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    Antiproliferative and Apoptotic Effects of Olive Leaf Extract Microcapsules on MCF-7 and A549 Cancer Cells
    (Amer Chemical Soc, 2023) Bal, Yildiz; Surmeli, Yusuf; Sanli-Mohamed, Gulsah
    Alginate microcapsules are a talented means for the deliveryofbroad curative biomacromolecules. In this study, we immobilized oliveleaf extract (OLE) by calcium alginate (CA) and chitosan-coated CA(CCA) and characterized the OLE-loaded CA and CCA. The cytotoxic effect,the cell cycle arrest, and the apoptotic effect of OLE and its microcapsuleswere investigated against breast adenocarcinoma (MCF-7) and lung carcinoma(A549). As a result, the loading capacity of OLE-CA and OLE-CCAwas found to be 80 and 99%, respectively, in optimal conditions. Also,OLE-CA and OLE-CCA were characterized by unique FTIRpeaks and morphological display relative to the empty CCA microcapsules.The cytotoxicity analysis showed that the IC50 values ofOLE-CA and OLE-CCA were determined to be 312 and 0.94 & mu;g mL(-1) against A549, respectively, whereasthese were found to be 865.4 and 425.5 & mu;g mL(-1) for MCF-7 cells. On the other hand, the OLE microcapsules did notpossess in any concentration of cytotoxic influence on the BEAS 2Bhealthy cell line. Also, the exposure of OLE-CCA to MCF-7 andA549 resulted in the arrest of more MCF-7 and A549 cells at the G0/G1phase compared to the OLE. A549 and MCF-7 cells were predominantlyfound in the late apoptosis phase and necrosis phase, respectively.Optical microscopy images confirmed that OLE microcapsules were moreeffective against MCF-7 and A549 than free OLE. The present work suggestedthat the OLE microcapsules might be administered as nutrition supplementsfor cancer therapy.
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    Exploring the Structural Insights of Thermostable Geobacillus esterases by Computational Characterization
    (Amer Chemical Soc, 2024) Surmeli, Yusuf; Durmus, Naciye; Sanli-Mohamed, Gulsah
    This study conducted an in silico analysis of two biochemically characterized thermostable esterases, Est2 and Est3, from Geobacillus strains. To achieve this, the amino acid sequences of Est2 and Est3 were examined to assess their biophysicochemical properties, evolutionary connections, and sequence similarities. Three-dimensional models were constructed and validated through diverse bioinformatics tools. Molecular dynamics (MD) simulation was employed on a pNP-C2 ligand to explore interactions between enzymes and ligand. Biophysicochemical property analysis indicated that aliphatic indices and theoretical T-m values of enzymes were between 82-83 and 55-65 degrees C, respectively. Molecular phylogeny placed Est2 and Est3 within Family XIII, alongside other Geobacillus esterases. DeepMSA2 revealed that Est2, Est3, and homologous sequences shared 12 conserved residues in their core domain (L39, D50, G53, G55, S57, G92, S94, G96, P108, P184, D193, and H223). BAN Delta IT analysis indicated that Est2 and Est3 had a significantly more rigid cap domain compared to Est30. Salt bridge analysis revealed that E150-R136, E124-K165, E137-R141, and E154-K157 salt bridges made Est2 and Est3 more stable compared to Est30. MD simulation indicated that Est3 exhibited greater fluctuations in the N-terminal region including conserved F25, cap domain, and C-terminal region, notably including H223, suggesting that these regions might influence esterase catalysis. The common residues in the ligand-binding sites of Est2-Est3 were determined as F25 and L167. The analysis of root mean square fluctuation (RMSF) revealed that region 1, encompassing F25 within the beta 2-alpha 1 loop of Est3, exhibited higher fluctuations compared to those of Est2. Overall, this study might provide valuable insights for future investigations aimed at improving esterase thermostability and catalytic efficiency, critical industrial traits, through targeted amino acid modifications within the N-terminal region, cap domain, and C-terminal region using rational protein engineering techniques.
