Gaseous signaling molecules are
gas
Gas is one of the four fundamental states of matter (the others being solid, liquid, and plasma).
A pure gas may be made up of individual atoms (e.g. a noble gas like neon), elemental molecules made from one type of atom (e.g. oxygen), or ...
eous
molecule
A molecule is a group of two or more atoms held together by attractive forces known as chemical bonds; depending on context, the term may or may not include ions which satisfy this criterion. In quantum physics, organic chemistry, and bioche ...
s that are either
synthesized internally (
endogenously) in the
organism
In biology, an organism () is any living system that functions as an individual entity. All organisms are composed of cells (cell theory). Organisms are classified by taxonomy into groups such as multicellular animals, plants, and ...
,
tissue or
cell
Cell most often refers to:
* Cell (biology), the functional basic unit of life
Cell may also refer to:
Locations
* Monastic cell, a small room, hut, or cave in which a religious recluse lives, alternatively the small precursor of a monastery ...
or are received by the organism, tissue or cell from outside (say, from the atmosphere or
hydrosphere
The hydrosphere () is the combined mass of water found on, under, and above the surface of a planet, minor planet, or natural satellite. Although Earth's hydrosphere has been around for about 4 billion years, it continues to change in shape. This ...
, as in the case of
oxygen
Oxygen is the chemical element with the symbol O and atomic number 8. It is a member of the chalcogen group in the periodic table, a highly reactive nonmetal, and an oxidizing agent that readily forms oxides with most elements as ...
) 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
Oxygen is the chemical element with the symbol O and atomic number 8. It is a member of the chalcogen group in the periodic table, a highly reactive nonmetal, and an oxidizing agent that readily forms oxides with most elements as ...
,
carbon dioxide
Carbon dioxide ( chemical formula ) is a chemical compound made up of molecules that each have one carbon atom covalently double bonded to two oxygen atoms. It is found in the gas state at room temperature. In the air, carbon dioxide is trans ...
,
sulfur dioxide,
nitrous oxide
Nitrous oxide (dinitrogen oxide or dinitrogen monoxide), commonly known as laughing gas, nitrous, or nos, is a chemical compound, an oxide of nitrogen with the formula . At room temperature, it is a colourless non-flammable gas, and has ...
,
hydrogen cyanide,
ammonia
Ammonia is an inorganic compound of nitrogen and hydrogen with the formula . A stable binary hydride, and the simplest pnictogen hydride, ammonia is a colourless gas with a distinct pungent smell. Biologically, it is a common nitrogenous wa ...
,
methane
Methane ( , ) is a chemical compound with the chemical formula (one carbon atom bonded to four hydrogen atoms). It is a group-14 hydride, the simplest alkane, and the main constituent of natural gas. The relative abundance of methane on Ea ...
,
hydrogen
Hydrogen is the chemical element with the symbol H and atomic number 1. Hydrogen is the lightest element. At standard conditions hydrogen is a gas of diatomic molecules having the formula . It is colorless, odorless, tasteless, non-toxic ...
,
ethylene, etc.
Select gaseous signaling molecules behave as neurotransmitters and are called
gasotransmitters. These include
nitric oxide,
carbon monoxide
Carbon monoxide (chemical formula CO) is a colorless, poisonous, odorless, tasteless, flammable gas that is slightly less dense than air. Carbon monoxide consists of one carbon atom and one oxygen atom connected by a triple bond. It is the simple ...
, and
hydrogen sulfide.
Historically, the study of gases and physiological effects was categorized under
factitious airs
Factitious airs was a term used for synthetic gases which emerged around 1670 when Robert Boyle coined the term upon isolating what is now understood to be hydrogen. ''Factitious'' means "artificial, not natural", so the term means "man-made gases ...
.
The biological roles of each of the gaseous signaling molecules are outlined below.
Gasotransmitters
Gasotransmitter
Gasotransmitters is a class of neurotransmitters. The molecules are distinguished from other bioactive endogenous gaseous signaling molecules based on a need to meet distinct characterization criteria. Currently, only nitric oxide, carbon monoxide ...
s are a class of
neurotransmitters. Only three gases are accepted to be classified as gasotransmitters including
nitric oxide,
carbon monoxide
Carbon monoxide (chemical formula CO) is a colorless, poisonous, odorless, tasteless, flammable gas that is slightly less dense than air. Carbon monoxide consists of one carbon atom and one oxygen atom connected by a triple bond. It is the simple ...
