Böck, August

Flohé, Leopold

Köhrle, Josef

English

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Selenoproteins – biochemistry and clinical relevance

Universität München: Elektronischen Publikationen

Biol. Chem., Vol. 388, pp. 985–986, October 2007 • Copyright  by Walter de Gruyter • Berlin • New York. DOI 10.1515/BC.2007.148
2007/250707
Article in press - uncorrected proof
Guest Editorial
Selenoproteins – biochemistry and clinical relevance
Klaus Schwarz (1914–1978), a pioneer of biomedical selenium
research.
Five decades ago, selenium had been recognized as an
essential trace element for bacteria by Jane Pinsent and
for higher vertebrates by Klaus Schwarz (see photo) and
Calvin M. Foltz, who isolated a selenium-containing com-
pound from hog kidney, the ‘factor 3’ that protected rats
against dietary liver necrosis. Fifteen years later, the first
selenoproteins were detected in mammals as well as in
bacteria indicating that the trace element might fulfil its
biological function as an integral constituent of enzymes.
In 2000, the German Research Council (Deutsche For-
schungsgemeinschaft, DFG) positively evaluated and
subsequently funded the Priority Program 1087 (Schwer-
punktprogramm) focusing on basic, applied and clinically
oriented research on selenoproteins, their biochemistry
and function. The current issue of Biological Chemistry
presents state-of-the-art reviews and original research
communications written by scientists who were directly
or indirectly supported by the Priority Program. This spe-
cial issue is expected to provide a topical view of the
frontiers of selenoprotein biochemistry and its clinical
relevance.
Selenoproteins represent a new class of peculiar
redox-active proteins containing the 21st proteinogenic
amino acid, selenocysteine (Sec), in their active center.
Selenium research has been significantly boosted by the
expansion of the genetic code by two more codons: UAG
for pyrrolysine and UGA encoding selenocysteine. Briefly,
UGA, the opal stop codon, can be cotranslationally rein-
terpreted as incorporation signal for selenocysteine,
which is the selenium homolog of cysteine, if further
requirements are met: (i) a context structural feature of
the selenoprotein mRNA, the selenocysteine insertion
sequence (SECIS) which is located in the 39UTR in euka-
ryotes and not immediately downstream of the UGA
codon, as initially detected in prokaryotes; (ii) specific
translation factors that recognize the latter in a selenium-
dependent manner; (iii) a Sec-loaded specific tRNASec to
incorporate selenocysteine into the nascent protein
chain; and (iv) the machinery to synthesize and charge
this tRNA. Altogether, a whole set of proteins is required
to specifically insert selenocysteine into the elongating
peptide chain and to suppress termination. Several of the
key factors required have only recently been identified
and now help to advance this flourishing research field.
A further major boost came to the selenium field in
2003, when the human selenogenome was identified by
novel algorithms that safely identified combinations of
UGA codons and SECIS hairpin loops that follow specific
folding patterns and expose key bases for recognition by
SECIS binding proteins. The human selenogenome com-
prises 25 genes which at least in part are translated into
different proteins with distinct functions. With this knowl-
edge, the biomedical relevance of selenium can no longer
be simply addressed by popular terms, such as ‘antioxi-
dative defence’ or ‘protection from oxidative stress’. Not
even the fact that 5 out of the 25 genes encode peroxi-
dases justifies this simplification, because some of the
glutathione peroxidases have evidently adopted surpris-
ing roles, such as dampening the generation of inflam-
matory mediators, regulating the insulin response or
assuring spermiogenesis. All three known thyroid hor-
mone deiodinases, more recently identified to be sele-
noproteins, are involved in thyroid hormone biosynthesis
and metabolism. The three thioredoxin reductases are
linked to hydroperoxide metabolism via the peroxire-
doxins, and thus involved in both intracellular and extra-
cellular redox control, but they are also pivotal to the
biosynthesis of deoxynucleotides. New horizons are
opened up by deletions or mutational alterations of sele-
noproteins or proteins involved in selenoprotein biosyn-
thesis. For example, the rigid spine syndrome proved to
be associated with mutations of selenoprotein N, and
impairment of growth, development and thyroid hormone
feedback regulation are linked to an impaired function of
SECIS binding protein 2. Fortunately, the number of
selenoprotein-encoding genes is so low that the alphabet
was just sufficient to provide letters for the selenopro-
teins with unknown functions such as Sel-H, I, K, M, N,
O, R, S, T, V, W, but it is large enough to forecast future
