Reviews

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Why Nature Chose Selenium Hans J. Reich*, ‡ and Robert J. Hondal*,†

† University of Vermont, Department of Biochemistry, 89 Beaumont Ave, Given Laboratory, Room B413, Burlington, Vermont 05405, United States ‡ University of WisconsinMadison, Department of Chemistry, 1101 University Avenue, Madison, Wisconsin 53706, United States

ABSTRACT: The authors were asked by the Editors of ACS Chemical Biology to write an article titled “Why Nature Chose Selenium” for the occasion of the upcoming bicentennial of the discovery of selenium by the Swedish chemist Jöns Jacob Berzelius in 1817 and styled after the famous work of Frank Westheimer on the biological chemistry of phosphate [Westheimer, F. H. (1987) Why Nature Chose Phosphates, Science 235, 1173−1178]. This work gives a history of the important discoveries of the biological processes that selenium participates in, and a point-by-point comparison of the chemistry of selenium with the atom it replaces in biology, sulfur. This analysis shows that redox chemistry is the largest chemical difference between the two chalcogens. This difference is very large for both one-electron and two-electron redox reactions. Much of this difference is due to the inability of selenium to form π bonds of all types. The outer valence electrons of selenium are also more loosely held than those of sulfur. As a result, selenium is a better nucleophile and will react with reactive oxygen species faster than sulfur, but the resulting lack of π-bond character in the Se−O bond means that the Se-oxide can be much more readily reduced in comparison to S-oxides. The combination of these properties means that replacement of sulfur with selenium in nature results in a selenium-containing biomolecule that resists permanent oxidation. Multiple examples of this gain of function behavior from the literature are discussed.

■ PREFACE declared, “...I, to mark its akin properties with tellurium, have Σεληνή The authors were asked by the Editors of ACS Chemical Biology named selenium, from , moon (goddess). What is more, “ ” it is in this regard, midway between sulfur and tellurium, and to write an article titled Why Nature Chose Selenium, styled ” after the famous work of Frank Westheimer titled “Why Nature has almost more characters of sulfur than of tellurium. ”1 ’ Berzelius was a proponent of the theory of “electrochemical Chose Phosphates. While Westheimer s elegant chemical ”20 explanations for the use of phosphate in biology have found dualism, which was a theory about the chemical nature of broad acceptance, currently the chemical reasons for the use of compounds. This theory held that all chemical compounds selenium in biology remain elusive and not widely agreed were held together due to neutralization of opposite electrical − upon.2 16 This work is written for the occasion of the charges, as does occur in ionic compounds. It is tempting to upcoming bicentennial of the discovery of selenium by the think that the naming of selenium was a type of homage to this Swedish chemist Jöns Jacob Berzelius in 1817. We hope readers theory as tellurium had been named after Tellus, the Latin of this review on the chemistry of the “mysterious moon goddess of the Earth (Earth Mother). Ultimately, electro- metal”17 will be illuminated by our views. chemical dualism could not describe all types of chemical bonding and fell out of favor as a theory, but Berzelius’ fi ■ DISCOVERY OF SELENIUM discovery of selenium remains as a signi cant achievement in chemistry. Oldfield describes the discovery of selenium by Berzelius as “ ” Serendipity, because he claims it was discovered during an ■ EARLY STUDIES OF SELENIUM IN BIOLOGY investigation into an illness of the workers in a chemical factory fi at Gripsholm, Sweden (in part owned by Berzelius) that The rst recognized role of selenium in biology was as a toxin. The investigation into the cause of “alkali disease” and “blind produced acetic, nitric, and sulfuric acids. As related by ” Oldfield, this illness was precipitated when the factory switched staggers, diseases of livestock in the American West and Plains to a new, local source of sulfur ore.18 As the story goes, States by Kurt Franke and others, showed that these diseases Berzelius thought this illness might be due to arsenic were forms of selenosis due to the ingestion of high doses of contamination of this sulfur ore, and the analysis of this ore selenium found in cereal crops, animal forage, and selenium led to the isolation of a new element (selenium). This story may be apocryphal, as it is not mentioned by Trofast, who has Received: January 12, 2016 reported on the discovery of selenium from a careful study of Accepted: March 7, 2016 Berzelius’ original notes.19 Trofast reports that Berzelius Published: March 7, 2016

© 2016 American Chemical Society 821 DOI: 10.1021/acschembio.6b00031 ACS Chem. Biol. 2016, 11, 821−841 ACS Chemical Biology Reviews accumulator plants such as Astragalus (known commonly as ■ DISEASES OF SELENIUM DEFICIENCY “ ” 21−24 locoweed ) grown in soils with high selenium content. It Besides exudative diathesis and liver necrosis, selenium is remarkable that Franke at a very early date was able to show deficiency results in a number of other diseases of animals that the toxic form of selenium in locally grown grains was in and humans.42 These include white muscle disease (a muscular the protein fraction of sulfuric acid hydrosylates. His experi- dystrophy disease mainly of sheep); mulberry heart disease, a ments showed that selenium was “adsorbed on the protein ff ”25 “ disease a ecting animal livestock and is so named due to molecule. He was able to conclude that There is evidence hemorrhage of the heart that gives the organ the color and that most of the selenium is in a compound very similar to appearance of a mulberry;42 and in humans, Keshan ”26 ’ − cystine. Franke s prescience that selenium would replace the Disease43 46 and Kashin−Beck Disease.47 Keshan Disease is a sulfur atom of an amino acid is little recognized26 and predates “ st” 27,28 type of cardiomyopathy and may have an underlying viral the discovery of the 21 amino acid, selenocysteine, by fi 48,49 29 etiology that is associated with selenium de ciency. Thressa Stadtman by 40 years! It should be noted that, while Kashin−Beck Disease is an osteoarticular disorder that blind staggers is often attributed to selenosis, it may in fact be resembles rheumatoid arthritis in some respects but is much caused by sulfate-related polioencephalomalacia due to more severe. The beginning stages of the disease may involve contamination of water sources by sodium sulfate and 30 destruction of the cartilage of the joints. The exact underlying magnesium sulfate. cause of the disease is not known with certainty, but the disease is strongly associated with both selenium and iodine ■ SELENIUMTOXIC AND ESSENTIAL deficiency.50 It was the discovery of Keshan Disease and 31 mammalian selenium-containing proteins that established Selenium, like the moon, has two faces, as it is both toxic to 45,46,51−53 all organisms and essential to many bacteria and animal species. selenium as an essential trace element for humans. The essentiality of selenium to bacteria was to be discovered by Pinsent, who found that selenium was necessary for the activity ■ CONNECTION WITH VITAMIN E 32 of E. coli formate dehydrogenase in 1954. A few years later, Although it has been shown independently by McCoy and selenium was discovered to be essential to animals 33 34,35 Thompson that there is a biochemical function of selenium that independently by Patterson and Schwarz. Karl Schwarz, must be distinct from that of vitamin E,37,54 the presence of who even earlier was studying dietary liver necrosis in rats, had vitamin E can prevent, or attenuate, various animal diseases that “ − found that the addition of methionine, vitamin E, or a third are associated with selenium deficiency.55 68 This implies that factor” to the diet could prevent this condition.36 It is the fi “ ” at least one biochemical function of selenium is strongly identi cation of this third factor that Schwarz would become connected with that of vitamin E. With the discovery of remembered for. Schwarz moved from Germany to the United glutathione peroxidase as a selenoenzyme,52,53 it became clear States and took a position at the National Institutes of Health that one common function of the two is protection against lipid investigating the cause of exudative diathesis in chicks and liver peroxidation.68 Another biochemical connection between necrosis in rats, diseases that were precipitated by a diet of selenium and vitamin E is vitamin C (ascorbic acid). The torula yeast. Torula yeast is low in vitamin E, selenium, and 37 reduction of dehydroascorbic acid to ascorbic acid is catalyzed sulfur amino acids, but rich in unsaturated fatty acids. These 69 ’ by thioredoxin reductase, a selenoenzyme. Ascorbic acid in diseases did not occur if American brewer s yeast (S. cerevisiae) turn can reduce the vitamin E radical formed in lipid bilayers was used instead. Schwarz was working on identifying the after quenching a radical species. It is interesting to note that missing factor found in brewer’s yeast that prevented these 38 the coxsackievirus implicated as the underlying cause of Keshan diseases. Schwarz initially thought that this missing factor Disease mutates to a more virulent form when the host is might be a vitamin, but experiments showed that the missing deficient in either selenium or vitamin E.70 This result could substance must be an inorganic compound. One of three mean that both nutrients protect the host DNA from a elements, arsenic, selenium, and tellurium were suspected as mutation associated with an oxidation event, which leads to a the missing nutritional factor.38 Schwarz isolated the missing “ ” more virulent form of the virus. Alternatively, Loscalzo has factor from acid hydrolysates of protein and called it Factor 3 offered a possible mechanism that does not involve mutation of because it was the third substance identified that could prevent 35 the virus. Low levels of glutathione peroxidase expression due dietary liver necrosis. Jukes relates the story that Schwarz was fi “ ” to selenium de ciency can result in oxidative stress that leads to able to identify selenium as Factor 3, the nutrient needed to myocardial injury and ventricular dysfunction, which in turn prevent liver necrosis in rats, after Dr. DeWitt Stetten, then an leads to cardiomyopathy characteristic of Keshan Disease.71 Associate Director of the National Institute of General Medical ’ Sciences, walked into Schwarz s laboratory and smelled the − distinct odor of a selenium-containing compound emanating ■ SELENIUM CANCER HYPOTHESIS from open test tubes of “Factor 3” in his laboratory.38 The odor There has been a great deal of interest in the area of cancer may have been from dimethyl diselenide, which has a very chemoprevention by selenium since the late 1960s. The earliest sharp odor and is a decomposition product of selenomethio- report of a relationship between selenium and cancer was by nine. Nelson and co-workers,72 who reported that a high dietary The two faces of selenium, essential and toxic, are unique in intake of selenium caused liver tumors in rats. However, that the range between the amounts needed to maintain health experiments conducted later in the same decade also on rats or cause toxicity is quite narrow. The U.S. Department of showed that low doses of sodium selenite (Na2SeO3) protected Agriculture has a R.D.A. of 55 μg/day for adults,39 while the against tumors induced by injection with dimethylaminoazo- World Health Organization has established a toxic limit of 800 benzene (a 50% reduction in tumor incidence was reported).73 μg/day for adults.40 For this reason, Jukes refers to selenium as Then in 1966, Shamberger and Rudolph showed that sodium “ ”41 the essential poison. selenide (Na2Se2) applied in a topical solution greatly reduced