, and
hydrogen sulfide.
Gaseous Signaling Molecules
Oxygen
Carbon dioxide
Carbon dioxide, CO
2, is one of the mediators of local
autoregulation
Autoregulation is a process within many biological systems, resulting from an internal adaptive mechanism that works to adjust (or mitigate) that system's response to stimuli. While most systems of the body show some degree of autoregulation, it ...
of blood supply. If its levels are high, the
capillaries
A capillary is a small blood vessel from 5 to 10 micrometres (μm) in diameter. Capillaries are composed of only the tunica intima, consisting of a thin wall of simple squamous endothelial cells. They are the smallest blood vessels in the body: ...
expand to allow a greater blood flow to that tissue.
Bicarbonate
In inorganic chemistry, bicarbonate (IUPAC-recommended nomenclature: hydrogencarbonate) is an intermediate form in the deprotonation of carbonic acid. It is a polyatomic anion with the chemical formula .
Bicarbonate serves a crucial biochem ...
, HCO
3−, ions are crucial for regulating blood pH. A person's breathing rate influences the level of CO
2 in their blood. Breathing that is too slow or shallow causes
respiratory acidosis
Respiratory acidosis is a state in which decreased ventilation (hypoventilation) increases the concentration of carbon dioxide in the blood and decreases the blood's pH (a condition generally called acidosis).
Carbon dioxide is produced continu ...
, while breathing that is too rapid leads to
hyperventilation, which can cause
respiratory alkalosis
Respiratory alkalosis is a medical condition in which increased respiration elevates the blood pH beyond the normal range (7.35–7.45) with a concurrent reduction in arterial levels of carbon dioxide. This condition is one of the four primary dis ...
.
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 CO
2 pressure of 40 mm Hg. With intentional hyperventilation, the CO
2 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
Nitric oxide, NO, is a key
vertebrate
Vertebrates () comprise all animal taxa within the subphylum Vertebrata () (chordates with backbones), including all mammals, birds, reptiles, amphibians, and fish. Vertebrates represent the overwhelming majority of the phylum Chordata, with c ...
biological messenger important in many physiological and pathological processes, acting, for instance, as a powerful vasodilator in humans (see
Biological functions of nitric oxide
Nitric oxide (nitrogen monoxide) is a molecule and chemical compound with chemical formula of N O. In mammals including humans, nitric oxide is a signaling molecule involved in several physiological and pathological processes. It is a powerful vas ...
).
Nitrous oxide
Nitrous oxide
Nitrous oxide (dinitrogen oxide or dinitrogen monoxide), commonly known as laughing gas, nitrous, or nos, is a chemical compound, an oxide of nitrogen with the formula . At room temperature, it is a colourless non-flammable gas, and has ...
, N
2O, 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
In organic chemistry, a thiol (; ), or thiol derivative, is any organosulfur compound of the form , where R represents an alkyl or other organic substituent. The functional group itself is referred to as either a thiol group or a sulfhydryl gro ...
. Some authors have shown that this process of NO reduction to N
2O takes place in
hepatocyte
A hepatocyte is a cell of the main parenchymal tissue of the liver. Hepatocytes make up 80% of the liver's mass.
These cells are involved in:
* Protein synthesis
* Protein storage
* Transformation of carbohydrates
* Synthesis of cholesterol, ...
s, specifically in their
cytoplasm
In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. ...
and
mitochondria, and suggested that the N
2O can possibly be produced in mammalian cells. It is well known that N
2O is produced by some bacteria during process called denitrification.
In 1981, it was first suggested from clinical work with nitrous oxide (N
2O) 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.
Apart from its direct
and indirect actions at opioid receptors, it was also shown that N
2O 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
Homocysteine is a non-proteinogenic α-amino acid. It is a homologue of the amino acid cysteine, differing by an additional methylene bridge (-CH2-). It is biosynthesized from methionine by the removal of its terminal Cε methyl group. In th ...
to
methionine, increases homocysteine concentration and decreases methionine concentration. This effect was shown in
lymphocyte
A lymphocyte is a type of white blood cell (leukocyte) in the immune system of most vertebrates. Lymphocytes include natural killer cells (which function in cell-mediated, cytotoxic innate immunity), T cells (for cell-mediated, cytotoxic ad ...
cell cultures and in human liver biopsy samples.
