃)₂S or DMS] is produced by the decomposition of dimethylsulfoniopropionate (DMSP) from dying phytoplankton cells in the ocean's photic zone, and is the major biogenic gas emitted from the sea, where it is responsible for the distinctive “smell of the sea” along coastlines. DMS is the largest natural source of sulfur gas, but still only has a residence time of about one day in the atmosphere and a majority of it is redeposited in the oceans rather than making it to land. However, it is a significant factor in the climate system, as it is involved in the formation of clouds.

Biologically and thermochemically driven sulfate reduction

Sulfur can be reduced both biologically and thermochemically. Dissimilatory sulfate reduction has two different definitions:

1. the microbial process that converts sulfate to sulfide for energy gain, and

2. a set of forward and reverse pathways that progress from the uptake and release of sulfate by the cell to its conversion to various sulfur intermediates, and ultimately to sulfide which is released from the cell.

Sulfide and thiosulfate are the most abundant reduced inorganic sulfur species in the environments and are converted to sulfate, primarily by bacterial action, in the oxidative half of the sulfur cycle. Bacterial sulfate reduction (BSR) can only occur at temperature from 0 up to 60–80 °C because above that temperature almost all sulfate-reducing microbes can no longer metabolize. Few microbes can form H₂S at higher temperatures but appear to be very rare and do not metabolize in settings where normal bacterial sulfate reduction is occurring. Bacterial sulfate reduction is geologically instantaneous happening on the order of hundreds to thousands of years. Thermochemical sulfate reduction (TSR) occurs at much higher temperatures (160–180 °C) and over longer time intervals, several tens of thousands to a few million years.

The main difference between these two reactions is obvious, one is organically driven and the other is chemically driven. Therefore, the temperature for thermochemical sulfate reduction is much higher due to the activation energy required to reduce sulfate. Bacterial sulfate reductions requires lower temperatures because the sulfur reducing bacteria can only live at relatively low temperature (below 60 °C). Bacterial sulfate reduction also requires a relatively open system; otherwise the bacteria will poison themselves when the sulfate levels rise above 5–10%.

The organic reactants involved in bacterial sulfate reduction are organic acids which are distinctive from the organic reactants needed for thermochemical sulfate reduction. In both cases sulfate is usually derived from the dissolution of gypsum or taken directly out of the seawater. The factors that control whether bacterial sulfate reduction or thermochemical sulfate reduction will occur are temperature, which is generally a product of depth, with bacterial sulfate reduction occurring in shallower levels than thermochemical sulfate reduction. Their solid products are similar but can be distinguished from one another petrographically, due to their differing crystal sizes, shapes and reflectivity.

Sulfur-oxidizing bacteria in hydrothermal vents

Hydrothermal vents emit hydrogen sulfide that support the carbon fixation of chemolithotrophic bacteria that oxidize hydrogen sulfide with oxygen to produce elemental sulfur or sulfate. The chemical reactions are as follows: 

CO₂ + 4H₂S + O₂ -> CH₂O + 4S⁰ + 3H₂O

CO₂ + H₂S + O₂ + H₂O -> CH₂O + SO₄^2- + 2H⁺

In modern oceans, Thiomicrospira, Halothiobacillus, and Beggiatoa are primary sulfur oxidizing bacteria, and form chemosynthetic symbioses with animal hosts. The host provides metabolic substrates (e.g., CO₂, O₂, H₂O) to the symbiont while the symbiont generates organic carbon for sustaining the metabolic activities of the host. The produced sulfate usually combines with the leached calcium ions to form gypsum, which can form widespread deposits on near mid-ocean spreading centers.

δ³⁴S

Although 25 isotopes are known for sulfur, only four are stable and of geochemical importance. Of those four, two (³²S, light and ³⁴S, heavy) comprise (99.22%) of S on Earth. The vast majority (95.02%) of S occurs as ³²S with only 4.21% in ³⁴S. The ratio of these two isotopes is fixed in our solar system and has been since its formation. The bulk Earth sulfur isotopic ratio is thought to be the same as the ratio of 22.22 measured from the Canyon Diablo troilite (CDT), a meteorite. That ratio is accepted as the international standard and is therefore set at δ0.00. Deviation from 0.00 is expressed as the δ³⁴S which is a ratio in per mill (‰). Positive values correlate to increased levels of ³⁴S, whereas negative values correlate with greater ³²S in a sample. 

