Servili, Burak

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Servili, Burak
B.,Servili
B. Servili
Burak, Servili
Servili, Burak
B.,Servili
B. Servili
Burak, Servili
Job Title
Misafir Öğr. Gör. Dr.
Email Address
Burak.servılı@khas.edu.tr
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Scholarly Output

5

Articles

4

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0

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1

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2021 - 20245
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Now showing 1 - 5 of 5
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    Article
    Citation Count: 12
    Sustainable production of formic acid from CO2 by a novel immobilized mutant formate dehydrogenase
    (Elsevier, 2023) Tulek, Ahmet; Gunay, Elif; Servili, Burak; Essiz, Sebnem; Binay, Baris; Yildirim, Deniz
    Formate dehydrogenase (NAD+-dependent FDH) is an enzyme that catalyzes the reversible oxidation of formate to CO2 while reducing NAD+ to NADH. The enzyme has been used in industrial and chemical applications for NADH regeneration for a long time. However, discovering the unique ability of FDHs, which is to reduce CO2 and produce formic acid, leads studies focusing on discovering or redesigning FDHs. Despite using various protein engineering techniques, these studies mostly target the same catalytic site amino acids of FDHs. Here, for the first time, the effect of an Asp188 mutation on a potential allosteric site in NAD+-dependent CtFDH around its subunit-subunit interface was studied by molecular modelling and simulation in the presence of bicarbonate and formate. Biochemical and kinetic characterization of this Asp188Arg mutant and wild type CtFDH enzymes were performed in detail. Both enzymes were also immobilized on newly synthesized MWCNT-Ni-O-Si/Ald and MWCNT-Ni-O-Si/Glu supports designed to overcome well-known CtFDH stability problems including thermostability and reuse resistance. Integrating mutation and immobilization provided about a 25-fold increase in catalytic efficiency for carbonate activity. The one-way ANOVA analysis also ensured significant effect of the mutation and immobilization on kinetic constants. After characterizing the immobilization of highly purified wild type and mutant enzyme with instrumental analysis techniques, the thermal stability of MWCNT-Ni-Si@wtCtFDH and MWCNT-Ni-Si@mt-CtFDH was found to increase about 11-and 18-fold, respectively, compared to their free counterparts at 50 degrees C. The mutant CtFDH and its immobilized counterpart produced around 2-fold more formic acid than those of wild type CtFDH and its immobilized counterpart under the same conditions. MWCNT-Ni-Si@wt-CtFDH and MWCNT-Ni-Si@mt-CtFDH remained around 82 % and 86 % of their initial activities respectively after lots of recycling. Integration of subunit interface amino acid position of NAD+ dependent FDHs engineering and immobilization provides a new insight can be scientifically and rationally employed for this current application FDHs as a solution to produce formic acids from renewable sources.
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    Article
    Citation Count: 2
    Correlated conformational dynamics of the human GluN1-GluN2A type N-methyl-D-aspartate (NMDA) receptor
    (SPRINGER, 2021) Esşiz, Şebnem; Gencel, Melis; Aktolun, Muhammed; Demir, Ayhan; Carpenter, Timothy S.; Servili, Burak
    N-Methyl-D-aspartate receptors (NMDARs) are glutamate-gated ion channels found in the nerve cell membranes. As a result of overexcitation of NMDARs, neuronal death occurs and may lead to diseases such as epilepsy, stroke, Alzheimer's disease, and Parkinson's disease. In this study, human GluN1- GluN2A type NMDAR structure is modeled based on the X-ray structure of the Xenopus laevis template and missing loops are added by ab-initio loop modeling. The final structure is chosen according to two different model assessment scores. To be able to observe the structural changes upon ligand binding, glycine and glutamate molecules are docked into the corresponding binding sites of the receptor. Subsequently, molecular dynamics simulations of 1.3 mu s are performed for both apo and ligand-bound structures. Structural parameters, which have been considered to show functionally important changes in previous NMDAR studies, are monitored as conformational rulers to understand the dynamics of the conformational changes. Moreover, principal component analysis (PCA) is performed for the equilibrated part of the simulations. From these analyses, the differences in between apo and ligand-bound simulations can be summarized as the following: The girdle right at the beginning of the pore loop, which connects M2 and M3 helices of the ion channel, partially opens. Ligands act like an adhesive for the ligand-binding domain (LBD) by keeping the bi-lobed structure together and consequently this is reflected to the overall dynamics of the protein as an increased correlation of the LBD with especially the amino-terminal domain (ATD) of the protein.
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    Doctoral Thesis
    Yapısal ve Mutasyonel Çalışmalar: Nmda Tipi Glutamat Reseptörü ve Format Dehidrogenaz Enziminin Moleküler Dinamik Simülasyonları
    (2023) Servili, Burak; Eşsiz, Şebnem
