NDLI: Selenium in Thioredoxin Reductase: A Mechanistic Perspective †

Content Provider	PubMed Central
Author	Lacey, Brian M. Eckenroth, Brian E. Flemer, Stevenson Hondal, Robert J.
Abstract	Most high M r thioredoxin reductases (TRs) have the unusual feature of utilizing a vicinal disulfide bond (Cys1-Cys2) which form an eight-membered ring during the catalytic cycle. Many eukaryotic TRs have replaced the Cys2 position of the dyad with the rare amino acid selenocysteine (Sec). Here we demonstrate that Cys- and Sec-containing TRs are distinguished by the importance each class of enzymes places on the 8-membered ring structure in the catalytic cycle. This hypothesis was explored by studying the truncated enzyme missing the C-terminal ring structure in conjunction with oxidized peptide substrates to investigate the reduction and opening of this dyad. The peptide substrates were identical in sequence to the missing part of the enzyme, containing either a disulfide or selenylsulfide linkage, but were differentiated by the presence (cyclic) and absence (acyclic) of the ring structure. The ratio of these turnover rates informs that the ring is only of modest importance for the truncated mouse mitochondrial Sec-TR (ring/no ring = 32), while the ring structure is highly important for the truncated Cys-TRs from D. melanogaster and C. elegans (ring/no ring > 1000). All three enzymes exhibit a similar dependence upon leaving group pK a as shown by the use of the acyclic peptides as substrates. These two factors can be reconciled for Cys-TRs if the ring functions to simultaneously allow for attack by a nearby thiolate while correctly positioning the leaving group sulfur atom to accept a proton from the enzymic general acid. For Sec-TRs the ring is unimportant because the lower pK a of the selenol relative to a thiol obviates its need to be protonated upon S-Se bond scission and permits physical separation of the selenol and the general acid. Further study of the biochemical properties of the truncated Cys and Sec TR enzymes demonstrates that the chemical advantage conferred on the eukaryotic enzyme by a selenol is the ability to function at acidic pH.
Related Links	http://dx.doi.org/10.1021/bi800951f
Ending Page	12821
Page Count	12
Starting Page	12810
File Format	PDF
ISSN	00062960
e-ISSN	15204995
Journal	Biochemistry
Issue Number	48
Volume Number	47
Language	English
Publisher Date	2008-12-02
Access Restriction	Open
Subject Keyword	Biochemistry Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Biochemistry

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