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Rare, but Essential – the Amino Acid Selenocysteine

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Rare, but Essential – the Amino Acid Selenocysteine Molecular Biology Rare, but essential – the amino acid selenocysteine Based at the University of Bonn, Germany, Professor Dr Ulrich Schweizer is leading research into revealing the role of selenoproteins in mammalian physiology. By elucidating the mechanisms underlying their function, his work is yielding new insights into a wide array of human diseases affecting the brain and thyroid hormones. At the core of Prof Dr Schweizer’s research is the rare selenium-containing 21st amino acid selenocysteine (Sec), the defining component of selenoproteins. elenocysteine (Sec) is an the trace element selenium (Se) replaces the essential amino acid component sulphur atom of cysteine. Selenium possesses in selenoproteins, which are similar but more reactive properties than involved in a variety of cellular and sulphur, and is always housed in the active metabolic processes. Increasingly, centre of selenoenzymes. Stheir deregulation is being associated with neurodegenerative and other diseases, INVESTIGATING THE RAREST AMINO for which the underlying mechanisms ACID have remained unclear. However, using Sec eluded the Nobel Prize winning scientists novel transgenic mouse models, Prof Dr who deciphered the genetic code, because Schweizer and his team have uncovered Sec is encoded by what has been regarded a wealth of information regarding the exclusively as a termination codon, UGA. mechanisms behind their function. His team’s How can the cell distinguish between extensive research has found that reducing termination and Sec incorporation? There is a the expression of selenoproteins in the specific element within the mRNA sequence mammalian brain impairs brain development that directs the re-coding of UGA, called the and healthy functioning, consequently selenocysteine insertion sequence (SECIS). causing a broad spectrum of disorders, The SECIS is recognised by a SECIS-binding including epilepsy and neurodegeneration. protein, which in turn instructs the ribosome not to terminate but to incorporate Sec – see Selenoproteins are proteins within which Sec the figure overleaf. is incorporated in the polypeptide chain. The importance of Sec had, until recently, The human genome contains 25 been overlooked – perhaps due to its low selenoprotein-coding genes. Mice have the abundance and discovery after the other 20 same selenoprotein genes as humans, but canonical amino acids. In Sec, an atom of one less. Out of the selenoproteins encoded by the human and rodent genomes, around half of their functions remain unknown. Sec eluded the Dr Schweizer and other scientists realised that the genetic analysis of transgenic mice Nobel Prize in which specific gene function has been disrupted or altered could shed light on winning scientists the roles of individual selenoproteins. In fact, several selenoproteins are essential for who deciphered mammals. With the rapid development of the genetic code human genetics more and more mutations 75 Molecular Biology Detail RESEARCH OBJECTIVES Prof Dr Schweizer’s research focuses Among all trace elements, what is so Would you rather invite five smart people on the biochemistry and molecular special about selenium in particular? home for dinner or instead five thousand biology of selenoproteins. His previous Selenium is unique in that selenoproteins boring guests? research has found that reducing have selenium attached by stable selenoprotein expression in the brain chemical bonds – making analysis much Have you had any thoughts on how the leads to developmental defects and easier than for example zinc, which is less knowledge you have gained regarding neurodegeneration in mouse models. tightly bound. Also, selenoproteins can be the function of specific selenoproteins detected based on genome sequences. in epilepsy could be used to develop FUNDING So identification of a selenoprotein in targeted therapeutic treatments? Deutsche Forschungsgemeinschaft rattle snakes or polar bears does not This is too early at this moment, but I (DFG), German-Israeli Fund require wet chemistry. Another advantage firmly believe that biochemistry helps is the limited number of selenoproteins. to i) diagnose disorders, ii) understand COLLABORATORS Roughly two dozen selenoprotein genes their pathomechanisms, and with this Dr Schweizer collaborates with many foster my hope to finally understand all knowledge iii) guides rational treatment scientists in his field, but he would like their functions within my lifetime. strategies. There are many very good to highlight the mentorship of Dr Dolph have been identified in humans that disrupt teamed up with protein crystallographers has since found that selenoproteins are examples in the medical field for this