antioxidants Review Biological Chemistry of Hydrogen Selenide Kellye A. Cupp-Sutton † and Michael T. Ashby *,† Department of Chemistry and Biochemistry, University of Oklahoma, Norman, OK 73019, USA; [email protected] * Correspondence: [email protected]; Tel.: +1-405-325-2924 † These authors contributed equally to this work. Academic Editors: Claus Jacob and Gregory Ian Giles Received: 18 October 2016; Accepted: 8 November 2016; Published: 22 November 2016 Abstract: There are no two main-group elements that exhibit more similar physical and chemical properties than sulfur and selenium. Nonetheless, Nature has deemed both essential for life and has found a way to exploit the subtle unique properties of selenium to include it in biochemistry despite its congener sulfur being 10,000 times more abundant. Selenium is more easily oxidized and it is kinetically more labile, so all selenium compounds could be considered to be “Reactive Selenium Compounds” relative to their sulfur analogues. What is furthermore remarkable is that one of the most reactive forms of selenium, hydrogen selenide (HSe− at physiologic pH), is proposed to be the starting point for the biosynthesis of selenium-containing molecules. This review contrasts the chemical properties of sulfur and selenium and critically assesses the role of hydrogen selenide in biological chemistry. Keywords: biological reactive selenium species; hydrogen selenide; selenocysteine; selenomethionine; selenosugars; selenophosphate; selenocyanate; selenophosphate synthetase thioredoxin reductase 1. Overview of Chalcogens in Biology Chalcogens are the chemical elements in group 16 of the periodic table. This group, which is also known as the oxygen family, consists of the elements oxygen (O), sulfur (S), selenium (Se), tellurium (Te), and the radioactive element polonium (Po). O, S, and Se are essential for life, although Se is only required in trace amounts of about 15 mg in a typical 70 kg adult human [1]. The conventional roles of oxygen in aerobic respiration and photosynthesis (O2), water (~65 wt % of the human body), and a myriad of oxygen-containing bioorganic molecules (amino acids, nucleotides, etc.), may be contrasted − with the sometimes deleterious properties of biological reactive oxygen species (ROS: OH•,O2 •, H2O2, etc.) [2–4]. Similarly, sulfur serves a conventional role in the amino acids (e.g., Cys and Met) and − in biological reactive sulfur species (RSS: H2S, OSCN [5,6], polysulfides, etc.) [7–13]. Although it is toxic in large doses, selenium is an essential micronutrient for animals [14–17]. In plants, it sometimes occurs in toxic amounts as forage, e.g., locoweed [18]. Selenium is a component of the amino acids selenocysteine (Sec, the “21st amino acid”) [19] and selenomethionine (SeM) [20]. In humans, according to proteomics, Sec is incorporated into at least 25 different proteins [21–23]. The identified proteins, including glutathione peroxidases and certain forms of thioredoxin reductase, incorporate Sec into their active sites, whereas SeM is randomly incorporated into proteins [21,22,24–26]. As selenium compounds are generally more reactive than the corresponding sulfur derivatives (vide infra), one might argue that all biologically relevant selenium compounds are “Reactive Selenium Species”. The present review focuses on hydrogen selenide (H2Se), typically the least stable oxidation state for selenium in a biological setting and the putative reactant that leads to all known selenium-containing biomolecules. Antioxidants 2016, 5, 42; doi:10.3390/antiox5040042 www.mdpi.com/journal/antioxidants Antioxidants 2016, 5, 42 2 of 17 18 2. Chemistry of Sulfur vs. Selenium 2. Chemistry of Sulfur vs. Selenium Sulfur is approximately 105 times more abundant in the human body than selenium, but the 5 latterSulfur element is approximatelyis selected for certain 10 times biological more abundantfunctions [27]. in the It humanis particularly bodythan remarkable selenium, that but this the is achieved,latter element as there is selected are no forother certain two biologicalmain-group functions elements [27 that]. It isexhibit particularly more similar remarkable physical that and this chemicalis achieved, properties as there [28]. are noNonetheless, other two main-groupthe selective elementsuse of selenium that exhibit must more eventually similar rely physical upon andthe uniquechemical chemical properties properties [28]. Nonetheless, of the element. the Despite selective th usee fact of that selenium the average must atomic eventually mass rely of Se upon is more the thanunique twice chemical that of propertiesS, the atomic of radii the element.are remarkable Despite similar, the fact as a that consequence the average of d-block atomic contraction mass of Se [29],is more as are than the twice bond thatlengths of S, that the are atomic observed radii in are main-group remarkable compounds similar, as (Table a consequence 1). Furthermore, of d-block the electronegativitiescontraction [29], as of arethe thetwo bondelements lengths are comp thatarable, are observed and both in are main-group more similar compounds to carbon (Table(χ = 2.55)1). thanFurthermore, any other the elements electronegativities of the periodic of thetable. two Ho elementswever, important are comparable, differences and exist both between are more the similar two elements.to carbon S (χ forms= 2.55) stronger than any covalent other bonds elements relative of the to periodic Se (Table table. 