822 DOI: 10.1021/acschembio.6b00031 ACS Chem. Biol. 2016, 11, 821−841 ACS Chemical Biology Reviews

(730-fold) tumor formation in an induced mouse skin tumor selenium offered any protection against cancer.102 This result 74 model compared to DL-α-tocopherol. was extremely disappointing (to say the least) and contrary to To help resolve the question of whether or not low levels of many previous studies that supported the selenium−cancer selenium were carcinogenic or not, the National Cancer hypothesis. Institute funded several studies that showed that selenium in Hatfield and Gladyshev have discussed some of the reasons − the diet up to 8 ppm did not induce tumorigenesis,75 77 for the large difference in experimental outcomes between the although there was still fear about the subject of selenium previous work (especially the work by Clark and co-workers) toxicity among the general public and some in the scientific and the SELECT study.103 They note three significant community even after these studies.78 In a very influential letter differences: (i) The study by Clark et al.100 was initially to the editor of the Canadian Medical Association Journal, undertaken to examine the effect of selenium supplementation Shamberger and Frost hypothesized that, “If selenium had an for those at risk for skin cancer and so only considered risk effect on public health, areas adequate or deficient could be factors for skin cancer during the randomization of subjects. (ii) expected to show different disease incidences or death rates.”79 The SELECT study used a different form of selenium, They pointed to a then recent study by Kubota and co-workers selenomethionine, while the study by Clark et al. used selenized who had constructed a forage crop map of the U.S. that yeast. While selenomethionine can be used to make selenium- indicated which areas of the country had high or low containing proteins, other forms of selenium could be selenium.80 Using these data, they showed a correlation important for chemoprevention of cancer. (iii) Last, partic- between areas of the U.S. with low forage crop selenium and ipants in the SELECT trial had higher initial plasma levels of a higher death rate. They also highlighted a study by Allaway selenium than those in the study by Clark et al. This last fact and co-workers who had measured plasma selenium levels in suggests that supranutritional dietary selenium does not provide multiple cities and counties in the U.S., and these measured low cancer protection, though epidemiology indicates that selenium plasma selenium levels were correlated with higher cancer death deficiency can increase cancer incidence (vide supra). rates.81 These ideas prompted Schrauzer to do a global study One seemingly contradictory fact about selenium and cancer that examined the relationship between dietary selenium intake is that overexpression of multiple selenoproteins such as (they also measured plasma selenium) and cancer. He found glutathione peroxidase-2, Sep15, and thioredoxin reductase may help to promote cancer growth once the tumor has taken inverse correlations for cancers of the large intestine, rectum, − prostate, breast, ovary, and the lung.82 With respect to hold.103 105 The fact that increased expression of a deficiency of selenium in soils, it should be noted that this is selenoenzyme such as thioredoxin reductase might help support such a concern in Finland that the government has mandated tumor growth highlights an interesting fact about cancer cells the inclusion of selenium in fertilizer for agricultural land.83 To and selenium. Cancer cells produce more reactive oxygen combat Keshan Disease in low selenium areas of China, species (ROS) than normal cells and are adapted to a higher 106,107 Chinese health officials began adding sodium selenite to table level of endogenously produced oxidants. Thioredoxin salt.45 and thioredoxin reductase are overexpressed in many human 108,109 In the decades since 1970, numerous epidemiological, cancer types, and this important selenium-containing selenium supplementation studies, and clinical trials mostly antioxidant system helps to counteract oxidative stress supported the link between low selenium intake and a higher experienced by cancer cells and enables cancer cells to resist incidence of cancer (termed the selenium−cancer hypothesis). programmed cell death (apoptosis). This fact contradicts the There are far too many examples of these kinds of studies to original idea of why selenium might help to prevent cancer; give a complete listing here, but some important ones are given selenium, as part of antioxidant enzymes, helps to prevent − in the reference list.84 94 Willett and Stampfer, Clark and oxidative damage to DNA by free radicals and ROS. However, Alberts, Jackson and Combs, Schrauzer, and Ip give good selenium can be involved in killing cancer cells using the summaries of the issues surrounding selenium and chemo- opposite mechanism. Selenolates can react with molecular 110 prevention as well as a review of some of the important work oxygen to produce superoxide, and the superoxide may push − done in this area.95 99 the cancer cell over an “oxidative cliff” from which the cell 107,111 The selenium-cancer hypothesis perhaps reached its zenith in cannot recover, causing it to undergo apoptosis. Indeed, 1996 with a study led by Clark and Combs that showed that there are clinical trials currently being undertaken to treat supplementation with 200 μg/day of selenium in the form of cancer that take advantage of this chemical reaction with 112,113 selenized yeast led to significant reductions in colon, prostate, selenium using sodium selenite. Selenite and methanese- and lung cancers in a multicenter, double-blind, randomized, leninic acid, common forms of selenium in biology, are also placebo-controlled cancer prevention trial.100 Notably, a very good oxidants. Both can oxidize thiol groups of enzymes, Kaplan−Meier curve showed that selenium supplementation which could help push cancer cells toward apoptosis. Here, we “ ” resulted in significant reductions in total cancer mortality (i.e., see two more faces of selenium, as an antioxidant and an increased survival probability) over a 10 year time period.100 In oxidant. response to this very positive outcome, the National Institutes of Health undertook an extremely large (35 533 men) ■ FORMS OF SELENIUM IN BIOLOGY randomized, placebo-controlled selenium supplementation A very nice short review of the subjects discussed above can be trial. This trial was named the Selenium and Vitamin E Cancer found in ref 114. We now turn to the chemical forms of Prevention Trial (SELECT).101 An important distinction selenium used in biology and the types of chemistry selenium between the earlier trial and the SELECT study was the use can perform. There are multiple chemical forms of selenium of 200 μg/day of L-selenomethionine as the source of selenium used in biology. Eight of these forms are shown in Figure 1. instead of selenized yeast. The study found that there were no The principal form is that of selenocysteine, the 21st amino significant differences in any of the cancer end points. In other acid in the genetic code where it is cotranslationally inserted words, they did not find evidence that supplementation with into the polypeptide chains of selenoproteins.27,28 In addition

