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Raczynska J.E.,Institute of Bioorganic Chemistry | Wlodawer A.,Macromolecular Crystallography LaboratoryNational Cancer InstituteFrederick 21702Maryland | Jaskolski M.,Polish Academy of SciencesPoznan Poland
Proteins: Structure, Function and Bioinformatics | Year: 2016

In a recently published article (Yao, Flight, Rouchka, and Moseley, Proteins 2015;83:1470-1487) the authors proposed novel Zn coordination patterns in protein structures, apparently discovered using an unprejudiced approach to the information collected in the Protein data Bank (PDB), which they advocated as superior to the prior-knowledge-informed paradigm. In our assessment of those propositions we demonstrate here that most, if not all, of the "new" coordination geometries are fictitious, as they are based on incorrectly interpreted protein crystal structures, which in themselves are often not error-free. The flaws of interpretation include partial or wrong Zn sites, missed or wrong ligands, ignored crystal symmetry and ligands, etc. In conclusion, we warn against using this and similar meta-analyses that ignore chemical and crystallographic knowledge, and emphasize the importance of safeguarding structural databases against bad apples. © 2016 Wiley Periodicals, Inc.

News Article | December 12, 2016
Site: www.eurekalert.org

"Through the Installation Grants we encourage some of the best early-career researchers to share their expertise across Europe by setting up laboratories in selected EMBC Member States," explains EMBO Director Maria Leptin. "Each year, we receive applications from outstanding scientists, and it is a pleasure to be able to support them during this challenging career phase in order to establish scientific excellence across the whole continent." EMBO Installation Grants are awarded annually. They are funded primarily by the participating Member States Estonia, Poland, Portugal, Turkey and the Czech Republic. Grantees are selected by a committee of EMBO Members on the basis scientific excellence as the primary selection criterion. Each Installation Grantee receives 50,000 euros annually for three to five years to support the establishment of an independent research group. In addition to financial support, the recipients receive networking opportunities and practical support by becoming part of the EMBO Young Investigator network. Since 2006, EMBO has supported 89 group leaders through Installation Grants. Of the most recent awardees, four will establish laboratories in Turkey, two in Poland, two in Portugal, one in Estonia, and one in the Czech Republic. The next application deadline for EMBO Installation Grants is 15 April 2017. Melih Acar, Hematopoietic stem cell regulation, moving to Bahcesehir University, School of Medicine, Istanbul, TR, from UT Southwestern Medical Center, Dallas, TX, US Jaan-Olle Andressoo, Gene knock-up to treat Parkinson's disease, moving to Tallinn Institute of Technology, EE, from University of Helsinki, FI Claus Maria Azzalin, Telomeres, cancer and aging, moving to Institute of Molecular Medicine, Lisbon, PT, from Institute of Biochemistry, ETH Zurich, CH Murat Alper Cevher, Characterization of mediator-estrogen receptor interaction, moving to Bilkent University, Ankara, TR, from Rockefeller University, NY, US Rafal Ciosk, Cell fate plasticity in development and tissue homeostasis, moving to Institute of Bioorganic Chemistry, Poznan, PL, from Friedrich Miescher Institute for Biomedical Research, Basel, CH Elif Nur Firat-Karalar, Function and regulation of the centrosome/cilium complex, moving to Koç University, Istanbul, TR, from Stanford University, CA, USA Catarina Homem, Temporal and metabolic regulation of stem cells, Chronic Diseases Research Center, moving to Nova Medical School, PT, from Institute of Molecular Biotechnology of Austria, Vienna, AT Abdullah Kahraman, Non-coding cancer driver mutations in isoform networks, moving to Sabanci University, Istanbul, TR, from Institute of Molecular Life Sciences, University of Zurich, CH Vladimír Varga, Construction of the eukaryotic flagellum, moving to Institute of Molecular Genetics of the ASCR, Prague, CZ, from University of Oxford, UK Piotr Ziolkowski, Crossover control in plants, moving to Adam Mickiewicz University, Poznan, PL, from University of Cambridge, Cambridge, UK EMBO is an organization of more than 1700 leading researchers that promotes excellence in the life sciences. The major goals of the organization are to support talented researchers at all stages of their careers, stimulate the exchange of scientific information, and help build a European research environment where scientists can achieve their best work. EMBO helps young scientists to advance their research, promote their international reputations and ensure their mobility. Courses, workshops, conferences and scientific journals disseminate the latest research and offer training in techniques to maintain high standards of excellence in research practice. EMBO helps to shape science and research policy by seeking input and feedback from our community and by following closely the trends in science in Europe. ?For more information: http://www. The European Molecular Biology Conference (EMBC) is an intergovernmental organization comprising 29 Member States. EMBC promotes a strong transnational approach to the life sciences. Within EMBC, Member States pool their resources to improve the quality of research at a national level and to contribute to the advancement of basic research in Europe. For more information: http://www.

