Arsenic biochemistry

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S-Adenosylmethionine
, a source of methyl groups in many biogenic arsenic compounds

Arsenic biochemistry refers to

organoarsenic compounds are produced biologically and various organic and inorganic arsenic compounds are metabolized by numerous organisms. This pattern is general for other related elements, including selenium, which can exhibit both beneficial and deleterious effects. Arsenic biochemistry has become topical since many toxic arsenic compounds are found in some aquifers,[1] potentially affecting many millions of people via biochemical processes.[2]

Sources of arsenic

Organoarsenic compounds in nature

Arsenic poisoning is a global problem arising from naturally occurring arsenic in ground water.

The evidence that arsenic may be a beneficial nutrient at trace levels below the background to which living organisms are normally exposed has been reviewed.

Scopulariopsis brevicaulis produces significant amounts of trimethylarsine if inorganic arsenic is present.[6] The organic compound arsenobetaine is found in some marine foods such as fish and algae, and also in mushrooms in larger concentrations. In clean environments, the edible mushroom species Cyanoboletus pulverulentus hyperaccumulates arsenic in concentrations reaching even 1,300 mg/kg in dry weight; cacodylic acid is the major As compound.[7] A very unusual composition of organoarsenic compounds was found in deer truffles (Elaphomyces spp.).[8] The average person's intake is about 10–50 μg/day. Values about 1000 μg are not unusual following consumption of fish or mushrooms; however, there is little danger in eating fish since this arsenic compound is nearly non-toxic.[9]

A topical source of arsenic are the green pigments once popular in wallpapers, e.g. Paris green. A variety of illness have been blamed on this compound, although its toxicity has been exaggerated.[10]

Trimethylarsine, once known as Gosio's gas, is an intensely malodorous organoarsenic compound that is commonly produced by microbial action on inorganic arsenic substrates.[11]

Arsenic (V) compounds are easily reduced to arsenic (III) and could have served as an electron acceptor on primordial Earth.

biota
.

Incorrect claims of arsenic-based life (phosphorus substitution)

Although phosphate and arsenate are structurally similar, there is no evidence that arsenic replaces phosphorus in DNA or RNA.[13] A 2010 experiment involving the bacteria GFAJ-1 that made this claim was refuted by 2012.[14][15]

Anthropogenic arsenic compounds

Anthropogenic (man-made) sources of arsenic, like the natural sources, are mainly arsenic oxides and the associated anions. Man-made sources of arsenic, include wastes from mineral processing, swine and poultry farms.[16] For example, many ores, especially sulfide minerals, are contaminated with arsenic, which is released in roasting (burning in air). In such processing, arsenide is converted to arsenic trioxide, which is volatile at high temperatures and is released into the atmosphere. Poultry and swine farms make heavy use of the organoarsenic compound roxarsone as an antibiotic in feed.[17][18] Some wood is treated with copper arsenates as a preservative. The mechanisms by which these sources affect "downstream" living organisms remains uncertain but are probably diverse. One commonly cited pathway involves methylation.[19]

The monomethylated acid, methanearsonic acid (CH3AsO(OH)2), is a precursor to fungicides (tradename Neoasozin) in the cultivation of rice and cotton. Derivatives of

4-hydroxy-3-nitrobenzenearsonic acid (3-NHPAA or Roxarsone), ureidophenylarsonic acid, and p-arsanilic acid
. These applications are controversial as they introduce soluble forms of arsenic into the environment.

Arsenic-based drugs

Despite, or possibly because of, its long-known toxicity, arsenic-containing potions and drugs have a history in

chemotherapeutic agent, discovered by Paul Ehrlich.[21] The treatment, however, led to many problems causing long lasting health complications.[22] Around 1943 it was finally superseded by penicillin
. The related drug Melarsoprol is still in use against late-state African trypanosomiasis (sleeping sickness), despite its high toxicity and possibly fatal side effects.

promyelocytic leukemia
.

Methylation of arsenic

Inorganic arsenic and its compounds, upon entering the food chain, are progressively metabolised (detoxified) through a process of methylation.[19] The methylation occurs through alternating reductive and oxidative methylation reactions, that is, reduction of pentavalent to trivalent arsenic followed by addition of a methyl group (CH3).[24]

Cacodylic acid, formed in the liver after ingestion of arsenic.

In mammals, methylation occurs in the liver by

S-adenosyl methionine.[25]
Exposure to toxic doses begin when the liver's methylation capacity is exceeded or inhibited.