surprises.
Bereitgestellt von | Universitaetsbibliothek der LMU Muenchen
Angemeldet | 129.187.254.47
Heruntergeladen am | 18.11.13 10:44
986 Guest Editorial
Article in press - uncorrected proof
The elucidation of the biology of selenium gained fur-
ther momentum with the successful application of trans-
genic technology. Knockout and conditional knockout
models and transgenic expression of selenoproteins
helped to advance the field and to illustrate that several
of the selenoproteins already play a critical role during
mammalian development, e.g., thioredoxin reductases
and one of the glutathione peroxidases, thus explain-
ing why a complete knockout of the mouse trsp
(tRNASec) is embryonically lethal. Inverse genetics also
revealed that selenium biochemistry is indispensible for
appropriate brain function, an aspect that had not
become obvious from nutritional selenium deprivation.
In the meantime, selenogenomes of various species
have been characterized, i.e., those of important human
pathogens. Their functional analysis is still rudimentary.
However, they reveal that the use of the trace element
changed dramatically during evolution. The machinery for
selenoprotein biosynthesis being lost in yeast and terres-
tric plants, it is otherwise conserved from archaea and
bacteria up to protozoa and higher animals, although
with marked differences. Furthermore, selenoprotein
families are not regularly conserved between related spe-
cies and rarely between domains, kingdoms and phyla.
Certainly, this diversification must be seen as a major
obstacle in any attempt to deduce the function, e.g., of
a human protein by studying well-investigated but gene-
tically remote model organisms. On the other hand, the
chance to selectively target the unrelated selenoproteins
of pathogenic microorganisms is being discussed as a
challenging therapeutic option.
The Priority Program markedly supported selenopro-
tein research in Germany based on long-standing tradi-
tion and work of pioneers in the field, who initially were
instrumental and successful in convincing the national
and later on the international review board of this pro-
gram – first, to install it and then to grant two prolon-
gations. Novel scientific and clinical relevant information
has been obtained, e.g., illustrating the role of selenium
in development, male fertility, carcinogenesis, endocri-
nology and stem cell research. In addition, the program
advanced research to target drugs to selenocysteine-
active sites of proteins, assisted by modeling and struc-
ture analyses of some selenoproteins. Novel bio-
informatic tools and combinatorial chemistry programs
were successfully implemented, which helped to create
a high interdisciplinary technology-advancing and com-
munication-fostering program. At the end of the funding
period, intense collaborations between the funded
teams, strong international networks, and even collabo-
rations with joint publications between former or current
reviewers or scientists invited to the program workshops
have been established and are partially documented
here.
The DFG, its advisory bodies and review boards are
thanked for taking the initiative to foster a rapidly emerg-
ing field just in time. This facilitated the recruitment and
education of many young scientists and their introduction
into the field, and thereby effected a smooth change of
researchers in our community. This program also mark-
edly helped to blow away some ‘odd flavor’ from the
field, which definitely is not a paramedic one but hard-
core science and biochemistry with all its methodological
and conceptual facets. Some selenium compounds,
such as H2Se and its methylated derivatives still smell,
but others are essential for human and animal health,
disease prevention and even therapy.
The editors of this highlight issue hope that you enjoy
the compiled scientific selenium-related papers, some of
them being mini-reviews, some being original work or a
combination of both – all critically peer-reviewed accord-
ing to the procedures of Biological Chemistry. We would
like to thank all authors, their teams, and the Editorial
Board as well as the DFG for this opportunity to present
an update on the state-of-the-art in the selenoprotein
field.
August Böck
Department Biologie 1 – Mikrobiologie
Universität München
Maria-Ward-Straße 1a
D-80638 München
Germany
e-mail: august.boeck@lrz.uni-muenchen.de
Leopold Flohé
MOLISA GmbH
Universitätsplatz 2
D-39106 Magdeburg
Germany
e-mail: L.Flohe@t-online.de
Josef Köhrle
Institut für Experimentelle Endokrinologie
Campus Charité Mitte
Charité Universitätsmedizin Berlin
Humboldt-Universität zu Berlin
Charitéplatz 1
D-10117 Berlin
Germany
e-mail: Josef.Koehrle@charite.de
Bereitgestellt von | Universitaetsbibliothek der LMU Muenchen
Angemeldet | 129.187.254.47
Heruntergeladen am | 18.11.13 10:44


