title: Biochemical discrimination between selenium and sulfur 1: a single residue provides selenium specificity to human selenocysteine lyase.
abstract: Selenium and sulfur are two closely related basic elements utilized in nature for a vast array of biochemical reactions. While toxic at higher concentrations, selenium is an essential trace element incorporated into selenoproteins as selenocysteine (Sec), the selenium analogue of cysteine (Cys). Sec lyases (SCLs) and Cys desulfurases (CDs) catalyze the removal of selenium or sulfur from Sec or Cys and generally act on both substrates. In contrast, human SCL (hSCL) is specific for Sec although the only difference between Sec and Cys is the identity of a single atom. The chemical basis of this selenium-over-sulfur discrimination is not understood. Here we describe the X-ray crystal structure of hSCL and identify Asp146 as the key residue that provides the Sec specificity. A D146K variant resulted in loss of Sec specificity and appearance of CD activity. A dynamic active site segment also provides the structural prerequisites for direct product delivery of selenide produced by Sec cleavage, thus avoiding release of reactive selenide species into the cell. We thus here define a molecular determinant for enzymatic specificity discrimination between a single selenium versus sulfur atom, elements with very similar chemical properties. Our findings thus provide molecular insights into a key level of control in human selenium and selenoprotein turnover and metabolism.
authors.affiliation: Structural Genomics Consortium, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden.
authors.forename: Ruairi
authors.initials: R
authors.lastname: Collins
authors.forename: Ann-Louise
authors.initials: AL
authors.lastname: Johansson
authors.forename: Tobias
authors.initials: T
authors.lastname: Karlberg
authors.forename: Natalia
authors.initials: N
authors.lastname: Markova
authors.forename: Susanne
authors.initials: S
authors.lastname: van den Berg
authors.forename: Kenneth
authors.initials: K
authors.lastname: Olesen
authors.forename: Martin
authors.initials: M
authors.lastname: Hammarström
authors.forename: Alex
authors.initials: A
authors.lastname: Flores
authors.forename: Herwig
authors.initials: H
authors.lastname: Schüler
authors.forename: Lovisa Holmberg
authors.initials: LH
authors.lastname: Schiavone
authors.forename: Peter
authors.initials: P
authors.lastname: Brzezinski
authors.forename: Elias S J
authors.initials: ES
authors.lastname: Arnér
authors.forename: Martin
authors.initials: M
authors.lastname: Högbom
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D020134:Catalytic Domain; D019295:Computational Biology; D017124:Conserved Sequence; D018360:Crystallography, X-Ray; D006801:Humans; D008190:Lyases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D051381:Rats; D012643:Selenium / Q000737:chemistry / Q000378:metabolism*; D013379:Substrate Specificity; D013455:Sulfur / Q000378:metabolism*
chemical_list: D013455:Sulfur; D008190:Lyases; C034278:selenocysteine lyase; D012643:Selenium