There are two major forms of arsenic that can enter the body, arsenic (III) and arsenic (V).[26] Arsenic (III) enters the cells though aquaporins 7 and 9, which is a type of aquaglyceroporin.[26] Arsenic (V) compounds use phosphate transporters to enter cells.[26] The arsenic (V) can be converted to arsenic (III) by the enzyme purine nucleoside phosphorylase.[26] This is classified as a bioactivation step, as although arsenic (III) is more toxic, it is more readily methylated.[27]

There are two routes by which inorganic arsenic compounds are methylated.[28] The first route uses Cyt19 arsenic methyltransferase to methylate arsenic (III) to a mono-methylated arsenic (V) compound.[26] This compound is then converted to a mono-methylated arsenic (III) compound using Glutathione S-Transferase Omega-1 (GSTO1).[26] The mono-methylated arsenic (V) compound can then be methylated again by Cyt19 arsenic methyltransferase, which forms a dimethyl arsenic (V) compound, which can be converted to a dimethyl arsenic (III) compound by Glutathione S-Transferase Omega-1 (GTSO1).[26] The other route uses glutathione (GSH) to conjugate with arsenic (III) to form an arsenic (GS) 3 complex.[26] This complex can form a monomethylated arsenic (III) GS complex, using Cyt19 arsenic methyltransferase, and this monomethylated GS complex is in equilibrium with the monomethylated arsenic (III).[26] Cyt19 arsenic methyltransferase can methylate the complex one more time, and this forms a dimethylated arsenic GS complex, which is in equilibrium with a dimethyl arsenic (III) complex.[26] Both of the mono-methylated and di-methylated arsenic compounds can readily be excreted in urine.[27] However, the monomethylated compound was shown to be more reactive and more toxic than the inorganic arsenic compounds to human hepatocytes (liver), keratinocytes in the skin, and bronchial epithelial cells (lungs).[29]

Studies in experimental animals and humans show that both inorganic arsenic and methylated metabolites cross the placenta to the fetus, however, there is evidence that methylation is increased during pregnancy and that it could be highly protective for the developing organism.[30]

Enzymatic methylation of arsenic is a detoxification process; it can be methylated to methylarsenite, dimethylarsenite or trimethylarsenite, all of which are trivalent. The methylation is catalyzed by arsenic methyltransferase (AS3MT) in mammals, which transfers a methyl group on the cofactor S-adenomethionine (SAM) to arsenic (III). An orthologue of AS3MT is found in bacteria and is called CmArsM. This enzyme was tested in three states (ligand free, arsenic (III) bound and SAM bound). Arsenic (III) binding sites usually use thiol groups of cysteine residues. The catalysis involves thiolates of Cys72, Cys174, and Cys224. In an SN2 reaction, the positive charge on the SAM sulfur atom pulls the bonding electron from the carbon of the methyl group, which interacts with the arsenic lone pair to form an As−C bond, leaving SAH.[31]

Excretion

In humans, the major route of excretion of most arsenic compounds is via the urine. The biological half-life of inorganic arsenic is about 4 days, but is slightly shorter following exposure to arsenate than to arsenite. The main metabolites excreted in the urine of humans exposed to inorganic arsenic are mono- and dimethylated arsenic acids, together with some unmetabolized inorganic arsenic.[25]

The biotransformation of arsenic for excretion is primarily done through the nuclear factor erythroid 2 related factor 2 (

MRP1 or MRP2) which removes the arsenic out of the cell and into bile for excretion.[34]
This adduct can also decompose back into inorganic arsenic.

Of particular note in the excretion of arsenic is the multiple methylation steps that take place which may increase the toxicity of arsenic[36] due to MMeAsIII being a potent inhibitor of glutathione peroxidase,[37] glutathione reductase, pyruvate dehydrogenase,[38] and thioredoxin reductase.[39]

Arsenic toxicity

Main articles:
Arsenic toxicity and Arsenic poisoning

Arsenic is a cause of mortality throughout the world; associated problems include heart, respiratory, gastrointestinal, liver, nervous and kidney diseases.[2][25]

Arsenic interferes with cellular longevity by

pyruvate to acetyl-CoA by NAD+. With the enzyme inhibited, the energy system of the cell is disrupted resulting in a cellular apoptosis episode. Biochemically, arsenic prevents use of thiamine resulting in a clinical picture resembling thiamine deficiency. Poisoning with arsenic can raise lactate levels and lead to lactic acidosis
.

thiolate ligands, which convert highly toxic organoarsenicals to less toxic derivatives. It is generally assumed that arsenates bind to cysteine
residues in proteins.