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    Immobilization of Olive Leaf Extract with Chitosan Nanoparticles as an Adjunct to Enhance Cytotoxicity
    (Amer Chemical Soc, 2023) Ozdamar, Burcu; Surmeli, Yusuf; Sanli-Mohamed, Gulsah
    We immobilized the olive leaf extract (OLE) with chitosannanoparticles(CNPs) by optimizing the effect of various immobilization conditions,and OLE-loaded CNPs (OLE-CNPs) were then elaborately characterizedphysicochemically by scanning electron microscopy (SEM), Fourier transforminfrared (FT-IR) spectroscopy, dynamic light scattering (DLS), andatomic force microscopy (AFM). Under optimal conditions, CNPs wereable to accommodate the OLE with a loading capacity of 97.5%. Theresulting OLE-CNPs had a spherical morphology, and their average diameterwas approximately 100 nm. The cytotoxic influence, cell cycle distribution,and apoptosis stage of OLE and OLE-CNPs were analyzed on lung carcinoma(A549) and breast adenocarcinoma (MCF-7) cell lines. In an in vitrocytotoxic assay, IC50 values of OLE-CNPs were determinedto be 540 & mu;g/mL for A549 and 810 & mu;g/mL for MCF-7. Thetreatment of both A549 and MCF-7 with OLE-CNPs caused the highestcell arrest in G0/G1 in a dose-independent manner. OLE-CNPs affectedcell cycle distribution in a manner different from free OLE treatmentin both cancer cells. A549 and MCF-7 cells were predominantly foundin the late apoptosis and necrosis phases, respectively, upon treatmentof 1000 & mu;M OLE-CNPs. Our results suggest that CNPs enhance theutility of OLEs as nutraceuticals in cancer and that OLE-CNPs canbe utilized as an adjunct to cancer therapy.
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    In silico investigation of sequences and predicted three-dimensional homology models of thermoalkaliphilic GH13 ?-amylases
    (Springer, 2023) Tutuncu, Havva Esra; Surmeli, Yusuf
    Thermoalkaliphilic GH13 alpha-amylases are extensively used in various industrial processes, especially detergent formulations, saccharification of starch, production of bioethanol, and textile industry. This study purposed the comparative analysis of the evolutionary relationships, enzyme sequence similarities, three-dimensional structures, and protein-ligand interactions of three thermoalkaliphilic GH13 alpha-amylases of various bacterial sources (Caldicellulosiruptor changbaiensis = CcAmy, Caldicellulosiruptor saccharolyticus = CsAmy, Streptomyces mobaraensis = SmAmy). To do this, six thermoalkaliphilic amylase candidate sequences obtained from unreviewed protein entries of UniProt/TrEMBL database were investigated for their evolutionary relationships and sequence similarities by MEGA11 and Clustal Omega, respectively. The 3D homology models of the three a-amylases were built and cross-validated by various bioinformatics programs. Protein-ligand interactions were analyzed via molecular docking utilizing three ligands (maltobiose, maltotriose, and maltotetraose). The alignment analysis showed that six amylase candidates possessed highly conserved seven CSRs, three catalytic residues and seven Ca2+-binding site residues. Molecular phylogeny indicated that SmAmy belonged to GH13_32 subfamily, indicating that it could be a-amylase, whereas CcAmy and CsAmy belonged to GH13_36, indicating that they could be intermediary a-amylase having additional specificities like cyclomaltodextrinase and neopullulanase. Analysis of 3D models indicated that three a-amylases were structurally similar to each other containing three main domains (A, B, and C). BAN Delta IT analysis showed that all a-amylases might exhibit higher thermostability than the BlAmy. Docking analysis showed that active site residues including catalytic triad residues were involved in the polar interactions between each ligand and enzyme. Therefore, this work suggested that three alpha-amylases might stand out as candidates for the industrial processes that require thermoalkaliphilicity properties.