News Article | October 26, 2016
Site: www.eurekalert.org

World-renowned scientists - Prof. Ryszard Kierzek from the Institute of Bioorganic Chemistry Polish Academy of Sciences in Poznan and Prof. Douglas H. Turner from the University of Rochester - are the winners of the 2016 edition of the Poland - U.S. Science Award. The award is granted jointly by the Foundation for Polish Science, the biggest private institution supporting science in Poland, and the American Association for the Advancement of Science (AAAS), the world's largest general scientific association. The award is presented to a pair of scientists, one working in Poland and one in the United States, for outstanding scientific achievements resulting from their collaboration. This award highlights the role of Polish American scientific cooperation. It shows that the outcomes of this cooperation are great scientific achievements, which result from complimentary work on the part of both scientists. Their shared achievements would have been impossible had they worked separately. "We hope that the successes of our laureates become an inspiration for conducting joint scientific investigations for other researchers," said Prof. Maciej Zylicz, President of the Foundation for Polish Science. Professors Kierzek and Turner are being recognized for their research on thermodynamics, biology and structure of ribonucleic acid (RNA) and RNA chemical synthesis. The researchers started their cooperation more than 30 years ago. Because of their scientific work, it has become possible to predict the structure of any RNA based on its sequence. Their research also elucidated RNA folding rules and the use of modified oligonucleotides to modulate biological activity of pathogenic RNAs. Just one of the applications of this new knowledge is inhibiting the growth of the influenza virus. Since the onset of Prof. Kierzek and Prof. Turner's work, the thermodynamics and structure of RNA has had a great influence on the scientific community, especially on biochemists and biologists. Their collaboration has been hugely fruitful, with more than 60 joint publications, all with numerous citations. Prof. Ryszard Kierzek graduated with a degree in chemistry at Adam Mickiewicz University in Poznan. He obtained his Ph.D. in 1978 at the Polish Academy of Sciences Institute of Bioorganic Chemistry. He worked as a postdoctoral fellow at City of Hope National Medical Center and research fellow at the University of Colorado at Boulder, as well as acting as a visiting professor at the University of Rochester. Presently, he is the head of RNA Chemistry and Biology Laboratory at the Institute of Bioorganic Chemistry Polish Academy of Sciences in Poznan. In his research he uses the chemistry, biology, thermodynamics, bioinformatics and structure of RNA to modulate biological activity of RNA correlated with human diseases. He has published 150 scientific articles, which have been cited more than 6,000 times. He is a laureate of the Foundation for Polish Science MISTRZ award. Prof. Douglas H. Turner studied chemistry at Harvard University. He obtained his Ph.D. in physical chemistry at Columbia University. After his postdoctoral fellowship at the University of California at Berkeley, he became a professor of chemistry at the University of Rochester, and works there to this day. Prof. Turner is an internationally acclaimed expert on biophysics of RNA, especially in RNA thermodynamics. The parameters he developed, known as "Turner Rules," allow for the prediction of RNA folding. He has published more than 230 scientific articles, cited more than 15,000 times. The Poland - U.S. Science Award was established in 2013. It is granted once every two years in a competition based on nominations. A Jury of eminent scientists from Poland and the United States chooses the awardees using the opinions of external experts. Prof. Mariusz Jaskólski of Adam Mickiewicz University in Poznan, Poland, and Dr. Alexander Wlodawer of the National Cancer Institute, USA, were the first winners of the Poland - U. S. Science Award. The Jaskólski - Wlodawer team received the award for studies in structural biology. This second competition saw 29 nominations. The awards ceremony will be held in Warsaw on November 15, 2016. Each of the winners will receive the equivalent of five thousand U.S. dollars. The American Association for the Advancement of Science (AAAS) is the world's largest general scientific society and publisher of the journal Science as well as Science Translational Medicine, Science Signaling, a digital, open-access journal, Science Advances, Science Immunology, and Science Robotics. AAAS was founded in 1848 and includes nearly 250 affiliated societies and academies of science, serving 10 million individuals. Science has the largest paid circulation of any peer-reviewed general science journal in the world. The non-profit AAAS is open to all and fulfills its mission to "advance science and serve society" through initiatives in science policy, international programs, science education, public engagement, and more. For the latest research news, log onto EurekAlert!, the premier science-news Web site, a service of AAAS. See http://www. . The Foundation for Polish Science was established in 1991. It is a non-governmental, non-political, non-profit institution based in Warsaw, Poland, with the mission of supporting science. It is the largest source of science funding in Poland outside of the state budget. The Foundation awards prizes, stipends, subsidies and grants to leading scientists and research teams, encourages the transfer of scientific achievements to business practice and supports all kinds of initiatives that serve science in Poland. The funding is awarded by way of a competition, where the most important criterion in granting support is scientific excellence. The achievements and output of FNP competition entrants is evaluated by scientists respected in their fields - both Polish and international. The Foundation offers over a dozen diverse programmes for scientists at different stages of their research careers. The motto of FNP is: "Supporting the best, so that they can become even better". http://www.