Formation of sulfur minerals through non-biogenic processes does not substantially differentiate between the light and heavy isotopes, therefore sulfur isotope ratios in gypsum or barite should be the same as the overall isotope ratio in the water column at their time of precipitation. Sulfate reduction through biologic activity strongly differentiates between the two isotopes because of the more rapid enzymic reaction with ³²S. Sulfate metabolism results in an isotopic depletion of -18‰, and repeated cycles of oxidation and reduction can result in values up to -50 ‰. Average present day seawater values of δ³⁴S are on the order of +21‰. 

Throughout geologic history the sulfur cycle and the isotopic ratios have coevolved with the biosphere becoming overall more negative with the increases in biologically driven sulfate reduction, but also show substantial positive excursion. In general positive excursions in the sulfur isotopes mean that there is an excess of pyrite deposition rather than oxidation of sulfide minerals exposed on land.

Marine sulfur cycle

The sulfur cycle in marine environments has been well-studied via the tool of sulfur isotope systematics expressed as δ³⁴S. The modern global oceans have sulfur storage of 1.3 × 10²¹ g, mainly occurring as sulfate with the δ³⁴S value of +21‰. The overall input flux is 1.0 × 10¹⁴ g/year with the sulfur isotope composition of ~3‰. Riverine sulfate derived from the terrestrial weathering of sulfide minerals (δ³⁴S = +6‰) is the primary input of sulfur to the oceans. Other sources are metamorphic and volcanic degassing and hydrothermal activity (δ³⁴S = 0‰), which release reduced sulfur species (e.g., H₂S and S⁰). There are two major outputs of sulfur from the oceans. The first sink is the burial of sulfate either as marine evaporites (e.g., gypsum) or carbonate-associated sulfate (CAS), which accounts for 6 × 10¹³ g/year (δ³⁴S = +21‰). The second sulfur sink is pyrite burial in shelf sediments or deep seafloor sediments (4 × 10¹³ g/year; δ³⁴S = -20‰). The total marine sulfur output flux is 1.0 × 10¹⁴ g/year which matches the input fluxes, implying the modern marine sulfur budget is at steady state. The residence time of sulfur in modern global oceans is 13,000,000 year.

Evolution of the sulfur cycle

The isotopic composition of sedimentary sulfides provides primary information on the evolution of the sulfur cycle. 

The total inventory of sulfur compounds on the surface of the Earth (nearly 10²² g S) represents the total outgassing of sulfur through geologic time. Rocks analyzed for sulfur content are generally organic-rich shales meaning they are likely controlled by biogenic sulfur reduction. Average seawater curves are generated from evaporites deposited throughout geologic time because again, since they do not discriminate between the heavy and light sulfur isotopes, they should mimic the ocean composition at the time of deposition. 

4.6 billion years ago (Ga) the Earth formed and had a theoretical δ³⁴S value of 0. Since there was no biologic activity on early Earth there would be no isotopic fractionation. All sulfur in the atmosphere would be released during volcanic eruptions. When the oceans condensed on Earth, the atmosphere was essentially swept clean of sulfur gases, owing to their high solubility in water. Throughout the majority of the Archean (4.6–2.5 Ga) most systems appeared to be sulfate-limited. Some small Archean evaporite deposits require that at least locally elevated concentrations (possibly due to local volcanic activity) of sulfate existed in order for them to be supersaturated and precipitate out of solution.

3.8–3.6 Ga marks the beginning of the exposed geologic record because this is the age of the oldest rocks on Earth. Metasedimentary rocks from this time still have an isotopic value of 0 because the biosphere was not developed enough (possibly at all) to fractionate sulfur.

3.5 Ga anoxyogenic photosynthesis is established and provides a weak source of sulfate to the global ocean with sulfate concentrations incredibly low the δ³⁴S is still basically 0. Shortly after, at 3.4 Ga the first evidence for minimal fractionation in evaporitic sulfate in association with magmatically derived sulfides can be seen in the rock record. This fractionation shows possible evidence for anoxygenic phototrophic bacteria.

2.8 Ga marks the first evidence for oxygen production through photosynthesis. This is important because there cannot be sulfur oxidation without oxygen in the atmosphere. This exemplifies the coevolution of the oxygen and sulfur cycles as well as the biosphere. 

2.7–2.5 Ga is the age of the oldest sedimentary rocks to have a depleted δ ³⁴S which provide the first compelling evidence for sulfate reduction.

2.3 Ga sulfate increases to more than 1 mM; this increase in sulfate is coincident with the "Great Oxygenation Event", when redox conditions on Earth's surface are thought by most workers to have shifted fundamentally from reducing to oxidizing. This shift would have led to an incredible increase in sulfate weathering which would have led to an increase in sulfate in the oceans. The large isotopic fractionations that would likely be associated with bacteria reduction are produced for the first time. Although there was a distinct rise in seawater sulfate at this time it was likely still only less than 5–15% of present-day levels.