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    Lipases for targeted industrial applications, focusing on the development of biotechnologically significant aspects: A comprehensive review of recent trends in protein engineering
    (Elsevier, 2024) Vardar-Yel, Nurcan; Tutuncu, Havva Esra; Surmeli, Yusuf
    Lipases are remarkable biocatalysts, adept at catalyzing the breakdown of diverse compounds into glycerol, fatty acids, and mono- and di -glycerides via hydrolysis. Beyond this, they facilitate esterification, transesterification, alcoholysis, acidolysis, and more, making them versatile in industrial applications. In industrial processes, lipases that exhibit high stability are favored as they can withstand harsh conditions. However, most native lipases are unable to endure adverse conditions, making them unsuitable for industrial use. Protein engineering proves to be a potent technology in the development of lipases that can function effectively under challenging conditions and fulfill criteria for various industrial processes. This review concentrated on new trends in protein engineering to enhance the diversity of lipase genes and employed in silico methods for predicting and comprehensively analyzing target mutations in lipases. Additionally, key molecular factors associated with industrial characteristics of lipases, including thermostability, solvent tolerance, catalytic activity, and substrate preference have been elucidated. The present review delved into how industrial traits can be enhanced through directed evolution (epPCR, gene shuffling), rational design (FRESCO, ASR), combined engineering strategies (i.e. CAST, ISM, and FRISM) as protein engineering methodologies in contexts of biodiesel production, food processing, and applications of detergent, pharmaceutics, and plastic degradation.
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    Recent advances of structure, function, and engineering of carboxylesterases for the pharmaceutical industry: A minireview
    (Elsevier, 2025) Surmeli, Yusuf; Vardar-Yel, Nurcan; Tutuncu, Havva Esra
    Carboxylesterases have a wide range of applications due to their catalytic efficiency, robust structure, and broad substrate specificity. These enzymes, which can hydrolyze carboxylic acid esters, amides, and thioesters, stand out with their regio- and enantioselective properties. They play a crucial role in synthesizing pharmaceutical intermediates, including secondary and tertiary alcohols, alpha-hydroxy acids, and various bioactive compounds. However, in some cases, the enantioselectivity of carboxylesterases may be insufficient to achieve conversions with the purity required by the pharmaceutical industry. This review summarizes the crucial role of carboxylesterases, particularly in the pharmaceutical field, focusing on the classification, structure, and engineering approaches. After introducing the main families of carboxylesterases, the structural studies are presented to give a comprehensive insight into the active site architecture and related key determinants for enantioselectivity. The protein engineering studies to improve the enantioselectivity of carboxylesterases are discussed along with solvent engineering and immobilization applications.
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    Sequence identification and in silico characterization of novel thermophilic lipases from Geobacillus species
    (Wiley, 2024) Surmeli, Yusuf; Tekedar, Hasan Cihad; Sanli-Mohamed, Gulsah
    Microbial lipases are utilized in various biotechnological areas, including pharmaceuticals, food, biodiesel, and detergents. In this study, we cloned and sequenced Lip21 and Lip33 genes from Geobacillus sp. GS21 and Geobacillus sp. GS33, then we in silico and experimentally analyzed the encoded lipases. For this purpose, Lip21 and Lip33 were cloned, sequenced, and their amino acid sequences were investigated for determination of biophysicochemical characteristics, evolutionary relationships, and sequence similarities. 3D models were built and computationally affirmed by various bioinformatics tools, and enzyme-ligand interactions were investigated by docking analysis using six ligands. Biophysicochemical property of Lip21 and Lip33 was also determined experimentally and the results demonstrated that they had similar isoelectric point (pI) (6.21) and T-m (75.5(degrees)C) values as T-m was revealed by denatured protein analysis of the circular dichroism spectrum and pI was obtained by isoelectric focusing. Phylogeny analysis indicated that Lip21 and Lip33 were the closest to lipases from Geobacillus sp. SBS-4S and Geobacillus thermoleovorans, respectively. Alignment analysis demonstrated that S144-D348-H389 was catalytic triad residues in Lip21 and Lip33, and enzymes possessed a conserved Gly-X-Ser-X-Gly motif containing catalytic serine. 3D structure analysis indicated that Lip21 and Lip33 highly resembled each other and they were alpha/beta hydrolase-fold enzymes with large lid domains. BAN Delta IT analysis results showed that Lip21 and Lip33 had higher thermal stability, compared to other thermostable Geobacillus lipases. Docking results revealed that Lip21- and Lip33-docked complexes possessed common residues (H112, K115, Q162, E163, and S141) that interacted with the substrates, except paranitrophenyl (pNP)-C10 and pNP-C12, indicating that these residues might have a significant action on medium and short-chain fatty acid esters. Thus, Lip21 and Lip33 can be potential candidates for different industrial applications.