Researchers at the Institute of Bioorganic Chemistry of the Russian Academy of Sciences have collaborated with colleagues from other research institutions and created a microfluidic system for ultra-high-performance screening in double emulsion droplets. This technique can be used when studying the unique properties of single living cells, and is 30,000 times more productive than robotic workstations. At the same time, it greatly simplifies the work of researchers involved in determining the functionality of biological objects for the creation of biomedicines. The results of this research were published in the PNAS journal. "Researchers tend to spend a lot of their working hours testing, purifying and isolating highly active proteins. So we have tried to solve this problem by developing an ultra-high-performance screening system for isolating biomolecules based on microfluidic emulsions. The result is a system that allows us to isolate interesting biological functions from the enormous diversity of any microscopic biological object, not only enzymes," explains Stanislav Terekhov, junior researcher at the Russian Academy of Sciences, one of the authors of the article. The idea came about three years ago, when Stanislav proposed developing a technology to quickly determine the activity of hundreds of millions of new enzymes produced by his colleague, Ivan Smirnov.This working group was engaged in creating and selecting biocatalysts from combinatorial libraries of enzymes that speed up reactions for which there are no natural enzymes. For example, for the inactivation of organophosphorus toxins, neuromuscular paralytic gases are relevant in connection with the growing use of pesticides and chemical warfare agents. The researchers had to spend years trying to obtain only a few dozen new proteins. Using the photolithography method used to create computer chips, researchers from the Institute of Bioorganic Chemistry and collaborators created microfluidic chips with channels with a thickness smaller than the diameter of a hair to generate emulsion droplets. The researchers used droplets of water-oil-water double emulsion to isolate single cells, allowing them to study their unique properties. Using microfluidic chips, Stanislav and his colleagues put the individual living cells into the droplets, after which the enzymatic and biological activity of the cells in the drops was studied using a fluorescence-activated cell sorter. The fluorescence drops helped detect the most active cells. The isolated cells in the drops were then further analyzed using classical molecular-biological methods and modern metabolic methods of analysis, as well as large-scale sequencing based on the Federal Clinical Research Centre's physical and chemical medicine. "As a result, we were able to obtain approximately 108 drops per hour, and in a day, we managed to isolate the necessary amount of enzymes with the required amount of activity," says Stanislav. "For example, we managed to improve the enzyme butyrylcholinesterase, which not only linked the organophosphorus toxin, but helped it to hydrolyze it, and link to the next toxin. Afterwards, we encapsulated bacterial cells in order to trace which microorganisms are inhibitors of the growth of the highly pathogenic bacteria Staphylococcus aureus. Thus, our screening method is suitable for discovering new drugs that are enzyme-based or based on microorganisms, their metabolites and other biological objects." This universal microfluidic screening platform that the researchers have developed requires significantly less time and financial resources. Explore further: A new type of monitoring provides information about the life of bacteria in microdroplets More information: Stanislav S. Terekhov et al. Microfluidic droplet platform for ultrahigh-throughput single-cell screening of biodiversity, Proceedings of the National Academy of Sciences (2017). DOI: 10.1073/pnas.1621226114