1). Additionally, However, important it is easier differences to oxidize Seexist than between S (Table the 1). two Moreover, elements. selenols S forms are stronger more covalentacidic than bonds thiols relative with toacid Se (Tabledissociation1). Additionally, constants thatit is are easier typically to oxidize 3–4 orders Se than of Smagnitude (Table1). Moreover,larger (Table selenols 1). are more acidic than thiols with acid dissociation constants that are typically 3–4 orders of magnitude larger (Table1). Table 1. General properties of sulfur and selenium. Table 1. General properties of sulfur and selenium. Property S Se Electron configurationProperty [Ne] 3s S23p4 [Ar] Se 3d104s24p4 AverageElectron atomic configuration mass (amu) [Ne]32.06 3s23p 4 [Ar] 3d1078.964s24p 4 CovalentAverage radius atomic (pm) mass [30] (amu) 100 32.06 78.96115 van der WaalsCovalent radius radius (pm) [30 [31]] 180 100 115190 van der Waals radius (pm) [31]134 (S–H) 180 146 190 (Se–H) Bond length (pm) [32] 180134 (S–C) (S–H) 146196 (Se–H) (Se–C) Bond length (pm) [32] 205180 (S–S) (S–C) 196232 (Se–C) (Se–Se) HX–H 381.6205 (S–H) (S–S) [33] 334.9 232 (Se–Se) (Se–H) [34] −1 HX–H 381.6 (S–H) [33] 334.9 (Se–H) [34] Bond energy (kJ·mol )− 1 CH3X–CH3 307.9 (S–C) [33] 234 (Se–C) [35] Bond energy (kJ·mol ) CH3X–CH3 307.9 (S–C) [33] 234 (Se–C) [35] 3 3 CHCHX–XCH3X–XCH3 273.6273.6 (S–S) (S–S) [[33]33] 197.6197.6 (Se–Se) (Se–Se) [36] [36] 1st1st 999.6 999.6 940.9940.9 IonizationIonization Energies Energies −1 2nd2nd 2251 2251 20452045 (kJ·mol(kJ·mol−1) [37])[ 37] 3rd3rd 3361 3361 29742974 · −1 ElectronElectron affinity affinity (kJ·mol (kJ mol−1) [38])[38 ] 200200 195195 PaulingPauling electronegativity electronegativity [39] [39] 2.58 2.58 2.552.55 3 PolarizabilityPolarizability (in (in Å Å3) ) 2.902.90 [40] [40] 3.893.89 [41 ][41] pK , (H X) 6.88 [42] 3.89 [43] pKa1, (Ha1 2X)2 6.88 [42] 3.89 [43] pK , (HX−) 14.15 [42] 15.1 [44] pKa2, (HXa2 −) 14.15 [42] 15.1 [44] pKa2,pK (Cys/Sec)a2, (Cys/Sec) [45] [45 ]8.22 8.22 [46,47] [46,47] 5.435.43 [48 ][48] 2.1. Selenium Selenium Compounds Compounds Are More Reactive Given thatthat freefree energy energy relationships relationships frequently frequently exist exist between between thermodynamics thermodynamics and kinetics and kinetics [49,50], [49,50],it is unsurprising it is unsurprising that Se compoundsthat Se compounds tend to tend be more to be reactive more reactive than S compounds.than S compounds. For example, For example, for the forexchange the exchange of thiols of andthiols selenolates and selenolates (note the(note proton the prot stateon ofstate each of each [51]) [51]) with with disulfides, disulfides, diselenides, diselenides, and andmixed mixed chalcogenides, chalcogenides, reaction reaction rates rates of seleniumof selenium as as a nucleophilea nucleophile and and as as an an electrophile electrophile areare 2–3 and 4 orders of of magnitude magnitude higher, higher, respectively, respectively, than than those those of of sulfur sulfur atat neutral neutral pH pH [52]:[52]: (1)(1) −+ RSSR++ 2RSe 2H RSeSeR+ 2 RSH (2) Antioxidants 2016, 5, 42 3 of 18 − + Antioxidants 2016, 5, 42 RSSR + 2RSe + 2H RSeSeR + 2RSH3 of (2) 17 From left to right,right, thethe greatergreater nucleophilicitynucleophilicity of Sec relative to CysCys may be attributed to the fact thatthat SeSe isis deprotonateddeprotonated andand SS isis protonatedprotonated atat neutralneutral pH,pH, andand toto thethe factfact thatthat aa S–HS–H covalentcovalent bondbond isis formedformed whenwhen selenolateselenolate reactsreacts andand CysCys is liberated. In the other direction, the greater electrophilicity of Se in this particular reaction isis attributedattributed toto propertiesproperties ofof thethe S–SS–S vs.vs. Se–SeSe–Se vs.vs. Se–S bonds, and not thethe nature ofof thethe leaving group. From these rate constants,constants, the ratio of cystine (RSSR) to selenocystine 4 (RSeSeR)(RSeSeR) isis givengiven by:by: KK == KK11 × KK2 2== k1 k ×1 ×k2/kk2−1/k × −k1−2 ×= 2.5k− 2×= 10 2.54 for× [Cys]10 for = [Cys][Sec]. =While [Sec].