Researcher:
Gül, Şeref

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Şeref

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Gül

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Gül, Şeref

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2016 - 201952020 - 202214

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Researcher Of Publications: search.filters.isAuthorOfPublication.29013d06-d6f1-4799-b11a-83e154ec2e52

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Now showing 1 - 10 of 19
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    Identification and characterization of a new class of (6−4) photolyase from Vibrio cholerae
    (Amer Chemical Soc, 2019) Ozcelik, Gozde; Ozturk, Nuri; N/A; N/A; Department of Chemical and Biological Engineering; Department of Molecular Biology and Genetics; Department of Chemical and Biological Engineering; Dikbaş, Uğur Meriç; Tardu, Mehmet; Gül, Şeref; Barış, İbrahim; Kavaklı, İbrahim Halil; Master Student; PhD Student; Researcher; Teaching Faculty; Faculty Member; Department of Molecular Biology and Genetics; Department of Chemical and Biological Engineering; Graduate School of Sciences and Engineering; Graduate School of Sciences and Engineering; College of Engineering; College of Sciences; College of Engineering; N/A; N/A; N/A; 111629; 40319
    Light is crucial for many biological activities of most organisms, including vision, resetting of circadian rhythm, photosynthesis, and DNA repair. The cryptochrome/photolyase family (CPF) represents an ancient group of UV-A/blue light sensitive proteins that perform different functions such as DNA repair, circadian photoreception, and transcriptional regulation. The CPF is widely distributed throughout all organisms, including marine prokaryotes. The bacterium Vibrio cholerae was previously shown to have a CPD photolyase that repairs UV-induced thymine dimers and two CRY-DASHs that repair UV-induced single-stranded DNA damage. Here, we characterize a hypothetical gene Vca0809 encoding a new member of CPF in this organism. The spectroscopic analysis of the purified protein indicated that this enzyme possessed a catalytic cofactor, FAD, and photoantenna chromophore 6,7-dimethyl 8-ribityllumazin. With a slot blot-based DNA repair assay, we showed that it possessed (6-4) photolyase activity. Further phylogenetic and computational analyses enabled us to classify this gene as a member of the family of iron-sulfur bacterial cryptochromes and photolyases (FeS-BCP). Therefore, we named this gene Vc(6-4) FeS-BCP.
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    Glu-370 in the large subunit influences the substrate binding, allosteric, and heat stability properties of potato ADP-glucose pyrophosphorylase
    (Elsevier Ireland Ltd, 2016) Çalışkan, Mahmut; Cevahir, Gül; N/A; Department of Chemical and Biological Engineering; N/A; Department of Molecular Biology and Genetics; N/A; Department of Chemical and Biological Engineering; Seferoğlu, Ayşe Bengisu; Gül, Şeref; Dikbaş, Uğur Meriç; Barış, İbrahim; Koper, Kaan; Kavaklı, İbrahim Halil; PhD Student; Researcher; Master Student; Teaching Faculty; Master Student; Faculty Member; Department of Molecular Biology and Genetics; Department of Chemical and Biological Engineering; Graduate School of Sciences and Engineering; College of Engineering; Graduate School of Sciences and Engineering; College of Sciences; Graduate School of Sciences and Engineering; College of Engineering; N/A; 289253; N/A; 111629; N/A; 40319
    ADP-glucose pyrophosphorylase (AGPase) is a key allosteric enzyme in plant starch biosynthesis. Plant AGPase is a heterotetrameric enzyme that consists of large (LS) and small subunits (SS), which are encoded by two different genes. In this study, we showed that the conversion of Glu to Gly at position 370 in the LS of AGPase alters the heterotetrameric stability along with the binding properties of substrate and effectors of the enzyme. Kinetic analyses revealed that the affinity of the (LSSSWT)-S-E370G AGPase for glucose 1-phosphate is 3-fold less than for wild type (WT) AGPase. Additionally, the (LSSSWT)-S-E370G AGPase requires 3-fold more 3-phosphogyceric acid to be activated. Finally, the LS(E370G)SS(WT)AGPase is less heat stable compared with the WT AGPase. Computational analysis of the mutant Gly-370 in the 3D modeled LS AGPase showed that this residue changes charge distribution of the surface and thus affect stability of the LS AGPase and overall heat stability of the heterotetrameric AGPase. In summary, our results show that LSE370 intricately modulate the heat stability and enzymatic activity of potato the AGPase.