Nitrous oxide does not bind as a ligand to the
heme
Heme, or haem (pronounced / hi:m/ ), is a precursor to hemoglobin, which is necessary to bind oxygen in the bloodstream. Heme is biosynthesized in both the bone marrow and the liver.
In biochemical terms, heme is a coordination complex "consis ...
and does not react with thiol-containing
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...
s. 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
Hemoglobin (haemoglobin BrE) (from the Greek word αἷμα, ''haîma'' 'blood' + Latin ''globus'' 'ball, sphere' + ''-in'') (), abbreviated Hb or Hgb, is the iron-containing oxygen-transport metalloprotein present in red blood cells (erythrocyt ...
,
myoglobin,
cytochrome oxidase
The enzyme cytochrome c oxidase or Complex IV, (was , now reclassified as a translocasEC 7.1.1.9 is a large transmembrane protein complex found in bacteria, archaea, and mitochondria of eukaryotes.
It is the last enzyme in the respiratory elect ...
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
Opioids are substances that act on opioid receptors to produce morphine-like effects. Medically they are primarily used for pain relief, including anesthesia. Other medical uses include suppression of diarrhea, replacement therapy for opioid use ...
and NMDA systerosclerosis, severe sepsis, severe malaria, or autoimmunity. Clinical tests involving humans have been performed, but the results have not yet been released.
Carbon suboxide
Carbon suboxide
Carbon suboxide, or tricarbon dioxide, is an organic, oxygen-containing chemical compound with formula and structure . Its four cumulative double bonds make it a cumulene. It is one of the stable members of the series of linear oxocarbons , w ...
, C
3O
2, can be produced in small amounts in any biochemical process that normally produces
carbon monoxide
Carbon monoxide (chemical formula CO) is a colorless, poisonous, odorless, tasteless, flammable gas that is slightly less dense than air. Carbon monoxide consists of one carbon atom and one oxygen atom connected by a triple bond. It is the simple ...
, 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 (C
3O
2)
n (mostly (C
3O
2)
6 and (C
3O
2)
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
The retina (from la, rete "net") is the innermost, light-sensitive layer of tissue of the eye of most vertebrates and some molluscs. The optics of the eye create a focused two-dimensional image of the visual world on the retina, which then ...
.
Sulfur dioxide
The role of
sulfur dioxide, SO
2, in mammalian biology is not yet well understood. Sulfur dioxide blocks nerve signals from the
pulmonary stretch receptors
Pulmonary stretch receptors are mechanoreceptors found in the lungs.
When the lung expands, the receptors initiate the Hering-Breuer reflex, which reduces the respiratory rate. This signal is transmitted by vagus nerve. Increased firing from the ...
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
Oleic acid is a fatty acid that occurs naturally in various animal and vegetable fats and oils. It is an odorless, colorless oil, although commercial samples may be yellowish. In chemical terms, oleic acid is classified as a monounsaturated omeg ...
. 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
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...
that produces endogenous SO
2 significantly increased the amount of lung tissue damage in the experiment. Conversely, adding
acetylcysteine or
glutathione
Glutathione (GSH, ) is an antioxidant in plants, animals, fungi, and some bacteria and archaea. Glutathione is capable of preventing damage to important cellular components caused by sources such as reactive oxygen species, free radicals, pe ...
to the rat diet increased the amount of endogenous SO
2 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
The heart is a muscular organ in most animals. This organ pumps blood through the blood vessels of the circulatory system. The pumped blood carries oxygen and nutrients to the body, while carrying metabolic waste such as carbon dioxide to t ...
and
blood vessel
The blood vessels are the components of the circulatory system that transport blood throughout the human body. These vessels transport blood cells, nutrients, and oxygen to the tissues of the body. They also take waste and carbon dioxide away ...
function, and aberrant or deficient sulfur dioxide metabolism can contribute to several different cardiovascular diseases, such as
arterial hypertension
Hypertension (HTN or HT), also known as high blood pressure (HBP), is a long-term medical condition in which the blood pressure in the arteries is persistently elevated. High blood pressure usually does not cause symptoms. Long-term high b ...