Borowczyk K.,International Center for Public Health | Borowczyk K.,University of Lodz | Shih D.M.,University of California at Los Angeles | Jakubowski H.,International Center for Public Health | And 2 more authors.
Journal of Alzheimer's Disease | Year: 2012

Homocysteine (Hcy)-thiolactone is toxic, induces epileptic seizures in rodents, and has been implicated in Alzheimer's disease. Paraoxonase 1 (Pon1), a component of high-density lipoprotein, hydrolyzes Hcy-thiolactone in vitro. Whether this reflects a physiological function and whether Pon1 can protect against Hcy-thiolactone toxicity was unknown. Here we show that Hcy-thiolactone was elevated in brains of Pon1 -/- mice (1.5-fold, p = 0.047) and that Pon1 -/- mice excrete more Hcy-thiolactone than wild type animals (2.4-fold, p = 0.047). The frequency of seizures induced by intraperitoneal injections of L-Hcy-thiolactone was significantly higher in Pon1 -/- mice compared with wild type animals (52.8% versus 29.5%, p = 0.042); the latency of seizures was lower in Pon1 -/- mice than in wild type animals (31.8 min versus 41.2 min, p = 0.019). Using the Pon1 null mice, we provide the first direct evidence that a specific Hcy metabolite, Hcy-thiolactone, rather than Hcy itself is neurotoxic in vivo. Our findings indicate that Pon1 protects mice against Hcy-thiolactone neurotoxicity by hydrolyzing it in the brain, and suggest a mechanism by which Pon1 can protect against neurodegeneration associated with hyperhomocysteinemia and Alzheimer's disease. © 2012-IOS Press and the authors. All rights reserved.

Perla-Kajan J.,International Center for Public Health | Perla-Kajan J.,University of Life Sciences in Poznań | Jakubowski H.,International Center for Public Health | Jakubowski H.,University of Life Sciences in Poznań | Jakubowski H.,Institute of Bioorganic Chemistry
FASEB Journal | Year: 2010

Genetic or nutritional disorders in homocysteine (Hcy) or folate metabolism elevate plasma Hcy-thiolactone and lead to vascular and/or brain pathologies. Hcy-thiolactone has the ability to form isopeptide bonds with protein lysine residues, which generates N-Hcy-protein with autoimmunogenic and prothrombotic properties. Paraoxonase (PON1), carried on high-density lipoproteins (HDLs) in the blood, hydrolyzes Hcy-thiolactone and protects against the accumulation of N-Hcy-protein in vitro. To determine its role in vivo, we studied how natural variation in Hcy-thiolactonase activity of PON1 affects plasma N-Hcy-protein levels in cystathionine β-synthase-deficient patients (n=28). We found that plasma N-Hcy-protein was negatively correlated with serum Hcy-thiolactonase activity (r=-0.43, P=0.01), i.e., the higher the Hcy-thiolactonase activity, the lower N-Hcy protein levels. This relation was faithfully replicated in vitro in experiments with radiolabeled Hcy-thiolactone. We also found that enzymatic activities of the PON1 protein measured with artificial substrates correlated less strongly (r=-0.36, P=0.025 for paraoxonase activity) or did not correlate at all (phenylacetate hydrolase and TBLase activities) with plasma N-Hcy protein. These findings provide evidence that the Hcy-thiolactonase activity of PON1 is a determinant of plasma N-Hcy-protein levels and that Hcy-thiolactonase/PON1 protects proteins against N-homocysteinylation in vivo, a novel mechanism likely to contribute to atheroprotective roles of HDL in humans. © FASEB.