At 1.8 Ga, Banded iron formations (BIF) are common sedimentary rocks throughout the Archean and Paleoproterozoic; their disappearance marks a distinct shift in the chemistry of ocean water. BIFs have alternating layers of iron oxides and chert. BIFs only form if the water is allowed to supersaturate in dissolved iron (Fe²⁺) meaning there cannot be free oxygen or sulfur in the water column because it would form Fe³⁺ (rust) or pyrite and precipitate out of solution. Following this supersaturation, the water must become oxygenated in order for the ferric rich bands to precipitate it must still be sulfur poor otherwise pyrite would form instead of Fe³⁺. It has been hypothesized that BIFs formed during the initial evolution of photosynthetic organisms that had phases of population growth, causing over production of oxygen. Due to this over production they would poison themselves causing a mass die off, which would cut off the source of oxygen and produce a large amount of CO₂ through the decomposition of their bodies, allowing for another bacterial bloom. After 1.8 Ga sulfate concentrations were sufficient to increase rates of sulfate reduction to greater than the delivery flux of iron to the oceans.

Along with the disappearance of BIF, the end of the Paleoproterozoic also marks the first large scale sedimentary exhalative deposits showing a link between mineralization and a likely increase in the amount of sulfate in sea water. In the Paleoproterozoic the sulfate in seawater had increased to an amount greater than in the Archean, but was still lower than present day values. The sulfate levels in the Proterozoic also act as proxies for atmospheric oxygen because sulfate is produced mostly through weathering of the continents in the presence of oxygen. The low levels in the Proterozoic simply imply that levels of atmospheric oxygen fell between the abundances of the Phanerozoic and the deficiencies of the Archean.

750 million years ago (Ma) there is a renewed deposition of BIF which marks a significant change in ocean chemistry. This was likely due to snowball earth episodes where the entire globe including the oceans was covered in a layer of ice cutting off oxygenation. In the late Neoproterozoic high carbon burial rates increased the atmospheric oxygen level to more than 10% of its present-day value. In the Latest Neoproterozoic another major oxidizing event occurred on Earth's surface that resulted in an oxic deep ocean and possibly allowed for the appearance of multicellular life.

During the last 600 million years, seawater SO₄ has varied between +10 and +30‰ in δ³⁴S, with an average value close to that of today. This coincides with atmospheric O2 levels reaching something close to modern values around the Precambrian–Cambrian boundary. 

Over a shorter time scale (ten million years) changes in the sulfur cycle are easier to observe and can be even better constrained with oxygen isotopes. Oxygen is continually incorporated into the sulfur cycle through sulfate oxidation and then released when that sulfate is reduced once again. Since different sulfate sources within the ocean have distinct oxygen isotopic values it may be possible to use oxygen to trace the sulfur cycle. Biological sulfate reduction preferentially selects lighter oxygen isotopes for the same reason that lighter sulfur isotopes are preferred. By studying oxygen isotopes in ocean sediments over the last 10 million years  were able to better constrain the sulfur concentrations in sea water through that same time. They found that the sea level changes due to Pliocene and Pleistocene glacial cycles changed the area of continental shelves which then disrupted the sulfur processing, lowering the concentration of sulfate in the sea water. This was a drastic change as compared to preglacial times before 2 million years ago.

The Great Oxidation Event and sulfur isotope mass-independent fractionation

The Great Oxygenation Event (GOE) is characterized by the disappearance of sulfur isotope mass-independent fractionation (MIF) in the sedimentary records at around 2.45 billion years ago (Ga). The MIF of sulfur isotope (Δ³³S) is defined by the deviation of measured δ³³S value from the δ³³S value inferred from the measured δ³⁴S value according to the mass dependent fractionation law. The Great Oxidation Event represented a massive transition of global sulfur cycles. Before the Great Oxidation Event, the sulfur cycle was heavily influenced by the ultraviolet (UV) radiation and the associated photochemical reactions, which induced the sulfur isotope mass-independent fractionation (Δ³³S ≠ 0). The preservation of sulfur isotope mass-independent fractionation signals requires the atmospheric O₂ lower than 10⁻⁵ of present atmospheric level (PAL). The disappearance of sulfur isotope mass-independent fractionation at ~2.45 Ga indicates that atmospheric pO₂ exceeded 10⁻⁵ present atmospheric level after the Great Oxygenation Event. Oxygen played an essential role in the global sulfur cycles after the Great Oxygenation Event, such as oxidative weathering of sulfides. The burial of pyrite in sediments in turn contributes to the accumulation of free O₂ in Earth's surface environment.