823 DOI: 10.1021/acschembio.6b00031 ACS Chem. Biol. 2016, 11, 821−841 ACS Chemical Biology Reviews

in−cytosine dinucleotide in carbon monoxide hydroge- nase,143,144 (ii) Se-methyl-N-acetylselenohexosamine, a seleno- sugar that is the major excretory selenium metabolite found in urine,145,146 (iii) excretory compounds dimethyl selenide (breath) and trimethylselenonium (urine),147,148 (iv) selenite, which can react with glutathione to produce selenodigluta- thione,149 and (vi) Se-methylselenocysteine, which in animals can be converted to methaneselenol by selenocysteine conjugate β-lyases.150,151 A more complete list of biologically important selenocompounds can be found in ref 131. Selenium from methaneselenol can be converted into excretory forms dimethyl selenide and trimethyselenonium, or it can be converted into selenophosphate and put into selenoproteins.152 Ip and Ganther have compiled a considerable amount of data implicating methaneselenol as the form of selenium that is − Figure 1. Different chemical forms of selenium used in biomolecules. anticarcinogenic.153 156 This may be due to redox cycling of (1) Selenocysteine (Sec, U). (2) 5-Methylaminomethyl-2-selenour- this compound that induces apoptosis due to the formation of idine. (3) Selenium, as selenocysteine, is a ligand for the superoxide.157 molybdopterin guanine dinucleotide cofactor of formate dehydrogen- ase. (4) Selenium, as selenocysteine, is a ligand for nickel in [NiFeSe] hydrogenases. (5) Selenium, as selenocysteine, is a putative ligand for ■ WHY SELENIUM? CLUES FROM THE iron in an iron−sulfur cluster. (6) Selenium is found in selenoneine, SELENOCYSTEINE INSERTION MACHINERY AND the selenium analog of ergothioneine. (7) Selenomethionine (SeMet). BIOGEOCHEMISTRY (8) Monoselenophosphate. Selenocysteine, a major form of biological selenium, is a true to being incorporated into proteins, selenium is found in proteinogenic amino acid because it meets the criteria met by nucleic acids, specifically as 5-methylaminomethyl-2-selenour- the other 20 common amino acids: (i) it is encoded by DNA idine (mnm5Se2U), where it is found in the wobble position of and it has its own unique codon (UGA); (ii) it has a unique the anticodon loop in tRNAGlu, tRNALys, and tRNAGln in tRNA that brings the aminoacylated selenocysteine residue to 115−119 the ribosome; (iii) is cotranslationally inserted into the numerous species of bacteria. The selenolate of 158 selenocysteine is a ligand for a number of coenzymes in polypeptide chain at the ribosome. The insertion of bacteria such as in (i) the molybdenum atom of molybdopterin selenocysteine is much more complicated than cysteine, and − guanine dinucleotide in formate dehydrogenase,120 124 (ii) the the other 19 proteinogenic amino acids as shown in Figure 2. nickel atom of NiFeSe hydrogenases,125,126 and (iii) iron in a putative iron−sulfur cluster in the methionine sulfoxide reductase from Metridium senile.127 Selenium is also found as the analog of ergothioneine in tuna, named selenoneine.128 This novel selenium biomolecule may be involved in mercury detoxification in fish.129 A methylated form is present in humans, but its function is not known.130 A very important dietary source of selenium is selenomethionine. Plants convert inorganic forms of selenium into selenomethionine, which is then converted into selenocysteine in animals via the trans- sulfuration pathway (reviewed in ref 131). Selenocysteine produced by this pathway is then converted into hydrogen selenide, which combines with ATP to produce selenophos- − phate132 134 in a reaction catalyzed by selenophosphate − synthetase.135 137 In bacteria (e.g., E. coli), selenophosphate is used as the nucleophile to attack the carbon−carbon double bond of dehydroalanyl-tRNA[Ser]Sec, yielding selenocysteyl- 138 Figure 2. Eukaryotic Sec-insertion machinery. In eukaryotes, tRNA[Ser]Sec. This specialized tRNA brings selenocysteine phosphoseryl-tRNASec kinase (PSTK) phosphorylates aminoacylated to the ribosome where it is incorporated into selenocysteine- serine to form O-phosphoseryl-tRNA. Sep (O-phosphoserine) containing proteins. Selenocysteyl-tRNA[Ser]Sec is also used tRNA:Sec (selenocysteine) tRNA synthase, abbreviated as SepSecS, to synthesize selenoproteins in eukaryotes, but a dehydroala- then converts O-phosphoseryl-tRNA to Sec-tRNA, using selenophos- nine-containing tRNA is not used as the acceptor for the attack phate as the nucleophile to displace the phosphate group. by selenophosphate. Instead, a phosphate group on O- Selenophosphate is produced by selenophosphate synthetase (SPS2). phosphoseryl-tRNA[Ser]Sec is displaced by selenophosphate The Sec-tRNA is then bound by a special eukaryotic elongation factor 139,140 (EFSec), and recruited to the ribosome at a UGA codon by the use of to produce selenocysteyl-tRNA[Ser]Sec. Alliums such as ′ garlic and onions tend to concentrate inorganic selenium in Se- a special stem-loop structure in the 3 -untranslated region of the 141 mRNA (SECIS element) and a SECIS binding protein (SBP2). The methylselenocysteine (not shown), which is converted into fi 161−165 β details of Sec-insertion were rst characterized in bacteria, and selenophosphate by a pathway that utilizes selenocysteine - it should be noted that there are substantial differences in the Sec- 142 − lyase and methaneselenol demethylase. insertion machineries of prokaryotes and eukaryotes.166 173 We also Other forms of selenium in biology not shown in Figure 1 note that eukaryotes require additional accessory proteins for Sec- are (i) selenocysteine as a ligand for the related molybdopter- insertion not depicted here.172,173

824 DOI: 10.1021/acschembio.6b00031 ACS Chem. Biol. 2016, 11, 821−841 ACS Chemical Biology Reviews

The codon for selenocysteine is UGA, normally a stop Msr reduces either free methionine sulfoxide or peptidyl codon. This UGA stop codon must be recoded as a sense methionine sulfoxide to methionine. There are four human codon for selenocysteine, and this recoding process requires an Msr’s, only one of which contains Sec.181 The Sec-containing elaborate apparatus involving numerous accessory proteins and Msr (MsrB1) is stereospecific for methionine-R-sulfoxide. The a special signal in the 3′-untranslated region of the mRNA of reduction of methionine-R-sulfoxide on actin promotes actin − the selenoprotein.159 169 The details of the selenocysteine- polymerization.182 Figure 3 shows the chemical processes insertion machinery are reviewed in refs 170−173. Second, it is extremely costly in terms of the cellular energy currency, ATP, to insert selenocysteine into a protein. It costs ∼25 mol of ATP to insert 1 mol of cysteine into a protein.174 Given the multiple accessory proteins required to insert selenocysteine into a protein, the biosynthetic costs of a selenoprotein must be considerably more than that of a cysteine-containing protein. A third consideration for biology is the geological distribution of selenium in the Earth’s crust, as sulfur is much more abundant relative to selenium. This ratio is estimated to be as low as 6000:1175 and as high as 55 500:1.176 In addition, selenium is not distributed evenly over the Earth’s crust.177 For example, there are both seleniferous and selenium deficient areas of China and the American west. Selenium deficient soils are especially consequential in China, New Zealand, and Finland.83 This means that animal life on land does not have equal access to this essential nutrient. Considering the three factors mentioned above, it is natural to ask the question, “why did nature choose selenium?” The answer of the authors is that selenium must be able to perform some chemical function necessary for biology that sulfur is not very good at. In other words, there is a very large chemical difference between the two elements. If the chemical differences between selenium and sulfur were small, then nature could abandon the use of selenium and not be dependent upon the factors listed above and use sulfur instead. The catalytic activity of the sulfur-containing enzyme may (or may not!) be lower Figure 3. Chemical processes mediated by Sec-containing enzymes (Enz-Se−, selenocysteine moiety of enzyme; GS−, glutathione; Trx, than that of the selenium-containing ortholog, but nature could − compensate by making more of the sulfur version of the thioredoxin: B+ H, a proton donor). enzyme if needed. In the following sections, we review the chemical differences between sulfur and selenium. shown to be, or likely to be, involved in the Sec-catalyzed reactions. In each case, the oxidized selenium (Enz-Sec-SeOH, ■ SELENIUM-CONTAINING ENZYMES Enz-Sec-SeI, or Enz-Sec-Se-SR) will be reduced back to Sec-Se− While selenium is found in a variety of biomolecules as noted by GSH or another reductant in a reaction that involves above, many of its important biological functions are due to its nucleophilic attack at selenium. use in proteins, and this is where our discussion will be focused. In each of these reactions the selenolate initially acts as a Most selenium-containing enzymes make use of the nucleo- nucleophile (attacking an O−O, I−C, S−S, or sulfinyl bond); philic and reducing properties of the selenolate (Sec-Se−) form the selenium of the formed selenenic acid derivative then acts of a selenocysteine to perform redox reactions. After being as an electrophile, being attacked by a thiolate, and the catalytic oxidized, the resulting selenenic acid (Sec-SeOH) oxidation cycle is completed by a reaction where selenolate behaves as a state is typically returned to selenolate by reduction with leaving group in the final reduction step of the catalytic cycle. It glutathione or a resolving Cys residue on the enzyme. The best can be shown that selenium is likely to be more effective than studied selenoenzymes are the glutathione peroxidases (Gpx), the sulfur analog as a nucleophile, or as a leaving group, but not iodothyronine deiodinases (DIO), thioredoxin reductases dramatically so. Typical Se/S rate ratios are 1 or 2 orders of (TrxR), and methionine sulfoxide reductases (Msr). There magnitude (vide infra). It should be pointed out that while are eight Gpx isozymes in humans, five of which contain selenocysteine is found in the three major divisions of life, selenium,178 and they are an essential part of the system that archeabacteria, eubacteria, and eukaryotes, there are entire scavenges hydroperoxides and hydrogen peroxide to prevent classes of organisms that lack selenocysteine (Lepidoptera for oxidative damage. There are three human Sec-containing example) where transformations such as the above are 183,184 iodothyronine deiodinases179 found in the thyroid gland and performed by cysteine. other tissues, and they function to reduce the aryl iodide bonds − ■ CHEMICAL PROPERTY COMPARISONS BETWEEN of thyroxine (T4) and triiodothyronine (T3)toaC H. There are three human Sec-containing thioredoxin reductases: a SULFUR AND SELENIUM cystolic form, a mitochondrial form, and a specialized testes- Even long before the interesting chemical and biological specific enzyme.180 TrxR’s help to maintain thiol−disulfide question “why selenium?” was raised, comparison of the redox homeostasis via reduction of the small protein properties of sulfur compounds and their selenium analogs had thioredoxin (Trx). Depending on the form of the enzyme, drawn the attention of many chemists interested in selenium,