,
atherosclerosis
Atherosclerosis is a pattern of the disease arteriosclerosis in which the wall of the artery develops abnormalities, called lesions. These lesions may lead to narrowing due to the buildup of atheromatous plaque. At onset there are usually no s ...
,
pulmonary arterial hypertension,
stenocardia.
It was shown that in children with pulmonary arterial hypertension due to congenital heart diseases the level of
homocysteine
Homocysteine is a non-proteinogenic α-amino acid. It is a homologue of the amino acid cysteine, differing by an additional methylene bridge (-CH2-). It is biosynthesized from methionine by the removal of its terminal Cε methyl group. In th ...
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
A mitogen-activated protein kinase (MAPK or MAP kinase) is a type of protein kinase that is specific to the amino acids serine and threonine (i.e., a serine/threonine-specific protein kinase). MAPKs are involved in directing cellular responses to ...
activity and activating
adenylyl cyclase
Adenylate cyclase (EC 4.6.1.1, also commonly known as adenyl cyclase and adenylyl cyclase, abbreviated AC) is an enzyme with systematic name ATP diphosphate-lyase (cyclizing; 3′,5′-cyclic-AMP-forming). It catalyzes the following reaction:
:A ...
and
protein kinase A
In cell biology, protein kinase A (PKA) is a family of enzymes whose activity is dependent on cellular levels of cyclic AMP (cAMP). PKA is also known as cAMP-dependent protein kinase (). PKA has several functions in the cell, including regulatio ...
. 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
Vasodilation is the widening of blood vessels. It results from relaxation of smooth muscle cells within the vessel walls, in particular in the large veins, large arteries, and smaller arterioles. The process is the opposite of vasoconstrictio ...
. 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
Isoprenaline, or isoproterenol (brand name: Isoprenaline Macure), is a medication used for the treatment of bradycardia (slow heart rate), heart block, and rarely for asthma. It is a non-selective β adrenoceptor agonist that is the isopropyla ...
adrenergic
Adrenergic means "working on adrenaline (epinephrine) or noradrenaline (norepinephrine)" (or on their receptors). When not further qualified, it is usually used in the sense of enhancing or mimicking the effects of epinephrine and norepinephrine ...
hyperstimulation, and strengthens the myocardial antioxidant defense reserve.
Hydrogen cyanide
Some authors have shown that
neuron
A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa. ...
s can produce
hydrogen cyanide, HCN, upon activation of their
opioid
Opioids are substances that act on opioid receptors to produce morphine-like effects. Medically they are primarily used for pain relief, including anesthesia. Other medical uses include suppression of diarrhea, replacement therapy for opioid use ...
receptors
Receptor may refer to:
*Sensory receptor, in physiology, any structure which, on receiving environmental stimuli, produces an informative nerve impulse
*Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds to a n ...
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
Neurotransmission (Latin: ''transmissio'' "passage, crossing" from ''transmittere'' "send, let through") is the process by which signaling molecules called neurotransmitters are released by the axon terminal of a neuron (the presynaptic neuron), ...
). Moreover, increased endogenous neuronal HCN production under opioids was seemingly needed for adequate opioid
analgesia
Pain management is an aspect of medicine and health care involving relief of pain (pain relief, analgesia, pain control) in various dimensions, from acute and simple to chronic and challenging. Most physicians and other health professional ...
, 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
Muscarinic acetylcholine receptors, or mAChRs, are acetylcholine receptors that form G protein-coupled receptor complexes in the cell membranes of certain neurons and other cells. They play several roles, including acting as the main end-rec ...
cholinergic
Cholinergic agents are compounds which mimic the action of acetylcholine and/or butyrylcholine. In general, the word " choline" describes the various quaternary ammonium salts containing the ''N'',''N'',''N''-trimethylethanolammonium cati ...
receptors in cultured
pheochromocytoma
Pheochromocytoma (PHEO or PCC) is a rare tumor of the adrenal medulla composed of chromaffin cells, also known as pheochromocytes. When a tumor composed of the same cells as a pheochromocytoma develops outside the adrenal gland, it is referred t ...
cells ''increases'' HCN production, in a living organism (''in vivo'') muscarinic cholinergic stimulation actually ''decreases'' HCN production.