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    The structure-based molecular-docking screen against core clock proteins to identify small molecules to modulate the circadian clock
    (Humana Press Inc., 2022) N/A; Department of Chemical and Biological Engineering; Department of Chemical and Biological Engineering; Kavaklı, İbrahim Halil; Gül, Şeref; Faculty Member; Researcher; Department of Chemical and Biological Engineering; College of Engineering; College of Engineering; 40319; N/A
    Circadian rhythms are part of the body’s clock, which regulates several physiological and biochemical variables according to the 24-h cycle. Ample evidence indicated disturbance of the circadian clock leads to an increased susceptibility to several diseases. Therefore, a great effort has been made to find small molecules that regulate circadian rhythm by high-throughput methods. Having crystal structures of core clock proteins, makes them amenable to structure-based drug design studies. Here, we describe virtual screening methods that can be utilized for the identification of small molecules regulating the activity of core clock protein Cryptochrome 1.
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    In silico analysis of a de novo OTC variant as a cause of ornithine transcarbamylase deficiency
    (Lippincott Williams and Wilkins, 2022) Ozdemir, Yesim; Cag, Murat; Gul, Seref; Yuksel, Zafer; Ergoren, Mahmut C.; Department of Chemical and Biological Engineering; Gül, Şeref; Researcher; Department of Chemical and Biological Engineering; College of Engineering; N/A
    Ornithine transcarbamylase deficiency (OTCD) is the most common X-linked hereditary disorder of urea cycle disorders that is caused by neonatal hyperammonemia. OTC gene sequence variations are common causes of OTCD. The current study presents a 28-month-old baby girl proband with phenotypical characteristics of OTCD such as irritability, somnolence, intermittent vomiting, and high levels of serum ammonium. Whole-exome sequencing revealed a de novo c.275G > A p. (Arg92Gln) variant within the OTC gene. In silico analysis revealed a possible differential affinity between wild-type and mutant OTCase, while Arg92Gln decreases the binding ability of OTCase to the substrate, which can disrupt the urea cycle and explains the molecular pathogenicity of clinical hyper-ammonemia. In light of the fact that the genotype and phenotype correlation of OTCD is still uncertain, the present in silico analysis outcome can enhance our knowledge on this complicated, rare, and severe genetic disorder.
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    Allosteric regulation of CRYs in mammalian circadian clock
    (Elsevier B.V., 2021) N/A; Department of Chemical and Biological Engineering; Department of Chemical and Biological Engineering; N/A; Kavaklı, İbrahim Halil; Gül, Şeref; Özcan, Onur; Faculty Member; Researcher; PhD Student; Department of Chemical and Biological Engineering; College of Engineering; College of Engineering; Graduate School of Sciences and Engineering; 40319; N/A; N/A
    Mammalian circadian clocks are composed of transcriptional-translational feedback loops. Transcriptional activators (BMAL1/CLOCK) form positive arm and transcriptional repressors (CRYPTOCHROMEs (CRYs) and PERIODs (PERs)) form the negative arm of the clock mechanism in mammals. CRYs have conserved primary (FAD binding) and secondary pockets critical to interact with different proteins. Despite high structural similarities between CRY1 and CRY2, studies suggest each CRY plays a different role in the circadian clock. For example, the binding of the CRY1 to CLOCK is regulated by a dynamic serine-rich loop (Ser-loop) around the secondary pocket. A recent report showed that a distant residue Arg-293 allosterically regulates the Ser-loop in CRY1. Here, using molecular dynamics simulations, we showed that Arg-311 to His mutation in CRY2 (homolog of Arg-293 of CRY1) had a minor effect on the allosteric path to Ser-loop.