825 DOI: 10.1021/acschembio.6b00031 ACS Chem. Biol. 2016, 11, 821−841 ACS Chemical Biology Reviews

Figure 4. Structures and oxidation numbers of sulfur and selenium compounds that result from two-electron oxidation reactions. Arrows show the conversion pathways between oxidation states. The open circle represents carbon, and the number inside the circle represents the oxidation number of sulfur or selenium that it is attached to. The magenta X denotes a slow reaction. The [O] symbol represents a two-electron oxidant. often with the intent of identifying chemical properties that thiol state at neutral pH, whereas selenocysteine is almost fully might make the selenium compounds useful. In many respects ionized to a selenolate. sulfur and selenium have very similar physical and chemical properties:10 they share all of the same oxidation states and functional group types (Figure 4), and their structures are often so similar that analogous compounds can easily cocrystallize. Here, we are interested in the significant chemical differences between the two chalcogens that might justify the metabolic cost of utilizing selenium. We will summarize some of those that have relevance to reactions of biological interest. Many of the significant differences between selenium and sulfur are a consequence of the usual changes on going from lighter to heavier elements. Heavier elements are more Figure 6. Comparison of selenol and thiol pKa values. polarizable (“softer”) than lighter ones, and this usually leads to more rapid electrophilic and nucleophilic substitutions at the element. Most bond strengths to selenium are weaker than ■ NUCLEOPHILICITY those to sulfur, and this results in substantially faster bond- In spite of their lower basicity, selenolate ions are more breaking reactions. The weaker bonds to selenium mean that * − nucleophilic by roughly 1 order of magnitude than thiolates, the sigma orbital of the Se X bond is lower in energy than presumably a consequence of the higher polarizability of that of a S−X bond, hence more reactive as an electron 189,190 selenium (Figure 7). This is true for SN2 substitutions as acceptor. Thus, all oxidation states of selenium are much more well as for aromatic substitutions.191 In protic solvents the electrophilic compared to sulfur analogs. It is also generally weaker hydrogen bond acceptor properties of selenolates vs observed that higher oxidation states become relatively less thiolates contribute to higher nucleophilicity. Selenides are also stable for the heavier elements, and this is also true for selenium more nucleophilic than sulfides.189 vs sulfur. Heavier elements are also more tolerant of hypervalent bonding situations. The single most important use of selenium by synthetic organic chemists, the selenoxide elimination (Figure 5) to form alkenes, occurs at ca. 100 °C milder temperatures and is ca. 100 000 times as fast as related sulfoxide eliminations.185,186

■ ACIDITY The weaker bond to hydrogen, together with the increase in size and polarizability of the heavier atom, results in substantially lower basicity of selenolate versus thiolate by 3− 187,188 4pKa units (Figure 6). Thus, cysteine is largely in the

Figure 7. Comparison of selenium and sulfur nucleophilicities in SN2 substitutions using phenyl selenolate/thiolate,189 thioselenolate/ thiocyanate,190 dimethyl selenide/sulfide with methyl iodide,189 and phenyl selenolate/thiolate with 4-nitro-1-bromofuran.191 Selenocys- Figure 5. Relative rates of selenoxide185 and sulfoxide186 syn- teine is also more nucleophilic then cysteine in a substitution at an acyl eliminations. Y = S, or Se, here, and throughout the text. carbon.192

826 DOI: 10.1021/acschembio.6b00031 ACS Chem. Biol. 2016, 11, 821−841 ACS Chemical Biology Reviews

There is a much more significant difference in nucleophilicity example in Figure 9b ,the selenosulfide (also referred to as a between the two chalcogens at physiological pH, as selenols are selenenylsulfide) is only 3-fold more reactive than the completely converted to selenolates, whereas thiols are only disulfide.196 This relatively small number may in part be due slightly ionized. Since the selenolates/thiolates are almost to stronger hydrogen bonding of the more basic thiolate at the certainly the active nucleophile, selenolates have the double transition state. advantage of both higher intrinsic nucleophilicity and a much higher fraction of the active form. In direct comparisons, this ■ HYPERVALENCY leads to ∼2 orders of magnitude higher reactivity for selenolates One of the few bonding situations where Se−X bonds are versus thiols around pH 7. Some examples of this increased stronger than S−X bonds occurs in hypervalent compounds, reactivity using selenocystamine (9) and cystamine (10) are i.e., where the number of bonds plus lone pairs is greater than shown in Figure 8. While nature may take advantage of this that allowed by the Lewis octet rule. Thus, selenuranes (R4Se) form more easily than sulfuranes (R S) and are much more 4 − − stable. The same is true for the ate complexes R3Se and R3S . − → A computation of the energy of association (Me2Y+Me − − − Me3Y )is 0.3 kcal/mol for Y = S and 13.1 kcal/mol for Y = Se.198 This effect has complex origins, but contributing factors are smaller steric effects due to the longer bonds to selenium and a lower LUMO sigma* orbital which leads to a more favorable three-center four-electron hypervalent bonding situation. This greater tolerance for hypervalency (also shared by the neighboring element pairs Cl/Br and P/As, and which continues with the heavier elements Te, I, and Sb) can be seen in many contexts. For example, the hypervalent sulfurane 12-S decomposes at −67 °C with a half-life of 46 min, while the selenurane 12-Se has to be “heated” to 0 °C before the decomposition rate is comparable, corresponding to a differ- ence in activation energy of 2.9 kcal/mol.199 The addition Figure 8. Comparison of nucleophilic substitution by selenolate/ fi fi 196 product of chlorine and dialkyl sul des (e.g., the Corey-Kim thiolate on a disul de and a peroxide. These reactions were done reagent200) is an ionic structure 13, whereas that of dialkyl near neutral pH, where the cystamine (10) is largely in the SH form. 201 When corrected to pH 10,15 the relative rates are much smaller. selenides is covalent (14). Another occurrence of stronger Se−X bonds occurs in bonding to metals. For example, Hg−Se − 202 ff bonds are stronger than Hg S bonds. di erence in nucleophilicity at physiological pH, the pKa values of the nucleophilic cysteines in the context of a protein microenvironment can be greatly perturbed as evidenced by the pKa values of the active site Cys residues of papain, caricain, and ficin, which are 3.3, 2.9 and 2.5, respectively.193 As such, nature may be able to increase the nucleophilicity of sulfur so as to minimize this difference at physiological pH,194 and it was concluded that selenium is not a “chemical necessity” in TrxR.195 ■ LEAVING GROUP ABILITY Since selenolate is less basic than thiolate, selenolates are usually better leaving groups. As shown in Figure 9a, the selenol ■ ELECTROPHILICITY ester 11 (Y = Se) decomposes to ketene 180-fold faster than 197 The greater tolerance for hypervalency of selenium has an the thiol ester 11-S, while in the biologically more relevant important consequence, that nucleophilic attack on selenium (which typically forms or passes through hypervalent − intermediates such as R4Se or R3Se ) usually occurs much more rapidly than at sulfur, since the intermediate selenium compounds are lower in energy than sulfur analogs.203 Thus, selenium compounds of all types are much better electrophiles than sulfur analogs, and this can be seen in various contexts. For example, bis(phenylthio)methane 15 is deprotonated with n-BuLi,204 whereas the selenium analog 16 is attacked at selenium.205

Figure 9. Comparison of selenolate/thiolate leaving group abilities: In a closely related comparison, the rate of Ph/Tolyl (a) Ketene formation from an acyl selenide/sulfide. (b) Selenosulfide/ exchange of diphenyl selenide (17-Se) with tolyllithium is >2 × disulfide exchange with thiolate as nucleophile. 104 times as fast as with diphenyl sulfide (17-S).206

827 DOI: 10.1021/acschembio.6b00031 ACS Chem. Biol. 2016, 11, 821−841 ACS Chemical Biology Reviews

One of the consequences of the longer bond length of heavier elements is a reduced ability to form π-bonds of all types as introduced above. This means that even though a Nucleophilic substitutions at a selenenyl halide such as 18-Se chalcogen-oxygen double bond is commonly depicted for is substantially faster than at the analogous sulfenyl center, with convenience (as in Figure 4), a much better representation of kSe/kS ranging from 6000 for a dithiocarbamate to 150 for 207 the electronic structure of these compounds, particularly for cyanide. Similarly, nucleophilic attack of cyanide on selenium, is given in Figure 11. PhSeSO2Ar is 5 orders of magnitude faster than on 208 PhSSO2Ar.