Leukocytes generate HCN during
phagocytosis
Phagocytosis () is the process by which a cell uses its plasma membrane to engulf a large particle (≥ 0.5 μm), giving rise to an internal compartment called the phagosome. It is one type of endocytosis. A cell that performs phagocytosis is ...
.
[
The ]vasodilatation
Vasodilation is the widening of blood vessels. It results from relaxation of smooth muscle cells within the vessel walls, in particular in the large veins, large arteries, and smaller arterioles. The process is the opposite of vasoconstrictio ...
, caused by sodium nitroprusside
Sodium nitroprusside (SNP), sold under the brand name Nitropress among others, is a medication used to lower blood pressure. This may be done if the blood pressure is very high and resulting in symptoms, in certain types of heart failure, and d ...
, 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
Nitroglycerin (NG), (alternative spelling of nitroglycerine) also known as trinitroglycerin (TNG), nitro, glyceryl trinitrate (GTN), or 1,2,3-trinitroxypropane, is a dense, colorless, oily, explosive liquid most commonly produced by nitrating ...
and other non-cyanogenic nitrates which do not cause blood cyanide levels to rise.
Ammonia
Ammonia, NH3, also plays a role in both normal and abnormal animal physiology
Physiology (; ) is the scientific study of functions and mechanisms in a living system. As a sub-discipline of biology, physiology focuses on how organisms, organ systems, individual organs, cells, and biomolecules carry out the chemical ...
. It is biosynthesised through normal amino acid metabolism, but is toxic in high concentrations. The liver
The liver is a major organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the synthesis of proteins and biochemicals necessary for digestion and growth. In humans, it ...
converts ammonia to urea through a series of reactions known as the urea cycle
The urea cycle (also known as the ornithine cycle) is a cycle of Biochemistry, biochemical reactions that produces urea (NH2)2CO from ammonia (NH3). Animals that use this cycle, mainly amphibians and mammals, are called ureotelic.
The urea cycle ...
. Liver dysfunction, such as that seen in cirrhosis
Cirrhosis, also known as liver cirrhosis or hepatic cirrhosis, and end-stage liver disease, is the impaired liver function caused by the formation of scar tissue known as fibrosis due to damage caused by liver disease. Damage causes tissue rep ...
, may lead to elevated amounts of ammonia in the blood (hyperammonemia
Hyperammonemia is a metabolic disturbance characterised by an excess of ammonia in the blood. It is a dangerous condition that may lead to brain injury and death. It may be primary or secondary.
Ammonia is a substance that contains nitrogen. It i ...
). Likewise, defects in the enzymes responsible for the urea cycle, such as ornithine transcarbamylase
Ornithine transcarbamylase (OTC) (also called ornithine carbamoyltransferase) is an enzyme () that catalyzes the reaction between carbamoyl phosphate (CP) and ornithine (Orn) to form citrulline (Cit) and phosphate (Pi). There are two classes of OT ...
, lead to hyperammonemia. Hyperammonemia contributes to the confusion and coma of hepatic encephalopathy
Hepatic encephalopathy (HE) is an altered level of consciousness as a result of liver failure. Its onset may be gradual or sudden. Other symptoms may include movement problems, changes in mood, or changes in personality. In the advanced stage ...
, as well as the neurologic disease common in people with urea cycle defects and organic aciduria
Organic acidemia, is a term used to classify a group of metabolic disorders which disrupt normal amino acid metabolism, particularly branched-chain amino acids, causing a buildup of acids which are usually not present.
The branched-chain amino a ...
s.
Ammonia is important for normal animal acid/base balance. After formation of ammonium from glutamine
Glutamine (symbol Gln or Q) is an α-amino acid that is used in the biosynthesis of proteins. Its side chain is similar to that of glutamic acid, except the carboxylic acid group is replaced by an amide. It is classified as a charge-neutral ...
, α-ketoglutarate may be degraded to produce two molecules of bicarbonate
In inorganic chemistry, bicarbonate (IUPAC-recommended nomenclature: hydrogencarbonate) is an intermediate form in the deprotonation of carbonic acid. It is a polyatomic anion with the chemical formula .
Bicarbonate serves a crucial biochem ...
, 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
Methane ( , ) is a chemical compound with the chemical formula (one carbon atom bonded to four hydrogen atoms). It is a group-14 hydride, the simplest alkane, and the main constituent of natural gas. The relative abundance of methane on Ea ...
