Selenoprotein gene nomenclature

The human genome contains 25 genes coding for selenocysteine-containing proteins (selenoproteins). These proteins are involved in a variety of functions, most notably redox homeostasis. Selenoprotein enzymes with known functions are designated according to these functions: TXNRD1, TXNRD2, and TXNRD3 (thioredoxin reductases), GPX1, GPX2, GPX3, GPX4 and GPX6 (glutathione peroxidases), DIO1, DIO2, and DIO3 (iodothyronine deiodinases), MSRB1 (methionine-R-sulfoxide reductase 1) and SEPHS2 (selenophosphate synthetase 2). Selenoproteins without known functions have traditionally been denoted by SEL or SEP symbols. However, these symbols are sometimes ambiguous and conflict with the approved nomenclature for several other genes. Therefore, there is a need to implement a rational and coherent nomenclature system for selenoprotein-encoding genes. Our solution is to use the root symbol SELENO followed by a letter. This nomenclature applies to SELENOF (selenoprotein F, the 15 kDa selenoprotein, SEP15), SELENOH (selenoprotein H, SELH, C11orf31), SELENOI (selenoprotein I, SELI, EPT1), SELENOK (selenoprotein K, SELK), SELENOM (selenoprotein M, SELM), SELENON (selenoprotein N, SEPN1, SELN), SELENOO (selenoprotein O, SELO), SELENOP (selenoprotein P, SeP, SEPP1, SELP), SELENOS (selenoprotein S, SELS, SEPS1, VIMP), SELENOT (selenoprotein T, SELT), SELENOV (selenoprotein V, SELV) and SELENOW (selenoprotein W, SELW, SEPW1). This system, approved by the HUGO Gene Nomenclature Committee, also resolves conflicting, missing and ambiguous designations for selenoprotein genes and is applicable to selenoproteins across vertebrates

Synthesis of Alpha-Methyl Selenocysteine and Its Utilization As a Glutathione Peroxidase Mimic

Selenocysteine (Sec) is the 21st amino acid in the genetic code where this amino acid is primarily involved in redox reactions in enzymes because of its high reactivity toward oxygen and related reactive oxygen species. Sec has found wide utility in synthetic peptides, especially as a replacement for cysteine. One limitation of using Sec in synthetic peptides is that it can undergo β‐syn elimination reactions after oxidation, rendering the peptide inactive due to loss of selenium. This limitation can be overcome by substituting Cα‐H with a methyl group. The resulting Sec derivative is α‐methylselenocysteine ((αMe)Sec). Here, we present a new strategy for the synthesis of (αMe)Sec by alkylation of an achiral methyl malonate through the use of a selenium‐containing alkylating agent synthesized in the presence of dichloromethane. The seleno‐malonate was then subjected to an enzymatic hydrolysis utilizing pig liver esterase followed by a Curtius rearrangement producing a protected derivative of (αMe)Sec that could be used in solid‐phase peptide synthesis. We then synthesized two peptides: one containing Sec and the other containing (αMe)Sec, based on the sequence of glutathione peroxidase. This is the first reported incorporation of (αMe)Sec into a peptide as well as the first reported biochemical application of this unique amino acid. The (αMe)Sec‐containing peptide had superior stability as it could not undergo β‐syn elimination and it also avoided cleavage of the peptide backbone, which we surprisingly found to be the case for the Sec‐containing peptide when it was incubated for 96 hours in oxygenated buffer at pH 8.0

Synthesis of alpha‐methyl selenocysteine and its utilization as a glutathione peroxidase mimic

Selenocysteine (Sec) is the 21st amino acid in the genetic code where this amino acid is primarily involved in redox reactions in enzymes because of its high reactivity toward oxygen and related reactive oxygen species. Sec has found wide utility in synthetic peptides, especially as a replacement for cysteine. One limitation of using Sec in synthetic peptides is that it can undergo β‐syn elimination reactions after oxidation, rendering the peptide inactive due to loss of selenium. This limitation can be overcome by substituting Cα‐H with a methyl group. The resulting Sec derivative is α‐methylselenocysteine ((αMe)Sec). Here, we present a new strategy for the synthesis of (αMe)Sec by alkylation of an achiral methyl malonate through the use of a selenium‐containing alkylating agent synthesized in the presence of dichloromethane. The seleno‐malonate was then subjected to an enzymatic hydrolysis utilizing pig liver esterase followed by a Curtius rearrangement producing a protected derivative of (αMe)Sec that could be used in solid‐phase peptide synthesis. We then synthesized two peptides: one containing Sec and the other containing (αMe)Sec, based on the sequence of glutathione peroxidase. This is the first reported incorporation of (αMe)Sec into a peptide as well as the first reported biochemical application of this unique amino acid. The (αMe)Sec‐containing peptide had superior stability as it could not undergo β‐syn elimination and it also avoided cleavage of the peptide backbone, which we surprisingly found to be the case for the Sec‐containing peptide when it was incubated for 96 hours in oxygenated buffer at pH 8.0

Oxidized Forms of Ergothioneine Are Substrates for Mammalian Thioredoxin Reductase

Ergothioneine (EGT) is a sulfur-containing amino acid analog that is biosynthesized in fungi and bacteria, accumulated in plants, and ingested by humans where it is concentrated in tissues under oxidative stress. While the physiological function of EGT is not yet fully understood, EGT is a potent antioxidant in vitro. Here we report that oxidized forms of EGT, EGT-disulfide (ESSE) and 5-oxo-EGT, can be reduced by the selenoenzyme mammalian thioredoxin reductase (Sec-TrxR). ESSE and 5-oxo-EGT are formed upon reaction with biologically relevant reactive oxygen species. We found that glutathione reductase (GR) can reduce ESSE, but only with the aid of glutathione (GSH). The reduction of ESSE by TrxR was found to be selenium dependent, with non-selenium-containing TrxR enzymes having little or no ability to reduce ESSE. In comparing the reduction of ESSE by Sec-TrxR in the presence of thioredoxin to that of GR/GSH, we find that the glutathione system is 10-fold more efficient, but Sec-TrxR has the advantage of being able to reduce both ESSE and 5-oxo-EGT directly. This represents the first discovered direct enzymatic recycling system for oxidized forms of EGT. Based on our in vitro results, the thioredoxin system may be important for EGT redox biology and requires further in vivo investigation