Figure 11. Dipolar nature of chalcogen-oxygen bonds. Y = S, Se. ■ COMBINATION OF NUCLEOPHILICITY, ELECTROPHILICITY, AND LEAVING GROUP Presumably because of stronger back-donation of the lone- pair electrons on oxygen to acceptor orbitals (sigma* and ABILITY possibly d orbitals) on sulfur compared to selenium, the Y−O In a very careful study of the pH-dependence of the degenerate dative bonds in selenoxides, selenones, seleninic acids, and exchange of cystamine (10) with cysteamine and selenocyst- selenonic acids are weaker for selenium, have substantially more amine (9) with selenocysteamine, all three effects are operating dipolar character, and are relatively less favored than for sulfur. in the same direction in the case of the selenolate/diselenide This can be seen in many property changes when S/Se exchange reaction: the higher nucleophilicity of selenolate at comparisons are made. For example, alkyl selenones are physiological pH, the better leaving group ability of selenolate, excellent alkylating agents,215,216 while sulfones are completely and the stronger intrinsic electrophilicity of the center selenium unreactive. atom. Using dynamic NMR techniques (line broadening for The differences in electronic structure noted above in the selenium, saturation transfer for sulfur), the selenolate/ chalcogen oxides leads to large differences in their chemical diselenide exchange reaction was measured to be 107 times as properties. For example, dimethyl selenoxide (pK of conjugate 209 a fast as that of the thiol/disulfide exchange reaction at pH 7. acid 2.55217) is substantially more basic than dimethyl sulfoxide − 218 π (pKa of conjugate acid 1.54 ). Thus, in an acid-catalyzed ■ WEAKER -BONDING reaction at a given pH, selenoxides will have ca. 104 as high a The larger size of selenium compared to sulfur (atomic radius concentration of the reactive protonated selenoxide compared of 115 pm compared to 100 pm for sulfur) results in larger to the protonated sulfoxide. This would already result in hybridized orbitals, and this plus the longer bond length leads dramatically higher reactivity, but in addition the selenium to weaker π overlap. One consequence of this is that bears more positive charge and is inherently more electrophilic selenoesters are much less stabilized than thioesters by than sulfur, combining to give very much higher rates of resonance with the carbonyl group.210 As shown in Figure nucleophilic attack at selenium. 10, the acyl transfer between selenocystamine (9)and Another example of the enhanced reactivity of the Se-oxide relative to an S-oxide is the racemization of selenoxides compared to sulfoxides. The acid-catalyzed racemization of sulfoxides is a slow and difficult process. Selenoxides racemize many orders of magnitude faster than the corresponding sulfoxides. The data for the selenoxide inversion in Figure 12 were obtained from dynamic NMR measurements, whereas the sulfoxide data were obtained from the epimerization of one diastereomer to the other. The inversions proceed by different Figure 10. Acyl-transfer equilibrium between a thiol ester and a fi + selenol ester.210 mechanisms; the selenoxide is rst order in [H ] independent of whether HCl or H2SO4 was used, so it follows path A. The sulfoxide, on the other hand, was too slow to measure with H2SO4. With HCl as the acid, the sulfoxide inversion rate can cystamine (10) strongly favors the thioester. Both nature and be measured but is second order in HCl, so it proceeds by a chemists have taken advantage of the high reactivity of mechanism than involves the formation of R2SCl2 (path B). A selenoesters as acyl transfer reagents. Selenoesters have been − direct comparison of the rates was thus not possible. However, 211 213 13 used to catalyze native chemical ligation reactions, and one can estimate that kSe/kS is minimally on the order of 10 at selenoprotein K uses its Sec residue to form a selenoester to pH 0, of which roughly 104 can be ascribed to the higher catalyze acyl-transfer of a palmitoyl group to a calcium basicity of the selenoxides, and 109 to the higher electrophilicity 214 channel. of the protonated selenoxides toward attack by water.219 A common effect seen in most heavier−lighter element ■ REDOX PROPERTIES comparisons is a stronger preference for lower oxidation states The greatest divergence between selenium and sulfur chemistry in the heavier elements. Selenium is no exception. This effect occurs in the redox reactions of the two elements. This is true can be seen directly in several contexts. For example, for both two-electron and one-electron processes. We will selenoxides are able to oxidize sulfides to sulfoxides.220 A begin our discussion with two-electron oxidation reactions. semiquantitative measure of this effect is provided by the

828 DOI: 10.1021/acschembio.6b00031 ACS Chem. Biol. 2016, 11, 821−841 ACS Chemical Biology Reviews

° Figure 12. Rates of acid-catalyzed inversion of sulfoxides and selenoxides in D2Oat25 C.

[2,3]sigmatropic rearrangement equilibrium between allyl ester of a divalent selenium species, which rapidly hydrolyzes to sulfoxides and selenoxides, where the equilibrium is slightly the allyl alcohol.223 on the sulfoxide side for sulfur and strongly on the selenenate The difference in electronic structure of the chalcogen oxides ester for selenium. In the specific case shown in Figure 13, this also leads to different rates of oxidation and reduction, first introduced in Figure 4. Although the first oxidation of sulfides/ selenides to sulfoxides/selenoxides is fairly comparable, with selenium being slightly more reactive, the second oxidation is very much more difficult for selenoxides. This is in part a consequence of the much higher dipolar character of the Se−O bond, resulting in lower nucleophilicity of the lone pair on Se. In fact, oxidation of sulfides to sulfoxides requires a delicate touch to avoid overoxidation to the sulfone because the second oxidation is only a little slower than the first. In comparison, any reasonable oxidants can be used with selenides, since the second oxidation to selenones is much slower. Another consequence of the higher dipolar character of selenoxides versus sulfoxides is that the lone pair on selenium is less nucleophilic than the lone pair on sulfur. Thus, sodium benzenesulfinate anion alkylates on sulfur to give the sulfone 19 (this is a standard synthetic method for the synthesis of sulfones), whereas the seleninate anion alkylates on oxygen to Figure 13. Equilibrium constants between selenoxide-selenenate (−80 give a seleninate ester 20.224 ° − ° 221 C) and sulfoxide-sulfenate in CD2Cl2 at 30 C. shift in equilibrium was approximately 13 kcal/mol (the two equilibria are not strictly comparable since they were measured at different temperatures). This is one of the largest S/Se The behavior of these reagents with dienes is similarly divergences reported.221 enlightening as SO2 forms the cyclic sulfone 21, whereas SeO2 forms the cyclic seleninate ester 22.225 It is believed that the Related to this is the divergent behavior of sulfur dioxide and fi selenium dioxide. SO is considered a mild reducing agent, SO2 reaction also proceeds through a cyclic sul nate ester, but 2 this rapidly rearranges to the more stable sulfone.226 whereas SeO2 is a mild oxidizing agent (Riley oxidation). Both reagents react with alkenes to form intermediate allylsulfinic and allylseleninic acids (Figure 14). However, the allylsulfinic 222 acid simply reverts to the alkene and SO2, maintaining the higher oxidation state at sulfur, whereas the allylseleninic acid undergoes [2,3]sigmatropic rearrangement to form the allyl

The redox reactions of thiol/selenols follow a pattern similar to that of the sulfides/selenides. The redox potential of selenols is much lower compared to that of thiols (−381 mV with DTT as the reductant vs −179 mV with glutathione as the reductant in the context of a glutaredoxin peptide fragment using either 227 Figure 14. Divergent behavior of SO2 and SeO2 toward alkenes. Sec or Cys). This means that the equilibrium constant for