L. Hatfield, NIH, Bethesda, and Prof Dr selenoprotein function. to become the first team to solve the crystal essential for brain development, and they Did you ever regret leaving the area opinion, among them all the inherited Josef Köhrle, Charité Berlin structure of one of these enzymes. Quite have succeeded in working out some of the of neurological disorders after your disorders that are included in the perinatal SELENIUM AT THE CORE OF CRUCIAL remarkably, the enzyme resembles ancient specific mechanisms involved. They have chance discovery of epilepsy in the screening programmes which help BIO ENZYME ACTIVE SITES peroxide-degrading enzymes and must have identified a specific class of GABAergic selenoprotein knockout mouse? many kids get the right treatment Dr Schweizer received his Proteins that function as enzymes, in which acquired its vertebrate-specific function after interneurons, in which dysfunction is To many people's surprise, no. Colleagues in time and thus prevent the degree in biochemistry at Sec is a key component, are known as losing its original function. fundamental to the clinical manifestation of often assume that research in the selenium development of severe mental University of Bayreuth and selenoenzymes. These are most established epilepsy, finding that two selenoproteins are field is hard to get funded. This is not disability. his PhD in Neurobiology as anti-oxidative enzymes that fight ‘free SURPRISING PHENOTYPE SHIFTS FOCUS intrinsically linked to this process. correct, at least in my case, probably at University of Würzburg. radicals’ within cells, and are therefore TO NEURONAL DEVELOPMENT AND because we are not doing nutritional What are your plans for the future of He then moved to Charité- implicated in ageing and metabolic DEGENERATION To do this, Prof Dr Schweizer and his science, but hard-core molecular biology your research? Universitätsmedizin Berlin to become disorders. In addition, selenium and the While completing his PhD on another topic, team disrupted neuronal selenoprotein and biochemistry. But it is true, if you say Clearly, I would like to further delineate a junior group leader at the Neuroscience selenoenzymes it is incorporated into, are Dr Schweizer discovered that one of the biosynthesis in their mice models, deleting you work on Alzheimer’s, stem cells or the functions of selenoproteins in the Research Centre. He is currently Professor critical to the regulation of thyroid hormone knockout mice he had created was epileptic, the gene that encodes the tRNA essential cancer, one catch word is often enough to brain and find out what exactly each of Biochemistry at Rheinische Friedrich- activity. This became apparent when patients sparking his realisation that selenoproteins for Sec biosynthesis. When specifically explain yourself... selenoprotein does in each brain cell Wilhelms-Universität Bonn. with mutations in the SECIS-binding protein may be of vital importance to brain function. inactivated in the neurons, the researchers type and how. In addition, I have recently were found to have growth delay and blunted Since then, Dr Schweizer and his researchers discovered a developmental defect Why do you think selenocysteine is started to investigate the biochemistry CONTACT response to thyroid hormones. Both can be have embarked on a project to investigate affecting a specific subgroup of inhibitory essential to mammals but is absent of selenoprotein biosynthesis, i.e., how Prof Dr Ulrich Schweizer explained by Sec's presence in deiodinases. the role of selenoproteins in neuronal interneurons. This found that there was from many other organisms? exactly the ribosome is instructed to Rheinische Friedrich-Wilhelms- Deiodinases are a group of selenoenzymes function, looking at how they are implicated not only a reduction of interneurons, but One reason might be that a selenoenzyme incorporate Sec – instead of terminating Universität Bonn / Universitätsklinikum that are responsible for the activation and in neurological disease. the mice also suffered from seizures and may be 1000-fold faster than the same protein biosynthesis. Along these lines, Bonn deactivation of thyroid hormones on the ataxia, a failure to gain postural control, and enzyme with cysteine. For complex cells, we are studying the function of the tRNA Institut für Biochemie tissue level. Thyroid hormones are known to Prior to this discovery, only few earlier a failure to coordinate their movements. like ours, the selenoenzyme thus saves a carrying Sec, which has recently been und Molekularbiologie be central to development and play a key role reports had highlighted the potential link Histological analysis of the mouse brain tissue lot of space that can be occupied by other found to be mutated in a patient with Nussallee 11 in energy expenditure and metabolism and, between epilepsy
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