    Yapısal biyoloji ve moleküler dinamik (MD) simülasyon çalışmaları, moleküler düzeyde moleküller arası/içi etkileşimleri anlamanın temellerinden, ilaç ve protein tasarımının önde gelen yöntemlerinden biridir. Bu tez, iki farklı alandaki protein simülasyonlarından oluşmaktadır: Sinir hücrelerinde elektrik sinyali yayılımında bir iyon kanalı reseptör kompleksi olan N-metil-D-aspartat reseptörü (NMDAR) ve formatın bikarbonata biyokatalizinde format dehidrojenaz enzimi (FDH). Tezin ilk amacı NMDAR iyon kanalının açık yapısını mutasyonlarla elde etmektir. İkinci amaç ise allosterik bölgede Asp188Arg mutasyonu yaparak FDH enziminin hem format hem de bikarbonat substratları ile etkileşimlerini anlamaktır. Bu mutasyon deneysel olarak FDH'nin bikarbonat/CO2 yakalama için kullanımı yönünde olan ters reaksiyon için daha aktif bir enzim yaratmıştır. Bu amaçla, nano ölçekli moleküler dinamik (NAMD) uygulaması, kök-ortalama-kare sapması, kök-ortalama-kare dalgalanması ve protein-ligand etkileşim analizi yöntemleriyle birlikte simülasyonları çalıştırmak için kullanılmıştır. İlk durumda, NMDAR iyon kanalının üst kapısındaki Lurcher motifindeki alanin (A7), deneysel çalışmalara dayanarak arginin/tirozin ile değiştirildi. Analiz sonucunda NMDAR iyon kanalının açık yapısı elde edildi. FDH'nin MD simülasyonlarında, bikarbonat bağlı yapı, enzimin subtrat ve koenzim bağlanma bölgelerini ayıran önemli bir tuz köprüsünü korumuştur. Ek olarak, bağlanma bölgesinden substrat taşınımı, vahşi tip ve mutasyona uğramış yapılar için farklı yollar sergilemiştir. Her iki protein sistemi için de MD, harici pertürbasyonların proteinlerin yapısı ve işlevi, yani işlevsel mutasyonlar üzerindeki etkisini incelemek için ana araç olarak kullanılmıştır. Her iki protein de hareketlerin zaman ölçeği, sistem boyutu ve istenen ters reaksiyon yönünde düşük enzim aktivitesi nedeniyle yapısal bir çalışma için karmaşık sistemler oluşturmuştur.
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    Article
    Citation Count: 0
    Newly Synthesized 6-Substituted Piperazine/Phenyl-9-cyclopentyl Containing Purine Nucleobase Analogs Act as Potent Anticancer Agents and Induce Apoptosis via Inhibiting Src in Hepatocellular Carcinoma Cells
    (Royal Soc Chemistry, 2023) Bilget Guven, Ebru; Durmaz Sahin, Irem; Altiparmak, Duygu; Servili, Burak; Essiz, Sebnem; Cetin-Atalay, Rengul; Tuncbilek, Meral
    Newly synthesized 6-substituted piperazine/phenyl-9-cyclopentyl-containing purine nucleobase analogs were tested for their in vitro anticancer activity against human cancer cells. Compounds 15, 17-24, 49, and 56 with IC50 values less than 10 mu M were selected for further examination on an enlarged panel of liver cancer cell lines. Experiments revealed that compound 19 utilizes its high cytotoxic potential (IC50 < 5 mu M) to induce apoptosis in vitro. Compound 19 displayed a KINOMEscan selectivity score S35 of 0.02 and S10 of 0.01 and demonstrated a significant selectivity against anaplastic lymphoma kinase (ALK) and Bruton's tyrosine kinase (BTK) over other kinases. Compounds 19, 21, 22, 23, and 56 complexed with ALK, BTK, and (discoidin domain-containing receptor 2) DDR2 were analyzed structurally for binding site interactions and binding affinities via molecular docking and molecular dynamics simulations. Compounds 19 and 56 displayed similar interactions with the activation loop of the kinases, while only compound 19 reached toward the multiple subsites of the active site. Cell cycle and signaling pathway analyses exhibited that compound 19 decreases phosho-Src, phospho-Rb, cyclin E, and cdk2 levels in liver cancer cells, eventually inducing apoptosis.
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    Article
    Citation Count: 0
    Synthesis of New Imidazo[1,2-A]pyridine Triazole Hybrid Molecules as Potential Apoptotic Antitumor Agents
    (Wiley-v C H verlag Gmbh, 2024) Halac, Fatma Albayrak; Essiz, Sebnem; Servili, Burak; Altundas, Ramazan; Sucu, Bilgesu Onur; Kulu, Irem
    Novel imidazo[1,2-a]pyridines bearing 1,2,3-triazole moieties at the C3 position were synthesized. After the characterization of the synthesized compounds, their in vitro therapeutic activities were evaluated in various cancer cell lines (MCF7, A549, HePG2 and T98G). Methoxy substituted derivative was identified as the most potent compound based on the results of its anti-proliferative activity on various cancer cell lines, as well as showing no cytotoxicity on the healthy human fibroblast cell line (MRC-5). As an indicator of apoptosis, a significant decrease in the level of PARP protein was observed in the MCF7 cells treated with this derivative. Molecular docking studies were conducted on wide range of targets such as phosphoinositide 3-kinase (PI3K), cyclin-independent kinase 2 (CDK2), mitogen-activated protein kinase (MEK), insulin-like growth-factor-1 (IGF-1), tubulin, DNA topoisomerase, poly (ADP-ribose) polymerase (PARP) and B-cell lymphoma-2 (BCL2). All the compounds tested showed the lowest binding energies with target PARP1. Moreover, CDK2 and tubulin displayed relatively good binding scores. The docking poses and scores were cross-checked with two different software and multiple protein conformations were included to incorporate flexible protein docking features. Finally, drug-likeness properties of the compounds are further tested via Swiss-ADME software. Novel imidazo[1,2-a]pyridine-1,2,3-triazole derivatives have been synthesized and evaluated for antiproliferative activity against MCF7, A549, HePG2, T98G cell lines. Compound 5c was found to be more potent on PARP protein in MCF7 cell line. The synthesized compounds were docked to PI3K, CDK2, MEK1, IGF-1, TUB1, DNA topoisomerase, PARP1, and BCL2. The best docking poses for PARP1 and CDK2 were obtained from 5c, 5d and 5 f. image