, CH4, is produced not only by the intestinal flora
Gut microbiota, gut microbiome, or gut flora, are the microorganisms, including bacteria, archaea, fungi, and viruses that live in the digestive tracts of animals. The gastrointestinal metagenome is the aggregate of all the genomes of the gut mi ...
and then absorbed into the blood
Blood is a body fluid in the circulatory system of humans and other vertebrates that delivers necessary substances such as nutrients and oxygen to the cells, and transports metabolic waste products away from those same cells. Blood in the cir ...
, but also is produced - in small amounts - by eukaryotic
Eukaryotes () are organisms whose Cell (biology), cells have a cell nucleus, nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the ...
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
Sepsis, formerly known as septicemia (septicaemia in British English) or blood poisoning, is a life-threatening condition that arises when the body's response to infection causes injury to its own tissues and organs. This initial stage is follo ...
or bacteria
Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one Cell (biology), biological cell. They constitute a large domain (biology), domain of prokaryotic microorganisms. Typically a few micrometr ...
l endotoxemia
Lipopolysaccharides (LPS) are large molecules consisting of a lipid and a polysaccharide that are bacterial toxins. They are composed of an O-antigen, an outer core, and an inner core all joined by a covalent bond, and are found in the outer m ...
, 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
Peristalsis ( , ) is a radially symmetrical contraction and relaxation of muscles that propagate in a wave down a tube, in an anterograde direction. Peristalsis is progression of coordinated contraction of involuntary circular muscles, whic ...
. And its excess causes not only belching, flatulence and belly pain, but also functional constipation.
Ethylene
Ethylene, H2C=CH2, serves as a hormone
A hormone (from the Greek participle , "setting in motion") is a class of signaling molecules in multicellular organisms that are sent to distant organs by complex biological processes to regulate physiology and behavior. Hormones are require ...
in plant
Plants are predominantly photosynthetic eukaryotes of the kingdom Plantae. Historically, the plant kingdom encompassed all living things that were not animals, and included algae and fungi; however, all current definitions of Plantae exclu ...
s. It acts at trace levels throughout the life of the plant by stimulating or regulating the ripening
Ripening is a process in fruits that causes them to become more palatable. In general, fruit becomes sweeter, less green, and softer as it ripens. Even though the acidity of fruit increases as it ripens, the higher acidity level does not make th ...
of fruit
In botany, a fruit is the seed-bearing structure in flowering plants that is formed from the ovary after flowering.
Fruits are the means by which flowering plants (also known as angiosperms) disseminate their seeds. Edible fruits in particu ...
, the opening of flower
A flower, sometimes known as a bloom or blossom, is the reproductive structure found in flowering plants (plants of the division Angiospermae). The biological function of a flower is to facilitate reproduction, usually by providing a mechani ...
s, and the abscission
Abscission () is the shedding of various parts of an organism, such as a plant dropping a leaf, fruit, flower, or seed. In zoology, abscission is the intentional shedding of a body part, such as the shedding of a claw, husk, or the autotomy of a ...
(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 () 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
Incense is aromatic biotic material that releases fragrant smoke when burnt. The term is used for either the material or the aroma. Incense is used for aesthetic reasons, religious worship, aromatherapy, meditation, and ceremony. It may also b ...
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
Abscission () is the shedding of various parts of an organism, such as a plant dropping a leaf, fruit, flower, or seed. In zoology, abscission is the intentional shedding of a body part, such as the shedding of a claw, husk, or the autotomy of a ...
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.
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
Ripening is a process in fruits that causes them to become more palatable. In general, fruit becomes sweeter, less green, and softer as it ripens. Even though the acidity of fruit increases as it ripens, the higher acidity level does not make th ...
of fruits, abscission
Abscission () is the shedding of various parts of an organism, such as a plant dropping a leaf, fruit, flower, or seed. In zoology, abscission is the intentional shedding of a body part, such as the shedding of a claw, husk, or the autotomy of a ...
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
Biosynthesis is a multi-step, enzyme- catalyzed process where substrates are converted into more complex products in living organisms. In biosynthesis, simple compounds are modified, converted into other compounds, or joined to form macromolecules ...