Jakubowski H.,International Center for Public Health | Jakubowski H.,Institute of Bioorganic Chemistry | Jakubowski H.,University of Life Sciences in Poznań
FEBS Letters | Year: 2016

Coded peptide synthesis must have been preceded by a prebiotic stage, in which thioesters played key roles. Fossils of the Thioester World are found in extant aminoacyl-tRNA synthetases (AARSs). Indeed, studies of the editing function reveal that AARSs have a thiol-binding site in their catalytic modules. The thiol-binding site confers the ability to catalyze aminoacyl~coenzyme A thioester synthesis and peptide bond formation. Genomic comparisons show that AARSs are structurally related to proteins involved in sulfur and coenzyme A metabolisms and peptide bond synthesis. These findings point to the origin of the amino acid activation and peptide bond synthesis functions in the Thioester World and suggest that the present-day AARSs had originated from ancestral forms that were involved in noncoded thioester-dependent peptide synthesis. © 2016 Federation of European Biochemical Societies.

Suszynska-Zajczyk J.,Institute of Bioorganic Chemistry | Utyro O.,Institute of Bioorganic Chemistry | Utyro O.,University of Life Sciences in Poznań | Jakubowski H.,Institute of Bioorganic Chemistry | And 2 more authors.
Molecular Genetics and Metabolism | Year: 2014

Scope: Hyperhomocysteinemia (HHcy) induced by dietary or genetic factors is linked to kidney disease. Bleomycin hydrolase (Blmh) metabolizes Hcy-thiolactone to Hcy. We aimed to explain the role of dietary HHcy in kidney disease. Methods and results: We examined kidney proteome in dietary HHcy and Blmh-knockout mouse models using 2D IEF/SDS-PAGE gel electrophoresis and MALDI-TOF mass spectrometry. We found that the kidney proteome was altered by dietary HHcy and the Blmh-/- genotype. Proteins involved in metabolism of lipoprotein (ApoA1), amino acid and protein (Acy1, Hspd1), carbohydrate (Pdhb, Fbp1-isoform 1, Eno1), and energy metabolism (Ndufs8, Ldhd) were down-regulated. Proteins involved in carbohydrate metabolism (Fbp1-isoform 2), oxidative stress response (Prdx2), and detoxification (Glod4) were up-regulated. The Blmh-/- genotype down-regulated Glod4 isoform 3 mRNA but did not affect isoform 1 mRNA expression in mouse kidneys, suggesting post-transcriptional regulation of the Glod4 protein by the Blmh+/+ genotype. Responses of ApoA1, Acy1, Hspd1, Ndufs8, Fbp1, Eno1, and Prdx2 to HHcy and/or Blmh deficiency mimic their responses to renal disease. Conclusion: Our findings indicate that Blmh interacts with diverse cellular processes - lipoprotein, amino acid and protein, carbohydrate, and energy metabolisms, detoxification, antioxidant defenses - that are essential for normal kidney homeostasis and that deregulation of these processes can account for the involvement of HHcy in kidney disease. © 2014 Elsevier Inc.

Suszynska-Zajczyk J.,Institute of Bioorganic Chemistry | Luczak M.,Institute of Bioorganic Chemistry | Marczak L.,Institute of Bioorganic Chemistry | Jakubowski H.,Institute of Bioorganic Chemistry | And 2 more authors.
Journal of Alzheimer's Disease | Year: 2014