829 DOI: 10.1021/acschembio.6b00031 ACS Chem. Biol. 2016, 11, 821−841 ACS Chemical Biology Reviews the oxidation of a diselenol to a diselenide greatly favors the diselenide. In comparison, the equilibrium constant for the dithiol/disulfide pair was 600-fold lower in this same experiment and favors the formation of the dithiol. A similar experiment conducted not on a peptide fragment but in the context of a folded protein (glutaredoxin-3) showed that the ratio of equilibrium constants was 8500:1 in favor of the diselenide.228 This experimental system also showed that the rate of formation of the diselenide was much faster than the rate of formation of the disulfide. While the examples above show that incorporation of Sec in place of Cys results in a very Figure 15. Probable mechanism of the reduction of seleninic acids by large change in redox potential in the context of a peptide or 245 protein microenvironment, Rozovsky and co-workers have thiols. shown that insertion of Sec does not necessarily confer a large 229 change in redox potential in the context of a protein. They Benzeneseleninic acid is reduced extremely rapidly by thiols; in fi thusly note that the lower redox potential of a selenosul de one experiment, i-Pr-SH reacted with PhSeO2H in under 30 s bond may not be the raison d’etre for the use of Sec. at −90 °C (Reich, H. J., Kolonko, K. J., unpublished results), Oxidation of a selenol to a selenenic acid is presumably faster whereas PhSO2H does not detectably react with thiols in weeks than the same oxidation of a thiol to a sulfenic acid, but there is at RT.243 The rate of reaction of the seleninic acid form of the very little data available for these compounds as they are synthetic selenoenzyme selenosubtilisin244 with an aromatic unstable and undergo rapid disproportionation to diselenides or thiol (3-carboxy-4-nitro-benzenethiol) gave an apparent second become further oxidized. There are some examples of the order rate constant of 1.8 × 104 M−1 s−1 (pH 5.0), while that of synthesis of stable sulfenic/selenenic acids that make use of an alkaneseleninic acid was ∼200-fold faster (3.3 × 106 M−1 bulky substituents to sterically crowd the chalcogen oxide to s−1).242 These fast rate constants mean the lifetime of a 230−234 protect it from condensation/disproportionation, but seleninic acid is on the order of seconds when the there is only one report that makes a direct comparison of the concentration of thiol is in the millimolar range. From such 233 chemical properties of the two so far as we are aware. A observations, one can estimate that the rate of reaction of thiols significant finding of this work was that the bond dissociation with seleninic acids is at least 106 faster than their reaction with energy (BDE) of the O−H bond in a selenenic acid (81.2 kcal/ sulfinic acids. mol) is higher than a Se−H bond (78.9 kcal/mol). Moreover, As discussed above, the reduction of seleninic acid to the −2 the opposite trend was reported for sulfur; the BDE for the O− and 0 oxidation states is very fast in comparison to the same H bond in a sulfenic acid was reported as 68.6 kcal/mol, which reduction of sulfinic acids. This represents a point of large is weaker than a S−H bond (87.6 kcal/mol). This greater divergence in the chemical reactivity of the respective strength of the O−H bond in the selenenic acid led to a slower chalcogens. The rate of oxidation of seleninic acids to selenonic rate of reaction with a peroxyl radical compared to the sulfenic acids is also a point of divergence in comparison to the acid.233 oxidation of sulfinic acids to sulfonic acids (noted by Gancarz Oxidation of selenenic/sulfenic acid results in formation of and Kice238), with the latter being ∼2200-fold faster. At pH 7.1, seleninic/sulfinic acids. The chemical comparison between the rate of oxidation of benzenesulfinic acid is 2.7 × 10−3 M−1 fi −1 −6 −1 −1 seleninic and sul nic acids is analogous to that between SeO2 s , while that of benzeneseleninic acid is 1.2 × 10 M s  243 and SO2, or between their hydrates, selenious acid (O using H O as the oxidant.  2 2 Se(OH)2) and sulfurous acid (O S(OH)2). That is, seleninic acids are weak oxidizing agents (in fact seleninic anhydride has ■ ONE-ELECTRON REDOX REACTIONS been proposed as a useful oxidant for many functional Figure 16 shows a pair of reactions in which the one involving 235−237 groups ), whereas sulfinic acids are weak reducing agents. selenium is much slower than the sulfur analog. In a very In a striking example of this (eq 1), Kice reported that significant paper, Koppenol and co-workers showed that when PhSeO2H and PhSO2H react with each other to reduce the a thiyl radical is formed in a peptide, Cα−H abstraction is 238 former and oxidize the latter (eq 1). greatly favored, while the same reaction of a selanyl radical is slow.15,246 The significance of this will be discussed in the following section. The one-electron redox potential of the two

Seleninic acids are weaker acids than sulfinic acids by about 2 239 240 pKa units (PhSeO2H 4.79, PhSO2H 2.76 ), a consequence of the higher electronegativity and better π-acceptor properties of sulfur versus selenium. No information on the basicity of + seleninic acids could be found (pKa of PhSe(OH)2 ). However, one can predict that they would be substantially more basic than sulfinic acids (in analogy with selenoxides and sulfoxides), and thus acid catalyzed substitutions at selenium would also be greatly accelerated. This is indeed what is observed. The reduction of seleninic acids by thiols is extremely fast 241−243 and may be biochemically important. This reaction Figure 16. Comparison of the rates of intramolecular hydrogen probably involves the sequence of steps outlined in Figure 15. abstraction by thiyl and selanyl radicals.246

830 DOI: 10.1021/acschembio.6b00031 ACS Chem. Biol. 2016, 11, 821−841 ACS Chemical Biology Reviews

Figure 17. Peroxidase cycle for Sec- and Cys-peroxidases. Both types have a nucleophilic selenolate/thiolate that reacts with an oxidant to form a selenenic/sulfenic acid, which is then resolved by another thiol to form a mixed selenosulfide/disulfide. The active enzyme is regenerated by the addition of a second mole of thiol. The addition of selenium to an enzyme imparts peroxidase activity because a selenolate is a good nucleophile, allowing for reaction with an oxidant, and the Se oxide is an excellent electrophile that allows it to be attacked by a thiol to release water. In the mechanism, a selenolate is also a leaving group. Chemically, sulfur is less reactive with respect to all three of these properties. However, Cys- peroxidases can be highly efficient catalysts presumably because the protein microenvironment can tune the reactivity of sulfur to compensate for the 261 ff − absence of selenium using a combination of these properties. One large di erence is the inability of the Cys-SO2 form of the Cys-peroxidases to − return to the active catalytic pathway by reduction with exogenous thiol, while reduction of the Sec-SeO2 form is possible for Sec-peroxidases as 242 − shown by the work of Hilvert et al. Peroxiredoxin is one exception to this rule, but it requires a special repair enzyme to reduce the Cys-SO2 form 262 − of the enzyme, while the reduction of Sec-SeO2 of Sec-peroxidases can be easily reduced by ascorbate and glutathione. chalcogens is also different; the RS•, RSH/H+ couple has a the redox properties of selenium more closely resemble a redox potential of 0.92 V, while the RSe•, RSeH/H+ couple has transition metal in comparison to sulfur. a potential of 0.43 V.246 This difference in redox potential The gain of peroxidase activity conferred by selenium led to means that a thiyl radical is capable of oxidizing tyrosine and the hypothesis that selenium confers resistance to irreversible tryptophan residues to form the corresponding amino acid oxidation and inactivation due to the difference in redox radical, while the selanyl radical will not perform the same chemistry between selenium and sulfur shown in Figure 4.12,263 oxidation.246 This hypothesis is a late manifestation of an idea that has been expressed in other forms, or went unrecognized by researchers ■ WHY SELENIUM? RATE ADVANTAGE VERSUS who did not realize the significance of their data. This REDOX ADVANTAGE hypothesis is reviewed below. Chaudierè and co-workers were the first to note that Sec may A seemingly logical conclusion to the question of “why “ ”249 ” fi have evolved in an enzyme to prevent self inactivation. selenium? was arrived at relatively early in the eld by This observation was made by studying the Cys-mutant of replacement of the catalytic Sec residue of several Sec- 247−250 Gpx1, which had much lower activity than the Sec-containing containing enzymes with a Cys residue. The replace- Gpx1 but was readily inactivated in the presence of its substrate, ment of Se with S resulted in mutant enzymes with greatly ̀ H2O2, and organic hydroperoxides. Chaudiere hypothesized impaired catalytic activity. Conversely, replacement of S with Se that the Cys-mutant Gpx1 was inactivated due to oxidation of in Cys-containing enzymes resulted in enhanced catalytic − β 228,251−253 “ the peroxidatic Cys residue to Cys-SO2 with possible - activity. Thus, one answer to the question of why elimination to form dehydroalanine. This hypothesis was selenium?” is that the use of Se in oxidoreductases of the type perhaps validated several decades later by Bellelli and co- discussed here provides a catalytic advantage to the enzyme. workers who crystallized the Cys-mutant of Sec-containing However, Stadtman made an observation that is often 264 Gpx4 from Schistosoma mansoni. This X-ray crystal structure overlooked in the study of selenium in biology. She found of the Gpx4 mutant showed the presence of a sulfonic acid that the catalytic activity of the Cys-containing selenophosphate residue (see Figure 18).264 The Cys-mutant of S. mansoni Gpx4 synthetase from E. coli had higher specific activity than the Sec- was inactive at all stages of purification, even though reducing containing enzyme from H. influenzae.254 She noted that “these agents were present. One interpretation of these data that results taken together suggest a role for selenocysteine of H. matches Chaudierè’s observation is that the Cys-mutant influenzae that is not catalytic.” Kanzok and co-workers also enzyme was able to react with the oxidant, but the S-oxide concluded that the use of selenium was not required in the that formed was not electrophilic enough to be resolved back to active site of TrxR because a Cys-ortholog enzyme had comparable activity toward its cognate substrate.195 If the use of Sec and other forms of selenium is not entirely related to enhanced catalytic function relative to sulfur, then a second possibility is related to selenium’s advantageous redox proper- ties discussed above. Besides the gain of increased catalytic activity of most reaction reaction types upon Se for S substitution in enzymes, an additional gain of function that occurs is a gain of peroxidase − activity.244,255 260 This gain of function fits well with its superior redox properties relative to sulfur described above. fi Figure 18. (A) A close-in view of the catalytic triad of S. mansoni Gpx4 The functional de nition of a peroxidase is outlined in Figure consisting of Cys43 oxidized to a sulfonic acid, Gln78, and Trp132 17. Selenium confers peroxidase activity to an enzyme because (PDB 2v1m). (B) A close-in view of the catalytic triad of it is both a good nucleophile and a good electrophile. This selenosubtilisin showing Sec221 in the seleninic acid form along property allows it to easily cycle between reduced and oxidized with Asp32 and His64 (PDB 1sel). The selenium atom is colored states without becoming permanently oxidized. In this respect, magenta.