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
1-Aminocyclopropane-1-carboxylic acid (ACC) is a disubstituted cyclic α-amino acid in which a cyclopropane ring is fused to the C atom of the amino acid. It is a white solid. Many cyclopropane-substituted amino acids are known, but this one oc ...
(ACC) by the enzyme ACC synthase (ACS). The activity of ACS determines the rate of ethylene production, therefore regulation of this enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...
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
Indole-3-acetic acid (IAA, 3-IAA) is the most common naturally occurring plant hormone of the auxin class. It is the best known of the auxins, and has been the subject of extensive studies by plant physiologists. IAA is a derivative of indole, con ...
(IAA) and cytokinin
Cytokinins (CK) are a class of plant hormones that promote cell division, or cytokinesis, in plant roots and shoots. They are involved primarily in cell growth and differentiation, but also affect apical dominance, axillary bud growth, and le ...
s.
Ethylene is perceived by a family of five transmembrane protein dimers such as the ETR1 protein in ''Arabidopsis''. The gene
In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
encoding
In communications and information processing, code is a system of rules to convert information—such as a letter, word, sound, image, or gesture—into another form, sometimes shortened or secret, for communication through a communication ...
an ethylene receptor has been cloned in '' Arabidopsis thaliana'' and then in tomato
The tomato is the edible berry of the plant ''Solanum lycopersicum'', commonly known as the tomato plant. The species originated in western South America, Mexico, and Central America. The Mexican Nahuatl word gave rise to the Spanish word ...
. Ethylene receptors are encoded by multiple genes in the ''Arabidopsis'' and tomato
The tomato is the edible berry of the plant ''Solanum lycopersicum'', commonly known as the tomato plant. The species originated in western South America, Mexico, and Central America. The Mexican Nahuatl word gave rise to the Spanish word ...
genome
In the fields of molecular biology and genetics, a genome is all the genetic information of an organism. It consists of nucleotide sequences of DNA (or RNA in RNA viruses). The nuclear genome includes protein-coding genes and non-coding g ...
s. 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
1-Aminocyclopropane-1-carboxylic acid (ACC) is a disubstituted cyclic α-amino acid in which a cyclopropane ring is fused to the C atom of the amino acid. It is a white solid. Many cyclopropane-substituted amino acids are known, but this one oc ...
(ACC). ACC is transported upwards in the plant and then oxidized in leaves. The ethylene produced causes nastic movements
Nastic movements are non-directional responses to stimuli (e.g. temperature, humidity, light irradiance), and are usually associated with plants. The movement can be due to changes in turgor. Decrease in turgor pressure causes shrinkage while ...
(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
The hypocotyl (short for "hypocotyledonous stem", meaning "below seed leaf") is the stem of a germinating seedling, found below the cotyledons (seed leaves) and above the radicle ( root).
Eudicots
As the plant embryo grows at germination, it se ...
with pronounced apical hook.
*In pollination
Pollination is the transfer of pollen from an anther of a plant to the stigma of a plant, later enabling fertilisation and the production of seeds, most often by an animal or by wind. Pollinating agents can be animals such as insects, birds, a ...
, when the pollen reaches the stigma, the precursor of the ethene, ACC
ACC most often refers to:
* Atlantic Coast Conference, an NCAA Division I collegiate athletic conference located in the US
*American College of Cardiology, A US-based nonprofit medical association that bestows credentials upon cardiovascular spec ...
, is secreted to the petal, the ACC releases ethylene with ACC oxidase.
*Stimulates leaf and flower senescence
*Stimulates senescence of mature xylem
Xylem is one of the two types of transport tissue in vascular plants, the other being phloem. The basic function of xylem is to transport water from roots to stems and leaves, but it also transports nutrients. The word ''xylem'' is derived from ...
cells in preparation for plant use
*Induces leaf abscission
Abscission () is the shedding of various parts of an organism, such as a plant dropping a leaf, fruit, flower, or seed. In zoology, abscission is the intentional shedding of a body part, such as the shedding of a claw, husk, or the autotomy of a ...
