Arsenic biochemistry refers to biochemical processes that can use arsenic or its compounds, such as arsenate. Arsenic is a moderately abundant element on the earth's crust, and although many arsenic compounds are often considered highly toxic, a wide variety of 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 arsenic compounds are highly toxic and it is found in some aquifers,[1] potentially affecting many millions of people via processes that are intrinsically biochemical.[2]
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Arsenic is a cause of mortality throughout the world; associated problems include heart, respiratory, gastrointestinal, liver, nervous and kidney diseases.[2][3] Genotoxicity involves inhibition of DNA repair and DNA methylation. The carcinogenic effect of arsenic arises from the oxidative stress induced by arsenic. Arsenic's high toxicity naturally led to the development of a variety of arsenic compounds as chemical weapons, e.g. dimethylarsenic chloride. Some were employed as chemical warfare agents, especially in World War I. This threat led to many studies on antidotes and an expanded knowledge of the interaction of arsenic compounds with living organisms. One result was the development of antidotes such as British anti-Lewisite. Many such antidotes exploit the affinity of As(III) for thiolate ligands, which convert highly toxic organoarsenicals to less toxic derivatives. It is generally assumed that arsenates bind to cysteine residues in proteins.
Trimethylarsine, once known as Gosio's gas is an intensely malodorous organoarsenic compound that is commonly produced by microbial action on inorganic arsenic substrates.[4] A topical source of this compound 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.[5]
Other organoarsenic compounds found in nature are arsenobetaine and arsenocholine,[6] both being found in many marine organisms.[2] Some As-containing nucleosides (sugar derivatives) are also known.[7] Several of these organoarsenic compounds arise via methylation processes. For example, the mold Scopulariopsis brevicaulis produce significant amounts of trimethylarsine if inorganic arsenic is present.[8] The organic compound arsenobetaine is found in some marine foods such as fish and algae, and also in mushrooms in larger concentrations. 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]
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.[10] 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.[11][12] 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 biomethylation.[13]
Inorganic arsenic and its compounds, upon entering the food chain, are progressively metabolised (detoxified) through a process of methylation.[13] 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).[14]
In mammals, methylation occurs in the liver by methyltransferases, the products being the (CH3)2AsOH (dimethylarsinous acid) and (CH3)2As(O)OH (dimethylarsinic acid), which have the oxidation states As(III) and As(V), respectively.[2] Although the mechanism of methylation of arsenic in humans has not been elucidated, the source of methyl is methionine, which suggests a role of S-adenosyl methionine.[3] Exposure to toxic doses begin when the liver's methylation capacity is exceeded or inhibited.
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.[15]
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.[3]
Despite, or possibly because of, its long-known toxicity, arsenic-containing potions and drugs have a history in medicine and quackery that continues into the 21st century.[16] Starting in the early 19th century and continuing into the 20th century, Fowler's solution, a toxic concoction of sodium arsenite, was sold. The organoarsenic compound Salvarsan was the first synthetic chemotherapeutic agent, discovered by Paul Ehrlich. The treatment, however, led to many problems, causing long lasting health complications.[17] Around 1943 it was finally superseded by penicillin.
In vitro studies suggest that arsenic trioxide (As2O3) inhibits the proliferation of myeloma cells via cell cycle arrest as well as triggering cell death.[18] These results suggest that arsenic trioxide may be a clinically useful treatment in patients with multiple myeloma[18] or leukemia.[19]
DNA and RNA contain phosphate in their structure. A hypothetical analog would use arsenate to partially or fully replace phosphate. A 2010 paper in Science[20] reports that GFAJ-1, a proteobacterium from Mono Lake, is facultatively capable of incorporating a small percentage of arsenate into its DNA under conditions of phosphorus starvation. However, other scientists have expressed doubts that arsenate has replaced phosphate in the DNA of this organism and have suggested that procedural errors and interpretative errors may have been responsible.[21][22][23][24] The sequence of the genome of the bacterium, GFAJ-1, is now posted in GenBank.[25]
A common objection to arsenic (V) as a chemical surrogate to phosphorus (V) in ancient systems is that it is easily reduced to arsenic (III) metabolically and therefore would not have been as freely available. However, recent research into arsenic metabolism has demonstrated that it may have evolved during the Archean eon providing evidence for the biogeochemical cycling and availability of arsenic (V) as an electron acceptor on primordial earth.[26] A modern day example would be Searles and Mono Lakes, in the Western United States, which have been established to harbor an arsenic respiring biosphere.[26] Each of these lakes contain a substantial amount of dissolved inorganic arsenic that is exploited by prokaryotic life through arsenic (III) and arsenate (V) based metabolic reactions.[27]
While arsenic tolerance and exploitation has been demonstrated to exist in these modern extreme biospheres, it has not yet been demonstrated to exist phosphorus-free. While some of the key properties of phosphate, such as its thermodynamic instability as well as its kinetic stability, make it advantageous for Earth's biological life, arsenic may be more thermodynamically realistic for life on other planets or moons such as Saturn's moon Titan.[28]
All known life forms use adenosine phosphate compounds (AMP, ADP and ATP) to transfer chemical energy. It is known that arsenic-bearing analogs of these compounds can form; however, it is unclear if they are ever utilized by living organisms.[29] It has been observed that some microorganisms of genera Bacillus and the unrelated family Halanaerobacteriales can use arsenic in its pentavalent oxidation state [arsenic (V)] as an electron acceptor.[27][30][31] The isolated microorganisms are observed to use lactate, sulfide, or hydrogen as electron donors.[27] In this role, arsenic effectively functions as an alternative to oxygen. This form of chemolithotrophy does not require that the arsenic be incorporated into any of the organism's essential compounds.