Selenoproteins - biochemistry and clinical relevance

Open Access LMU ( Ludwig-Maximilians-Univ. München)

Biol. Chem., Vol. 388, pp. 985–986, October 2007 • Copyright  by Walter de Gruyter • Berlin • New York. DOI 10.1515/BC.2007.1482007/250707Article in press - uncorrected proofGuest EditorialSelenoproteins – biochemistry and clinical relevanceKlaus Schwarz (1914–1978), a pioneer of biomedical seleniumresearch.Five decades ago, selenium had been recognized as anessential trace element for bacteria by Jane Pinsent andfor higher vertebrates by Klaus Schwarz (see photo) andCalvin M. Foltz, who isolated a selenium-containing com-pound from hog kidney, the ‘factor 3’ that protected ratsagainst dietary liver necrosis. Fifteen years later, the firstselenoproteins were detected in mammals as well as inbacteria indicating that the trace element might fulfil itsbiological function as an integral constituent of enzymes.In 2000, the German Research Council (Deutsche For-schungsgemeinschaft, DFG) positively evaluated andsubsequently funded the Priority Program 1087 (Schwer-punktprogramm) focusing on basic, applied and clinicallyoriented research on selenoproteins, their biochemistryand function. The current issue of Biological Chemistrypresents state-of-the-art reviews and original researchcommunications written by scientists who were directlyor indirectly supported by the Priority Program. This spe-cial issue is expected to provide a topical view of thefrontiers of selenoprotein biochemistry and its clinicalrelevance.Selenoproteins represent a new class of peculiarredox-active proteins containing the 21st proteinogenicamino acid, selenocysteine (Sec), in their active center.Selenium research has been significantly boosted by theexpansion of the genetic code by two more codons: UAGfor pyrrolysine and UGA encoding selenocysteine. Briefly,UGA, the opal stop codon, can be cotranslationally rein-terpreted as incorporation signal for selenocysteine,which is the selenium homolog of cysteine, if furtherrequirements are met: (i) a context structural feature ofthe selenoprotein mRNA, the selenocysteine insertionsequence (SECIS) which is located in the 39UTR in euka-ryotes and not immediately downstream of the UGAcodon, as initially detected in prokaryotes; (ii) specifictranslation factors that recognize the latter in a selenium-dependent manner; (iii) a Sec-loaded specific tRNASec toincorporate selenocysteine into the nascent proteinchain; and (iv) the machinery to synthesize and chargethis tRNA. Altogether, a whole set of proteins is requiredto specifically insert selenocysteine into the elongatingpeptide chain and to suppress termination. Several of thekey factors required have only recently been identifiedand now help to advance this flourishing research field.A further major boost came to the selenium field in2003, when the human selenogenome was identified bynovel algorithms that safely identified combinations ofUGA codons and SECIS hairpin loops that follow specificfolding patterns and expose key bases for recognition bySECIS binding proteins. The human selenogenome com-prises 25 genes which at least in part are translated intodifferent proteins with distinct functions. With this knowl-edge, the biomedical relevance of selenium can no longerbe simply addressed by popular terms, such as ‘antioxi-dative defence’ or ‘protection from oxidative stress’. Noteven the fact that 5 out of the 25 genes encode peroxi-dases justifies this simplification, because some of theglutathione peroxidases have evidently adopted surpris-ing roles, such as dampening the generation of inflam-matory mediators, regulating the insulin response orassuring spermiogenesis. All three known thyroid hor-mone deiodinases, more recently identified to be sele-noproteins, are involved in thyroid hormone biosynthesisand metabolism. The three thioredoxin reductases arelinked to hydroperoxide metabolism via the peroxire-doxins, and thus involved in both intracellular and extra-cellular redox control, but they are also pivotal to thebiosynthesis of deoxynucleotides. New horizons areopened up by deletions or mutational alterations of sele-noproteins or proteins involved in selenoprotein biosyn-thesis. For example, the rigid spine syndrome proved tobe associated with mutations of selenoprotein N, andimpairment of growth, development and thyroid hormonefeedback regulation are linked to an impaired function ofSECIS binding protein 2. Fortunately, the number ofselenoprotein-encoding genes is so low that the alphabetwas just sufficient to provide letters for the selenopro-teins with unknown functions such as Sel-H, I, K, M, N,O, R, S, T, V, W, but it is large enough to forecast futuresurprises.Bereitgestellt von | Universitaetsbibliothek