*Induces seed germination
*Induces root hair
Root hair, or absorbent hairs, are outgrowths of epidermal cells, specialized cells at the tip of a plant root. They are lateral extensions of a single cell and are only rarely branched. They are found in the region of maturation, of the root. Root ...
growth — increasing the efficiency of water and mineral absorption through rhizosheath formation
*Induces the growth of adventitious root Important structures in plant development are buds, shoots, roots, leaves, and flowers; plants produce these tissues and structures throughout their life from meristems located at the tips of organs, or between mature tissues. Thus, a living plan ...
s during flooding
* Stimulates survival under low-oxygen conditions ( hypoxia) in submerged plant tissues
*Stimulates epinasty — leaf petiole grows out, leaf hangs down and curls into itself
*Stimulates fruit ripening
Ripening is a process in fruits that causes them to become more palatable. In general, fruit becomes sweeter, less green, and softer as it ripens. Even though the acidity of fruit increases as it ripens, the higher acidity level does not make the ...
*Induces a climacteric rise in respiration
Respiration may refer to:
Biology
* Cellular respiration, the process in which nutrients are converted into useful energy in a cell
** Anaerobic respiration, cellular respiration without oxygen
** Maintenance respiration, the amount of cellul ...
in some fruit which causes a release of additional ethylene.
*Affects gravitropism
Gravitropism (also known as geotropism) is a coordinated process of differential growth by a plant in response to gravity pulling on it. It also occurs in fungi. Gravity can be either "artificial gravity" or natural gravity. It is a general featu ...
*Inhibits root growth in response to soil compaction, shade and flooding
*Stimulates nutational bending
*Inhibits stem growth and stimulates stem and cell broadening and lateral branch growth outside of seedling stage (see Hyponastic response
The hyponastic response is an upward bending of leaves or other plant
Plants are predominantly photosynthetic eukaryotes of the kingdom Plantae. Historically, the plant kingdom encompassed all living things that were not animals, and incl ...
)
*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 and )
*Induces flowering in pineapple
The pineapple (''Ananas comosus'') is a tropical plant with an edible fruit; it is the most economically significant plant in the family Bromeliaceae. The pineapple is indigenous to South America, where it has been cultivated for many centuri ...
s
*Inhibits short day induced flower initiation in ''Pharbitus nil'' and '' Chrysanthemum morifolium''
Small amounts of endogenous ethylene are also produced in mammals
Mammals () are a group of vertebrate animals constituting the class Mammalia (), characterized by the presence of mammary glands which in females produce milk for feeding (nursing) their young, a neocortex (a region of the brain), fur o ...
, including human
Humans (''Homo sapiens'') are the most abundant and widespread species of primate, characterized by bipedalism and exceptional cognitive skills due to a large and complex brain. This has enabled the development of advanced tools, cultu ...
s, due to lipid peroxidation. Some of endogenous ethylene is then oxidized to ethylene oxide
Ethylene oxide is an organic compound with the formula . It is a cyclic ether and the simplest epoxide: a three-membered ring consisting of one oxygen atom and two carbon atoms. Ethylene oxide is a colorless and flammable gas with a faintly sw ...
, which is able to alkylate
An alkylation unit (alky) is one of the conversion processes used in petroleum refineries. It is used to convert isobutane and low-molecular-weight alkenes (primarily a mixture of propene and butene) into alkylate, a high octane gasoline componen ...
DNA and protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...
s, including hemoglobin
Hemoglobin (haemoglobin BrE) (from the Greek word αἷμα, ''haîma'' 'blood' + Latin ''globus'' 'ball, sphere' + ''-in'') (), abbreviated Hb or Hgb, is the iron-containing oxygen-transport metalloprotein present in red blood cells (erythrocyt ...
(forming a specific adduct with its N-terminal valine
Valine (symbol Val or V) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α- amino group (which is in the protonated −NH3+ form under biological conditions), an α- carboxylic acid group (which is in the deprotona ...
, N-hydroxyethyl-valine). Endogenous ethylene oxide, just as like environmental (exogenous) one, can alkylate guanine
Guanine () ( symbol G or Gua) is one of the four main nucleobases found in the nucleic acids DNA and RNA, the others being adenine, cytosine, and thymine (uracil in RNA). In DNA, guanine is paired with cytosine. The guanine nucleoside is c ...
in DNA, forming an adduct 7-(2-hydroxyethyl)-guanine, and this poses an intrinsic carcinogenic risk. It is also mutagenic.
References
External links
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Biochemistry
Molecular biology
Molecules
Signal transduction