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    Unraveling the potential of uninvestigated thermoalkaliphilic lipases by molecular docking and molecular dynamic simulation: an in silico characterization study
    (Springer Heidelberg, 2024) Tutuncu, Havva Esra; Durmus, Naciye; Surmeli, Yusuf
    Thermoalkaliphilic lipase enzymes are mostly favored for use in the detergent industry. While there has been considerable research on Geobacillus lipases, a significant portion of these enzymes remains unexplored or undocumented in the scientific literature. This work performed in silico phylogeny, sequence alignment, structural and enzyme-substrate interaction analyses of the five thermoalkaliphilic lipases belonging to different Geobacillus species (Geobacillus stearothermophilus lipase = GsLip, Geobacillus sp. B4113_201601 lipase = Gb4Lip, Geobacillus kaustophilus HTA426 lipase = GkLip, Geobacillus sp. SP22 lipase = GspLip, Geobacillus sp. NTU 03 lipase = GntLip). For this purpose, unreviewed enzyme sequences of five Geobacillus thermoalkaliphilic lipases were analyzed at sequence and phylogeny levels. 3D homology enzyme models were built, validated, and investigated by different bioinformatics tools. The ligand interactions screening using seven para-nitrophenyl (pNP) esters and enzyme-ligand interactions were analyzed on Gb4Lip:pNP-C12 and BTL2:pNP-C12 by MD simulation. Biophysicochemical characteristic analysis showed that Gb4Lip had a theoretical T-m value of above 65 degrees C, and a higher aliphatic index indicating greater thermal stability. Sequence alignment showed a hydrophilic threonine in the alpha 6 helix of Gb4Lip, indicating high enzymatic activity. A normalized temperature factor B (B'-factor) analysis showed that the lid domains of five lipases significantly possessed lower B'-factor values, compared to G. thermocatenulatus lipase 2 (BTL2), indicating that they had higher rigidity. Molecular docking results indicated that the five lipases had the highest binding affinity toward pNP-C12. The RMSF investigation revealed that the thermostability of Gb4Lip is influenced by specific molecular elements: D202-S203 within the alpha B region of the lid domain, and E274-Q275 within the b3 strand, as well as W278 in the b3-b4 loop, and H282 in the b4 strand of the Ca2+-binding region. MD simulation analysis showed that catalytic residue S114 and at least one oxyanion hole residue (F17 and/or Q114) in Gb4Lip frequently formed hydrogen bonds with the pNP-C12 ligand at 343 K and 348 K throughout the simulation process, indicating that Gb4Lip might catalyze relatively long-chain ligand pNP-C12 with high performance. In conclusion, Gb4Lip might be a more suitable candidate as the detergent additive. In addition, this investigation can offer valuable perspectives on Family I.5 lipases such as Gb4Lip for future exploration in the field of protein engineering.