831 DOI: 10.1021/acschembio.6b00031 ACS Chem. Biol. 2016, 11, 821−841 ACS Chemical Biology Reviews the active form of the enzyme. This results in overoxidation and inactivation of the Cys residue of the mutant enzyme. Very recently, Ursini and co-workers presented evidence that Sec-containing rat Gpx4 avoids overoxidation of the Sec residue by using a backbone nitrogen to attack the selenenic acid intermediate to form an eight-membered ring selenenamide when glutathione becomes limiting.265 Formation of the selenenamide is thought to be a type of safety mechanism that prevents overoxidation and inactivation of the Sec-Gpx. The analogous sulfenamide could not be detected in the Cys- 265 Figure 19. Reaction of thiolato or selenolato nickel complexes with mutant rat Gpx4. Instead, the peroxidatic Cys residue of the 272 mutant became irreversibly oxidized to the sulfonic acid form. molecular oxygen. Only the sulfanato complex resulted in oxidation. The experimental evidence of selenenamide formation in the native protein fits well with earlier work by Reich and co- complex. In striking contrast, the selenolato complex resisted workers who synthesized model compound 23, which became oxidation. In follow up work, Maroney comments that oxidized to both the selenenamide 24 and seleninamide 25 in substitution of selenium for sulfur in the [NiFeSe]-hydrogenase 266 the presence of an oxidant. Selenenamides have the from D. baculatum (a strict anaerobe) makes “...the enzyme interesting property of being significantly more basic (3.4 pK more stable to oxidation and may be isolated in air in a state units) than the corresponding sulfenamides.267 This property that does not require reductive activation.”273 This view of should greatly enhance opening of the ring by an attacking selenium in an enzyme strongly diverges from the earliest view thiol. This is yet another large chemical difference between of the use of selenium in an enzyme expressed by Böck: ‘‘UGA sulfur and selenium. was originally a sense codon for Sec in the anaerobic world, perhaps 2 to 3 billion years ago, and after introduction of oxygen into the biosphere this highly oxidizable amino acid could be maintained only in anaerobic organisms or in aerobic systems which evolved special protective mechanisms.”162 Based on the results of Maroney, it is tempting to speculate on the exact opposite scenario: The use of Sec in proteins This story continues in 1993 when Hilvert and co-workers reached a maximum during the oxygen peak of the Permian discovered that selenosubtilisin, a semisynthetic selenoen- period and then declined as the amount of oxygen in the zyme,244 was not inactivated by oxidation to the Enz-Sec- atmosphere declined. − SeO2 form as the enzyme could regain activity by the addition In a followup to the work by Maroney more than a decade of two additional moles of thiol.242 There is very strong later, Armstrong and co-workers performed a study of the evidence that selenosubtilisin is capable of existing in the Enz- [NiFeSe]-hydrogenase from D. baculatum using protein film − 268 274 Sec-SeO2 form as supported both by X-ray crystallography voltammetry. The goal of the study was to more completely (see Figure 18B) and 77Se NMR spectroscopy.269 At the time, characterize the A and B states of the enzyme, with the A state the importance of this discovery as it relates to irreversible corresponding to an “Unready” form (formed upon reaction “ ” oxidative inactivation was unclear since little was then known with O2), while the B state corresponds to the Ready form. about the existence of the corresponding sulfinic acid form in The “Ready” and “Unready” states are so named because of proteins. This is not the only example of the seleninic acid form their kinetic characteristics with respect to reactivation of the in an enzyme. Branlant and co-workers converted glyceralde- enzyme (slow and fast, respectively). An important finding of hyde-3-phosphate dehydrogenase (GAPDH) into a selenoen- this work was that the enzyme was capable of hydrogenase “ ” zyme by producing the protein in a cysteine auxotroph and activity in the presence of 1% O2, and the Unready, A-form of replacing cysteine in the media with selenocysteine.256 the enzyme was reactivated 100-fold faster compared to the Replacement of Cys in GAPDH with Sec results in a gain of nonselenium containing A-form of the [NiFe]-hydrogenase peroxidase activity, but more importantly it showed that the from A. vinosum. Armstrong contemplated that the inactive A- − enzyme existed in the Enz-Sec-SeO2 form (by the use of mass form is due to the formation of a Se-oxide that is rapidly spectrometry) without resulting in inactivation.256 It is known, reduced to the active form of the enzyme.274 − however, that oxidation of GAPDH to the Enz-Cys-SO2 form The role of selenium in conferring oxygen tolerance to results in permanent oxidative inactivation.270 While these [NiFeSe]-hydrogenases was further addressed by Matias and examples show that the seleninic acid form of a selenoenzyme co-workers who solved the X-ray crystal structure of the can be part of a catalytic cycle, there is no evidence as of yet [NiFeSe]-hydrogenase from D. vulgaris.275 The electron density that a natural selenoenzyme uses this redox form. map of the [NiFeSe] complex was interpreted in terms of three It is not widely appreciated that selenium is also found as a structures in a 70:15:15 ratio, respectively, as shown in Figure ligand for metal clusters in hydrogenases as shown in Figure 1. 20. Structures I and II were persulfurated, while the third had a Early work on [NiFeSe]-hydrogenases showed that this class of direct Ni−Se linkage. Their analysis revealed that selenium in I enzymes was oxygen tolerant,271 unlike [Fe−Fe]-hydrogenases and II shields the nickel atom from small molecules such as and most [NiFe]-hydrogenases. Maroney and co-workers molecular oxygen, preventing inactivation from the formation provided evidence that selenium confers oxygen tolerance in of an oxo ligand at the nickel center. This may be due to [NiFeSe]-hydrogenases by synthesizing nickel-containing selenium’s ability to form strong metal bonds, as it does with mimics of the active site that had either sulfur or selenium mercury.202 However, the presence of the Sec residue in the ligands as shown in Figure 19.272 Reaction of the thiolato enzyme does not prevent other oxidation events such as the complex with molecular oxygen resulted in a monosulfinato conversion of Cys75 from a nickel sulfide to a nickel sulfinate.

832 DOI: 10.1021/acschembio.6b00031 ACS Chem. Biol. 2016, 11, 821−841 ACS Chemical Biology Reviews

Figure 20. Three structures of the NiFe center in the [NiFeSe]- hydrogenase from D. vulgaris.275 Structure I corresponds to the oxidized form, while structure III corresponds to the reduced form. Structure II is an intermediate between I and III.

