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Biochemical discrimination between selenium and sulfur 1 : a single residue provides selenium specificity to human selenocysteine lyase

Collins, Ruairi ; Johansson, Ann-Louise LU ; Karlberg, Tobias LU ; Markova, Natalia LU ; van den Berg, Susanne ; Olesen, Kenneth ; Hammarström, Martin ; Flores, Alex ; Schüler, Herwig LU orcid and Schiavone, Lovisa Holmberg , et al. (2012) In PLoS ONE 7(1).
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... (More)

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.

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publishing date
type
Contribution to journal
publication status
published
keywords
Amino Acid Sequence, Amino Acid Substitution, Animals, Catalytic Domain, Computational Biology, Conserved Sequence, Crystallography, X-Ray, Humans, Lyases/chemistry, Mice, Models, Molecular, Molecular Sequence Data, Rats, Selenium/chemistry, Substrate Specificity, Sulfur/metabolism
in
PLoS ONE
volume
7
issue
1
article number
e30581
publisher
Public Library of Science (PLoS)
external identifiers
  • scopus:84861954783
  • pmid:22295093
ISSN
1932-6203
DOI
10.1371/journal.pone.0030581
language
English
LU publication?
no
id
b4c255ec-d76c-4be4-a0b4-74578244ad9f
date added to LUP
2024-11-21 17:58:42
date last changed
2025-04-25 16:53:54
@article{b4c255ec-d76c-4be4-a0b4-74578244ad9f,
  abstract     = {{<p>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.</p>}},
  author       = {{Collins, Ruairi and Johansson, Ann-Louise and Karlberg, Tobias and Markova, Natalia and van den Berg, Susanne and Olesen, Kenneth and Hammarström, Martin and Flores, Alex and Schüler, Herwig and Schiavone, Lovisa Holmberg and Brzezinski, Peter and Arnér, Elias S J and Högbom, Martin}},
  issn         = {{1932-6203}},
  keywords     = {{Amino Acid Sequence; Amino Acid Substitution; Animals; Catalytic Domain; Computational Biology; Conserved Sequence; Crystallography, X-Ray; Humans; Lyases/chemistry; Mice; Models, Molecular; Molecular Sequence Data; Rats; Selenium/chemistry; Substrate Specificity; Sulfur/metabolism}},
  language     = {{eng}},
  number       = {{1}},
  publisher    = {{Public Library of Science (PLoS)}},
  series       = {{PLoS ONE}},
  title        = {{Biochemical discrimination between selenium and sulfur 1 : a single residue provides selenium specificity to human selenocysteine lyase}},
  url          = {{http://dx.doi.org/10.1371/journal.pone.0030581}},
  doi          = {{10.1371/journal.pone.0030581}},
  volume       = {{7}},
  year         = {{2012}},
}