der LMU MuenchenAngemeldet | 129.187.254.47Heruntergeladen am | 18.11.13 10:44986 Guest EditorialArticle in press - uncorrected proofThe elucidation of the biology of selenium gained fur-ther momentum with the successful application of trans-genic technology. Knockout and conditional knockoutmodels and transgenic expression of selenoproteinshelped to advance the field and to illustrate that severalof the selenoproteins already play a critical role duringmammalian development, e.g., thioredoxin reductasesand one of the glutathione peroxidases, thus explain-ing why a complete knockout of the mouse trsp(tRNASec) is embryonically lethal. Inverse genetics alsorevealed that selenium biochemistry is indispensible forappropriate brain function, an aspect that had notbecome obvious from nutritional selenium deprivation.In the meantime, selenogenomes of various specieshave been characterized, i.e., those of important humanpathogens. Their functional analysis is still rudimentary.However, they reveal that the use of the trace elementchanged dramatically during evolution. The machinery forselenoprotein biosynthesis being lost in yeast and terres-tric plants, it is otherwise conserved from archaea andbacteria up to protozoa and higher animals, althoughwith marked differences. Furthermore, selenoproteinfamilies are not regularly conserved between related spe-cies and rarely between domains, kingdoms and phyla.Certainly, this diversification must be seen as a majorobstacle in any attempt to deduce the function, e.g., ofa human protein by studying well-investigated but gene-tically remote model organisms. On the other hand, thechance to selectively target the unrelated selenoproteinsof pathogenic microorganisms is being discussed as achallenging therapeutic option.The Priority Program markedly supported selenopro-tein research in Germany based on long-standing tradi-tion and work of pioneers in the field, who initially wereinstrumental and successful in convincing the nationaland later on the international review board of this pro-gram – first, to install it and then to grant two prolon-gations. Novel scientific and clinical relevant informationhas been obtained, e.g., illustrating the role of seleniumin development, male fertility, carcinogenesis, endocri-nology and stem cell research. In addition, the programadvanced research to target drugs to selenocysteine-active sites of proteins, assisted by modeling and struc-ture analyses of some selenoproteins. Novel bio-informatic tools and combinatorial chemistry programswere successfully implemented, which helped to createa high interdisciplinary technology-advancing and com-munication-fostering program. At the end of the fundingperiod, intense collaborations between the fundedteams, strong international networks, and even collabo-rations with joint publications between former or currentreviewers or scientists invited to the program workshopshave been established and are partially documentedhere.The DFG, its advisory bodies and review boards arethanked for taking the initiative to foster a rapidly emerg-ing field just in time. This facilitated the recruitment andeducation of many young scientists and their introductioninto the field, and thereby effected a smooth change ofresearchers in our community. This program also mark-edly helped to blow away some ‘odd flavor’ from thefield, which definitely is not a paramedic one but hard-core science and biochemistry with all its methodologicaland conceptual facets. Some selenium compounds,such as H2Se and its methylated derivatives still smell,but others are essential for human and animal health,disease prevention and even therapy.The editors of this highlight issue hope that you enjoythe compiled scientific selenium-related papers, some ofthem being mini-reviews, some being original work or acombination of both – all critically peer-reviewed accord-ing to the procedures of Biological Chemistry. We wouldlike to thank all authors, their teams, and the EditorialBoard as well as the DFG for this opportunity to presentan update on the state-of-the-art in the selenoproteinfield.August Bo¨ckDepartment Biologie 1 – MikrobiologieUniversita¨t Mu¨nchenMaria-Ward-Straße 1aD-80638 Mu¨nchenGermanye-mail: august.boeck@lrz.uni-muenchen.deLeopold Flohe´MOLISA GmbHUniversita¨tsplatz 2D-39106 MagdeburgGermanye-mail: L.Flohe@t-online.deJosef Ko¨hrleInstitut fu¨r Experimentelle EndokrinologieCampus Charite´ MitteCharite´ Universita¨tsmedizin BerlinHumboldt-Universita¨t zu BerlinCharite´platz 1D-10117 BerlinGermanye-mail: Josef.Koehrle@charite.deBereitgestellt von | Universitaetsbibliothek der LMU MuenchenAngemeldet | 129.187.254.47Heruntergeladen am | 18.11.13 10:44

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