Homocysteine (Hcy) is a risk factor for Alzheimer's disease (AD). Bleomycin hydrolase (BLMH) participates in Hcy metabolism and is also linked to AD. The inactivation of the Blmh gene in mice causes accumulation of Hcy-thiolactone in the brain and increases susceptibility to Hcy-thiolactone-induced seizures. To gain insight into brain-related Blmh function, we used two-dimensional IEF/SDS-PAGE gel electrophoresis and MALDI-TOF/TOF mass spectrometry to examine brain proteomes of Blmh-/- mice and their Blmh+/+ littermates fed with a hyperhomocysteinemic high-Met or a control diet. We found that: 1) proteins involved in brain-specific function (Ncald, Nrgn, Stmn1, Stmn2), antioxidant defenses (Aop1), cell cycle (RhoGDI1, Ran), and cytoskeleton assembly (Tbcb, CapZa2) were differentially expressed in brains of Blmh-null mice; 2) hyperhomocysteinemia amplified effects of the Blmh-/- genotype on brain protein expression; 3) proteins involved in brain-specific function (Pebp1), antioxidant defenses (Sod1, Prdx2, DJ-1), energy metabolism (Atp5d, Ak1, Pgam-B), and iron metabolism (Fth) showed differential expression in Blmh-null brains only in hyperhomocysteinemic animals; 4) most proteins regulated by the Blmh-/- genotype were also regulated by high-Met diet, albeit in the opposite direction; and 5) the differentially expressed proteins play important roles in neural development, learning, plasticity, and aging and are linked to neurodegenerative diseases, including AD. Taken together, our findings suggest that Blmh interacts with diverse cellular processes from energy metabolism and anti-oxidative defenses to cell cycle, cytoskeleton dynamics, and synaptic plasticity essential for normal brain homeostasis and that modulation of these interactions by hyperhomocysteinemia underlies the involvement of Hcy in AD. © 2014 IOS Press and the authors. All rights reserved.

Borowczyk K.,International Center for Public Health | Borowczyk K.,University of Lodz | Tisonczyk J.,International Center for Public Health | Tisonczyk J.,Jagiellonian University | And 3 more authors.
Amino Acids | Year: 2012

Genetic or nutritional disorders in homocysteine (Hcy) metabolism elevate Hcy-thiolactone and cause heart and brain diseases. Hcy-thiolactone has been implicated in these diseases because it has the ability to modify protein lysine residues and generate toxic N-Hcy-proteins with auto-immunogenic, pro-thrombotic, and amyloidogenic properties. Bleomycin hydrolase (Blmh) has the ability to hydrolyze L-Hcy-thiolactone (but not D-Hcy-thiolactone) to Hcy in vitro, but whether this reflects a physiological function has been unknown. Here, we show that Blmh-/- mice excreted in urine 1.8-fold more Hcy-thiolactone than wild-type Blmh-/- animals (P = 0.02). Hcy-thiolactone was elevated 2.3-fold in brains (P = 0.004) and 2.0-fold in kidneys (P = 0.047) of Blmh-/- mice relative to Blmh-/- animals. Plasma N-Hcy-protein was elevated in Blmh-/- mice fed a normal (2.3-fold, P<0.001) or hyperhomocysteinemic diet (1.5-fold, P<0.001), compared with Blmh-/- animals. More intraperitoneally injected L-Hcy-thiolactone was recovered in plasma in Blmh-/- mice than in wild-type Blmh-/- animals (83.1 vs. 39.3 lM, P<0.0001). In Blmh-/- mice injected intraperitoneally with D-Hcy-thiolactone, D,L-Hcy-thiolactone, or L-Hcy-thiolactone, 88, 47, or 6.3%, respectively, of the injected dose was recovered in plasma. The incidence of seizures induced by L-Hcy-thiolactone injections (3,700 nmol/g body weight) was higher in Blmh -/- than in Blmh-/- mice (93.8 vs. 29.5%, P<0.001). Using the Blmh null mice, we provide the first direct evidence that a specific Hcy metabolite, Hcy-thiolactone, rather than Hcy itself, is neurotoxic in vivo. Taken together, our findings indicate that Blmh protects mice against L-Hcythiolactone toxicity by metabolizing it to Hcy and suggest a mechanism by which Blmh might protect against neurodegeneration associated with hyperhomocysteinemia and Alzheimer's disease. © 2011 Springer-Verlag. © 2011 Springer-Verlag.

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