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    Transcriptome analysis of the circadian clock gene bmal1 deletion with opposite carcinogenic effects
    (Springer Heidelberg, 2021) Emisoglu-Kulahli, Handan; Morgil, Hande; Aygenli, Fatih; Selvi, Saba; Ozturk, Nuri; Department of Chemical and Biological Engineering; Department of Chemical and Biological Engineering; N/A; Gül, Şeref; Kavaklı, İbrahim Halil; Özcan, Onur; Researcher; Faculty Member; N/A; Department of Chemical and Biological Engineering; College of Engineering; College of Engineering; N/A; N/A; 40319; N/A
    We have previously reported that the deletion of BMAL1 gene has opposite effects in respect to its contribution to the pathways that are effective in the multistage carcinogenesis process. BMAL1 deletion sensitized nearly normal breast epithelial (MCF10A) and invasive breast cancer cells (MDA-MB-231) to cisplatin- and doxorubicin-induced apoptosis, while this deletion also aggravated the invasive potential of MDA-MB-231 cells. However, the mechanistic relationship of the seemingly opposite contribution of BMAL1 deletion to carcinogenesis process is not known at genome-wide level. In this study, an RNA-seq approach was taken to uncover the differentially expressed genes (DEGs) and pathways after treating BMAL1 knockout (KO) or wild-type (WT) MDA-MB-231 cells with cisplatin and doxorubicin to initiate apoptosis. Gene set enrichment analysis with the DEGs demonstrated that enrichment in multiple genes/pathways contributes to sensitization to cisplatin- or doxorubicin-induced apoptosis in BMAL1-dependent manner. Additionally, our DEG analysis suggested that non-coding transcript RNA (such as lncRNA and processed pseudogenes) may have role in cisplatin- or doxorubicin-induced apoptosis. Protein-protein interaction network obtained from common DEGs in cisplatin and doxorubicin treatments revealed that GSK3 beta, NACC1, and EGFR are the principal genes regulating the response of the KO cells. Moreover, the analysis of DEGs among untreated BMAL1 KO and WT cells revealed that epithelial-mesenchymal transition genes are up-regulated in KO cells. As a negative control, we have also analyzed the DEGs following treatment with an endoplasmic reticulum (ER) stress-inducing agent, tunicamycin, which was affected by BMAL1 deletion minimally. Collectively, the present study suggests that BMAL1 regulates many genes/pathways of which the alteration in BMAL1 KO cells may shed light on pleotropic phenotype observed.
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    Identification of a novel de novo COMP gene variant as a likely cause of pseudoachondroplasia
    (Lippincott Williams and Wilkins, 2021) Tuncel, Gulten; Akcan, Nese; Sag, Sebnem O.; Bundak, Ruveyde; Mocan, Gamze; Temel, Sehime G.; Ergoren, Mahmut C.; Department of Chemical and Biological Engineering; Gül, Şeref; Researcher; Department of Chemical and Biological Engineering; College of Engineering; N/A
    Next-generation sequencing technology and advanced sequence analysis techniques are markedly speeding up the identification of gene variants causing rare genetic diseases. Pseudoachondroplasia (PSACH, MIM 177170) is a rare disease inherited in an autosomal dominant manner. It is known that variations in the cartilage oligomeric matrix protein (COMP) gene are associated with the disease. Here, we report a 39-month-old boy with short stature. He gave visible growth and development delayed phenotype after 12 months. Further genetic resequencing analysis was carried out to identified the disease-causing variant. Furthermore, computational approaches were used to characterize the effect of the variant. In this study, we identify and report a novel variation in the COMP gene, c.1420_1422del (p.Asn47del), causing a spontaneous form of PSACH in our patient. Our in silico model indicated that any mutational changes in this region are very susceptible to PASCH phenotype. Overall, this study is the first PSACH case in the Turkish Cypriot population. Moreover, this finding contributes to the concept that the genotype-phenotype correlation in COMP is still unknown and also improves our understanding of this complex disorder.
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    A CLOCK-binding small molecule disrupts the interaction between CLOCK and BMAL1 and enhances circadian rhythm amplitude
    (Elsevier, 2020) Akyel, Yasemin Kübra; Yılmaz, Fatma; Öztürk, Nuri; Öztürk, Narin; Okyar, Alper; N/A; N/A; Department of Chemical and Biological Engineering; N/A; Department of Molecular Biology and Genetics; Department of Industrial Engineering; Department of Chemical and Biological Engineering; Doruk, Yağmur Umay; Yarparvar, Darya; Gül, Şeref; Taşkın, Ali Cihan; Barış, İbrahim; Türkay, Metin; Kavaklı, İbrahim Halil; Master Student; PhD Student; Researcher; Other; Teaching Faculty; Faculty Member; Faculty Member; Department of Molecular Biology and Genetics; Department of Industrial Engineering; Department of Chemical and Biological Engineering; Graduate School of Sciences and Engineering; Graduate School of Sciences and Engineering; College of Engineering; N/A; College of Sciences; College of Engineering; College of Engineering; N/A; N/A; N/A; 291296; 111629; 24956; 40319
    Proper function of many physiological processes requires a robust circadian clock. Disruptions of the circadian clock can result in metabolic diseases, mood disorders, and accelerated aging. Therefore, identifying small molecules that specifically modulate regulatory core clock proteins may potentially enable better management of these disorders. In this study, we applied a structure-based molecular-docking approach to find small molecules that specifically bind to the core circadian regulator, the transcription factor circadian locomotor output cycles kaput (CLOCK). We identified 100 candidate molecules by virtual screening of ?2 million small molecules for those predicted to bind closely to the interface in CLOCK that interacts with its transcriptional co-regulator, Brain and muscle Arnt-like protein-1 (BMAL1). Using a mammalian two-hybrid system, real-time monitoring of circadian rhythm in U2OS cells, and various biochemical assays, we tested these compounds experimentally and found one, named CLK8, that specifically bound to and interfered with CLOCK activity. We show that CLK8 disrupts the interaction between CLOCK and BMAL1 and interferes with nuclear translocation of CLOCK both in vivo and in vitro. Results from further experiments indicated that CLK8 enhances the amplitude of the cellular circadian rhythm by stabilizing the negative arm of the transcription/translation feedback loop without affecting period length. Our results reveal CLK8 as a tool for further studies of CLOCK's role in circadian rhythm amplitude regulation and as a potential candidate for therapeutic development to manage disorders associated with dampened circadian rhythms.