Another example of selenium conferring resistance to oxidation comes from a Sec for Cys substitution in CYP119, Figure 22. (bar graph left) Activity of TrxR enzymes after H2O2 exposure. The blue bar is the activity of the Cys-TrxR (DmTrxR). The a cytochrome P450 heme-containing monooxygenase from → 276 red bar is mouse Sec-TrxR, and the green bar is the Cys Sec mutant Sulfolobus acidocaldarius. Oxidation of SeCYP119 with excess of DmTrxR. In this experiment, the enzymes were first exposed to m-chloroperbenzoic acid (mCPBA) led to the presence of a H2O2. Then, the H2O2 was quenched with catalase, and substrate new oxidized species that absorbed at 406 nm in a magnetic (Trx) was added. Then, the amount of activity remaining was circular dichroism spectrum. The identity of this oxidized measured. Reprinted with permission from ref 263. Copyright 2013 species could not be elucidated, but this oxidized form could be American Chemical Society. (top right) Depiction of the gain of reduced back to the original state in the presence of a reducing function that Sec confers to an enzyme in the “Sec-Rescue”-TrxR- agent such as DTT. Importantly, the introduction of selenium resistance to oxidative inactivation. into the enzyme protected against heme destruction compared to the protein containing sulfur (either selenium or sulfur are ligands for the iron center of the heme), where significantly ■ CONCLUSION more heme destruction occurred (Figure 21). Almost all chemical reactions involving selenium are faster in The most recent evidence for the hypothesis that selenium is comparison to the same reaction with sulfur. For this reason, it used to prevent irreversible oxidative inactivation comes from is tempting to conclude that nature chose selenium to replace Hondal’s laboratory, who tested this hypothesis in Sec- sulfur for this enhanced chemical reactivity in order to containing thioredoxin reductase (TrxR). The approach was accelerate enzymatic reactions. In contrast, our answer to this to compare the ability of the Sec-containing TrxR to resist question is that nature has chosen selenium due to its unique oxidative inactivation compared to a Cys-ortholog from D. ability to react with oxygen and related ROS in a readily melanogaster (DmTrxR).263 DmTrxR was used for direct reversible manner. Both sulfur and selenium are good mechanistic comparisons because it has similar enzyme nucleophiles that react with ROS in two-electron oxidation architecture to the mammalian Sec-containing enzyme, but events and, in so doing, become oxidized. The S-oxides and Se- Cys replaces Sec.195,277 DmTrxR is 50% inactivated at 1 mM oxides that are formed in this process show very strong H2O2, while the Sec-TrxR retained virtually all of its activity as divergence in their chemical reactivities, due in large part to shown in Figure 22. To support the hypothesis that selenium very weak π-bonding in the Se-oxide. As a result, Se-oxides have confers the ability to resist oxidative inactivation to an enzyme, a much stronger ability to be rapidly reduced back to the Cys was replaced with Sec using a sophisticated protein original state in comparison to S-oxides. The ability of selenium engineering technique called expressed protein ligation,278 and to both rapidly become oxidized and then be rapidly reduced “ ”12 then the ability of the mutant enzyme to resist H2O2-mediated has been referred to as the selenium paradox. Evidence for inactivation was measured by assaying for the remaining this “selenium paradox” comes from the gain of function that activity. As shown in Figure 22, replacement of a single atom in selenium confers to both natural and artificial selenoenzymes; the enzyme, selenium for sulfur, enabled resistance to oxidative selenium confers resistance to inactivation by oxidation as the 263 inactivation by H2O2, identical to the examples discussed numerous examples discussed above show. above. Because of this effect, we call this the “Sec-rescue”-TrxR. Closely related to the reversibility of two-electron oxidation Both the Sec-TrxR and the Sec-rescue-TrxR were also able to events is the enhanced stability of the selenayl radical compared resist inactivation by one-electron oxidants such as the hydroxyl to the thiyl radical.15,246 This means that selenium-containing radical as had been predicted by Steinmann and co-workers,15 proteins are much better able to withstand one-electron but Cys-containing DmTrxR could not. oxidation events.263 Both of these hypotheses fit well with

Figure 21. (Left panel) Protection against heme destruction by the introduction of selenium into the P450 monooxygenase from S. acidocaldarius.276 (Right panel) Heme destruction was pronounced in the cysteine-containing protein in the presence of excess mCPBA (indicated by dark, double arrows), but not so the selenium-containing version. An unidentified, oxidized form of Sec could be reduced back to the parent compound by addition of dithiothreitol (DTT) as indicated, but the oxidized form of Cys could not.

833 DOI: 10.1021/acschembio.6b00031 ACS Chem. Biol. 2016, 11, 821−841 ACS Chemical Biology Reviews the idea that oxygen in the biosphere is perhaps the strongest (4) Stadtman, T. C. (1996) Selenocysteine. Annu. Rev. Biochem. 65, evolutionary force in the history of life on Earth,279 and the 83−100. chemistry of selenium is ideally suited to respond to one- and (5) Flohe,́ L., Andreesen, J. R., Brigelius-Flohe,́ R., Maiorino, M., and two-electron oxidation events. Ursini, F. (2000) Selenium, the element of the moon, in life on Earth. IUBMB Life 49, 411−420. ̈ ́ ̈ ̈ ■ AUTHOR INFORMATION (6) Kohrle, J., Brigelius-Flohe, R., Bock, A., Gartner, R., Meyer, O., and Flohe,́ L. (2000) Selenium in biology: facts and medical Corresponding Authors perspectives. Biol. Chem. 81, 849−864. *Tel.: (608) 262-5794. E-mail: [email protected]. (7) Birringer, M., Pilawa, P., and Flohe,́ F. (2002) Trends in selenium *Tel.: 802-656-8282. Fax: 802-862-8220. E-mail: Robert. biochemistry. Nat. Prod. Rep. 19, 693−718. [email protected]. (8) Jacob, C., Giles, G. I., Giles, N. M., and Sies, H. (2003) Sulfur and selenium: the role of oxidation state in protein structure and function. Notes − fi Angew. Chem., Int. Ed. 42, 4742 4758. The authors declare no competing nancial interest. (9) Brandt, W., and Wessjohann, L. A. (2005) The functional role of selenocysteine (Sec) in the catalysis mechanism of large thioredoxin ■ ACKNOWLEDGMENTS reductases: Proposition of a swapping catalytic triad including a Sec- The authors would like to thank Michael Maroney of the His-Glu state. ChemBioChem 6,1−9. University of MassachussettsAmherst, Paul Copeland of (10) Wessjohann, L. A., Schneider, A., Abbas, M., and Brandt, W. Rutgers University, and Raymond F. Burk of Vanderbilt (2007) Selenium in chemistry and biochemistry in comparison to sulfur. Biol. Chem. 388, 997−1006. University (emeritus), for providing critical commentary and ́ encourgement. The authors would also like to thank Stephen (11) Arner, E. S. (2010) Selenoproteins: What unique properties can Everse of the University of Vermont and Francessco Angelucci arise with selenocysteine in place of cysteine? Exp. Cell Res. 316, ’ fi 1296−1303. of the University of L Aquila for help in constructing gures. (12) Hondal, R. J., and Ruggles, E. L. (2011) Differing views of the role of selenium in thioredoxin reductase. Amino Acids 41,73−89. ■ DEDICATION (13) Metanis, N., Beld, J., and Hilvert, D. (2001) The chemistry of This paper is dedicated to Raymond F. Burk on the occasion of selenocysteine. In Patai’s Chemistry of Functional Groups, John Wiley & his recent retirement from Vanderbilt University and for his Sons, Hoboken, NJ, pp 1−73. many years of dedication to the study of selenium biochemistry. (14) Kasaikina, M. V., Hatfield, D. L., and Gladyshev, V. N. (2012) Understanding selenoprotein function and regulation through the use ■ KEYWORDS of rodent models. Biochim. Biophys. Acta, Mol. Cell Res. 1823, 1633− 1642. Selenocysteine: The selenium analog of cysteine. It is the (15) Nauser, T., Steinmann, D., and Koppenol, W. H. (2012) Why 21st amino acid in the genetic code. do proteins use selenocysteine instead of cysteine? Amino Acids 42, Selenouracil: The selenium analog of thiouracil. Both 39−44. thiouracil and selenouracil are modified bases found in the (16) Hondal, R. J., Marino, S. M., and Gladyshev, V. N. (2013) anticodon loop of tRNA molecules. Selenocysteine in thiol/disulfide-like exchange reactions. Antioxid. Selenoxide elimination: A chemical method for generating Redox Signaling 18, 1675−1689. carbon−carbon double bonds that involves abstraction of a (17) Oldfield, J. E. (1974) The selenium story: some reflections on “ − hydrogen that is beta to the selenoxide. This reaction is very the moon-metal. N. Z. Vet. J. 22,85 94. (18) Oldfield, J. E. (1995) SeRENDIPITY. 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841 DOI: 10.1021/acschembio.6b00031 ACS Chem. Biol. 2016, 11, 821−841