By contrast, arsenic oxide is an approved and effective chemotherapeutic drug for the treatment of acute promyelocytic leukemia (APL).[3]

Toxicity of pentavalent arsenicals

Due to its similar structure and properties, pentavalent arsenic metabolites are capable of replacing the phosphate group of many metabolic pathways.

succinate, thus forming an unstable compound that ultimately results in a decrease of ATP net gain.[40] Arsenite (III) metabolites, on the other hand, have limited effect on ATP production in red blood cells.[40]

Toxicity of trivalent arsenicals

Enzymes and receptors that contain thiol or

sulfhydryl functional groups are actively targeted by arsenite (III) metabolites.[40] These sulfur-containing compounds are normally glutathione and the amino acid cysteine.[40] Arsenite derivatives generally have higher binding affinity compared to the arsenate metabolites.[40] These bindings restrict activity of certain metabolic pathways.[40] For example, pyruvate dehydrogenase (PDH) is inhibited when monomethylarsonous acid (MMAIII) targets the thiol group of the lipoic acid cofactor.[40] PDH is a precursor of acetyl-CoA, thus the inhibition of PDH eventually limits the production of ATP in electron transport chain, as well as the production of gluconeogenesis intermediates.[40]

Oxidative stress

Arsenic can cause oxidative stress through the formation of

NADPH to oxygen, synthesizing a superoxide, which is a reactive free radical. This superoxide can react to form hydrogen peroxide and a reactive oxygen species. The enzyme NADPH oxidase is able to generate more reactive oxygen species in the presence of arsenic, due to the subunit p22phax, which is responsible for the electron transfer, being upregulated by arsenic.[28] The reactive oxygen species are capable of stressing the endoplasmic reticulum, which increases the amount of the unfolded protein response signals.[28] This leads to inflammation, cell proliferation, and eventually to cell death.[28] Another mechanism in which reactive oxygen species cause cell death would be through the cytoskeleton rearrangement, which affects the contractile proteins.[28]

The reactive nitrogen species arise once the reactive oxygen species destroy the

mitochondria.[28] This leads to the formation of the reactive nitrogen species, which are responsible for damaging DNA in arsenic poisoning.[28] Mitochondrial damage is known to cause the release of reactive nitrogen species, due to the reaction between superoxides and nitric oxide (NO).[28] Nitric oxide (NO) is a part of cell regulation, including cellular metabolism, growth, division and death.[28] Nitric oxide (NO) reacts with reactive oxygen species to form peroxynitrite.[28] In cases of chronic arsenic exposure, the nitric oxide levels are depleted, due to the superoxide reactions.[28] The enzyme NO synthase (NOS) uses L-arginine to form nitric oxide, but this enzyme is inhibited by monomethylated arsenic (III) compounds.[28]

DNA damage

Arsenic is reported to cause

8-oxoguanine (8-OHdG) which leads to G:C to T:A mutations.[52] Inorganic arsenic can also cause DNA strand break even at low concentrations.[53]

Inhibition of DNA repair

Inhibition of DNA repair processes is considered one of main mechanism of inorganic arsenic genotoxicity. Nucleotide excision repair (NER) and base excision repair (BER) are the processes implicated in the repair of DNA base damage induced by ROS after arsenic exposure. In particular, the NER mechanism is the major pathway for repairing bulky distortions in DNA double helix, while the BER mechanism is mainly implicated in the repair of single strand breaks induced by ROS,[54][55][56][57] but inorganic arsenic could also repress the BER mechanism.[58][59][60]

Neurodegenerative mechanisms

Arsenic is highly detrimental to the innate and the adaptive immune system of the body.[61] When the amount of unfolded and misfolded proteins in endoplasmic reticulum stress is excessive, the unfolded protein response (UPR) is activated to increase the activity of several receptors that are responsible the restoration of homeostasis.[61] The inositol-requiring enzyme-1 (IRE1) and protein kinase RNA-like endoplasmic reticulum kinase (PERK) are two receptors that restrict the rate of translation.[61] On the other hand, the unfolded proteins are corrected by the production of chaperones, which are induced by the activating transcription factor 6 (ATF6).[61] If the number of erroneous proteins elevates, further mechanism is active which triggers apoptosis.[61] Arsenic has evidentially shown to increase the activity of these protein sensors.[61]

Immune dysfunction

Arsenic exposure in small children distorts the ratio of

granulocytes and monocytes lead to a chronic state of inflammation, which might result in cancer development.[62]

Arsenic poisoning treatment

There are three molecules that serve as

DMSA) and Unithiol (DMPS).[63]

When these agents

electrophilic
. Once bound to the chelating agent the molecules can be excreted, and therefore free inorganic arsenic atoms are removed from the body.

Other chelating agents can be used, but may cause more side effects than British Anti-Lewisite (BAL, Dimercaprol), succimer (

DMSA) and (DMPS). DMPS and DMSA also have a higher therapeutic index than BAL.[63]

These drugs are efficient for acute poisoning of arsenic, which refers to the instantaneous effects caused by arsenic poisoning. For example, headaches, vomiting or sweating are some of the common examples of an instantaneous effect. In comparison, chronic poisonous effects arise later on, and unexpectedly such as organ damage. Usually it is too late to prevent them once they appear. Therefore, action should be taken as soon as acute poisonous effects arise.[64]

See also

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