Economic importance

Sulfur is intimately involved in production of fossil fuels and a majority of metal deposits because of its ability to act as an oxidizing or reducing agent. The vast majority of the major mineral deposits on Earth contain a substantial amount of sulfur including, but not limited to: sedimentary exhalative deposits (SEDEX), Carbonate-hosted lead-zinc ore deposits (Mississippi Valley-Type MVT) and porphyry copper deposits. Iron sulfides, galena and sphalerite will form as by-products of hydrogen sulfide generation, as long as the respective transition or base metals are present or transported to a sulfate reduction site. If the system runs out of reactive hydrocarbons economically viable elemental sulfur deposits may form. Sulfur also acts as a reducing agent in many natural gas reservoirs and generally ore forming fluids have a close relationship with ancient hydrocarbon seeps or vents.

Important sources of sulfur in ore deposits are generally deep-seated, but they can also come from local country rocks, sea water, or marine evaporites. The presence or absence of sulfur is one of the limiting factors on both the concentration of precious metals and its precipitation from solution. pH, temperature and especially redox states determine whether sulfides will precipitate. Most sulfide brines will remain in concentration until they reach reducing conditions, a higher pH or lower temperatures. 

Ore fluids are generally linked to metal rich waters that have been heated within a sedimentary basin under the elevated thermal conditions typically in extensional tectonic settings. The redox conditions of the basin lithologies exert an important control on the redox state of the metal-transporting fluids and deposits can form from both oxidizing and reducing fluids. Metal-rich ore fluids tend to be by necessity comparatively sulfide deficient, so a substantial portion of the sulfide must be supplied from another source at the site of mineralization. Bacterial reduction of seawater sulfate or a euxinic (anoxic and H₂S-containing) water column is a necessary source of that sulfide. When present, the δ³⁴S values of barite are generally consistent with a seawater sulfate source, suggesting baryte formation by reaction between hydrothermal barium and sulfate in ambient seawater.

Once fossil fuels or precious metals are discovered and either burned or milled, the sulfur become a waste product which must be dealt with properly or it can become a pollutant. There has been a great increase in the amount of sulfur in our present day atmosphere because of the burning of fossil fuels. Sulfur acts as a pollutant and an economic resource at the same time.

Human impact

Human activities have a major effect on the global sulfur cycle. The burning of coal, natural gas, and other fossil fuels has greatly increased the amount of S in the atmosphere and ocean and depleted the sedimentary rock sink. Without human impact sulfur would stay tied up in rocks for millions of years until it was uplifted through tectonic events and then released through erosion and weathering processes. Instead it is being drilled, pumped and burned at a steadily increasing rate. Over the most polluted areas there has been a 30-fold increase in sulfate deposition.

Although the sulfur curve shows shifts between net sulfur oxidation and net sulfur reduction in the geologic past, the magnitude of the current human impact is probably unprecedented in the geologic record. Human activities greatly increase the flux of sulfur to the atmosphere, some of which is transported globally. Humans are mining coal and extracting petroleum from the Earth's crust at a rate that mobilizes 150 x 10¹² gS/yr, which is more than double the rate of 100 years ago. The result of human impact on these processes is to increase the pool of oxidized sulfur (SO₄) in the global cycle, at the expense of the storage of reduced sulfur in the Earth's crust. Therefore, human activities do not cause a major change in the global pools of S, but they do produce massive changes in the annual flux of S through the atmosphere.

When SO₂ is emitted as an air pollutant, it forms sulfuric acid through reactions with water in the atmosphere. Once the acid is completely dissociated in water the pH can drop to 4.3 or lower causing damage to both man-made and natural systems. According to the EPA, acid rain is a broad term referring to a mixture of wet and dry deposition (deposited material) from the atmosphere containing higher than normal amounts of nitric and sulfuric acids. Distilled water (water without any dissolved constituents), which contains no carbon dioxide, has a neutral pH of 7. Rain naturally has a slightly acidic pH of 5.6, because carbon dioxide and water in the air react together to form carbonic acid, a very weak acid. Around Washington, D.C., however, the average rain pH is between 4.2 and 4.4. Since pH is on a log scale dropping by 1 (the difference between normal rain water and acid rain) has a dramatic effect on the strength of the acid. In the United States, roughly 2/3 of all SO₂ and 1/4 of all NO₃ come from electric power generation that relies on burning fossil fuels, like coal.