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    Unique combination and in silico modeling of biallelic polr3a variants as a cause of wiedemann-rautenstrauch syndrome
    (Springernature, 2020) Temel, Sehime Gulsun; Ergoren, Mahmut Cerkez; Manara, Elena; Paolacci, Stefano; Tuncel, Gulten; Bertelli, Matteo; Department of Chemical and Biological Engineering; Gül, Şeref; Researcher; Department of Chemical and Biological Engineering; College of Engineering; N/A
    Neonatal progeroid syndrome or Wiedemann-Rautenstrauch syndrome (WRS; MIM 264090) is a rare genetic disorder that has clinical symptoms including premature aging, lipodystrophy, and variable mental impairment. Until recently genetic background of the disease was unclear. However, recent studies have indicated that WRS patients have compound heterozygote variations in thePOLR3A(RNA polymerase III subunit 3A; MIM 614258) gene that might be responsible for the disease phenotype. In this study we report a WRS patient that has compound heterozygote variations in thePOLR3Agene. One of the reported variations in our patient, c.3568C>T, p.(Gln1190Ter), is a novel variation that was not reported before. The other variant, c.3337-11T>C, was previously shown in WRS patients in trans with other variations.
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    In silico identification of widely used and well-tolerated drugs as potential SARS-CoV-2 3C-like protease and viral RNA-dependent RNA polymerase inhibitors for direct use in clinical trials
    (Taylor _ Francis, 2020) Asar, Sinan; Okyar, Alper; Department of Chemical and Biological Engineering; Department of Molecular Biology and Genetics; Gül, Şeref; Özcan, Onur; Barış, İbrahim; Kavaklı, İbrahim Halil; Researcher; Teaching Faculty; Faculty Member; Department of Chemical and Biological Engineering; Department of Molecular Biology and Genetics; Graduate School of Sciences and Engineering; N/A; N/A; 111629; 40319
    Despite strict measures taken by many countries, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to be an issue of global concern. Currently, there are no clinically proven pharmacotherapies for coronavirus disease 2019, despite promising initial results obtained from drugs such as azithromycin and hydroxychloroquine. Therefore, the repurposing of clinically approved drugs for use against SARS-CoV-2 has become a viable strategy. Here, we searched for drugs that target SARS-CoV-2 3C-like protease (3CL(pro)) and viral RNA-dependent RNA polymerase (RdRp) by in silico screening of the U.S. Food and Drug Administration approved drug library. Well-tolerated and widely used drugs were selected for molecular dynamics (MD) simulations to evaluate drug-protein interactions and their persistence under physiological conditions. Tetracycline, dihydroergotamine, ergotamine, dutasteride, nelfinavir, and paliperidone formed stable interactions with 3CL(pro)based on MD simulation results. Similar analysis with RdRp showed that eltrombopag, tipranavir, ergotamine, and conivaptan bound to the enzyme with high binding free energies. Docking results suggest that ergotamine, dihydroergotamine, bromocriptine, dutasteride, conivaptan, paliperidone, and tipranavir can bind to both enzymes with high affinity. As these drugs are well tolerated, cost-effective, and widely used, our study suggests that they could potentially to be used in clinical trials for the treatment of SARS-CoV-2-infected patients.