Person: SARIYAR AKBULUT, BERNA
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SARIYAR AKBULUT
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Publication Open Access Repurposing bioactive aporphine alkaloids as efflux pump inhibitors(ELSEVIER, 2019-11) SARIYAR AKBULUT, BERNA; Avci, Fatma Gizem; Atas, Basak; Aksoy, Cemile Selin; Kurpejovic, Eldin; Toplan, Gizem Gulsoy; Gurer, Caglayan; Guillerminet, Maxime; Orelle, Cedric; Jault, Jean-Michel; Akbulut, Berna SariyarExtrusion of drugs or drug-like compounds through bacterial efflux pumps is a serious health issue that leads to loss in drug efficacy. Combinatorial therapies of low-efficacy drugs with efflux pump inhibitors may help to restore the activities of such drugs. In this quest, natural products are attractive molecules, since in addition to their wide range of bioactivities they may inhibit efflux pumps. The current work repurposed the bioactive alkaloid roemerine as a potential efflux pump inhibitor. In Bacillus subtilis, both Bmr and BmrA, belonging to the major facilitator and the ATP-binding cassette superfamilies, respectively, were found to be inhibited by roemerine. Scanning electron microscopy and RNA-Seq analyses showed that it potentiated the effect of berberine. Growth rates and checkerboard assays confirmed the synergy of roemerine and berberine and that roemerine prevented berberine efflux by inhibiting Bmr. Transport assays with inverted membrane vesicles prepared from Escherichia cob overexpressing BmrA showed that increasing roemerine concentration decreased the transport of doxorubicin, the BmrA substrate, confirming that roemerine may also be considered as an inhibitor of BmrA. Thus, these findings suggest that conjugation of roemerine to substrates of efflux pumps, Bmr and BmrA, may help to potentiate the activity of their drug substrates.Publication Open Access Tyrosinase-based production of L-DOPA by Corynebacterium glutamicum(SPRINGER, 2021-12) SARIYAR AKBULUT, BERNA; Kurpejovic, Eldin; Wendisch, Volker F.; Akbulut, Berna SariyarAn increase in the number of elderly people suffering from the symptoms of Parkinson's disease is leading to an expansion in the market size of 3,4-dihydroxyphenyl-l-alanine (l-DOPA), which is the most commonly used drug for the treatment of this disease. Need for better quality products through economically feasible and sustainable processes makes biotechnological approaches attractive. The current study is focused on heterologous expression of Ralstonia solanacearum tyrosinase in Corynebacterium glutamicum cells to produce l-DOPA during growth on glucose or glucose/xylose mixtures. Whole-cells pre-grown on glucose were further exploited for biotransformation of l-tyrosine to l-DOPA. To prevent l-DOPA oxidation, not only the most commonly used agent, ascorbic acid, but also for the first time, thymol was evaluated. The highest l-DOPA titer was 0.26 +/- 0.02 g/L at the end of growth on a mixture of 1% xylose and 3% glucose in the presence of 200 mu M thymol as the oxidation inhibitor. The ability to co-utilize glucose and xylose to reach this titer could make these cells ideal for l-DOPA production using hydrolyzed lignocellulosic biomass. When the pre-grown cells were further used for biotransformation, the highest l-DOPA yield was 0.61 +/- 0.02 g/gDCW with 4 mM ascorbic acid. Since l-tyrosine biotransformation is primarily dependent on tyrosinase activity, yield in this route could be improved by optimizing reaction conditions. As the industrial workhorse for amino acid production, these C. glutamicum cells will clearly benefit from strain development efforts and bioprocess optimization towards sustainable and economically feasible l-DOPA production.Publication Open Access A review on the mechanistic details of OXA enzymes of ESKAPE pathogens(2023-01-01) SARIYAR AKBULUT, BERNA; ÖZBEK SARICA, PEMRA; Avci F. G., Tastekil I., Jaisi A., ÖZBEK SARICA P., SARIYAR AKBULUT B.The production of beta-lactamases is a prevalent mechanism that poses serious pressure on the control of bacterial resistance. Furthermore, the unavoidable and alarming increase in the transmission of bacteria producing extended-spectrum beta-lactamases complicates treatment alternatives with existing drugs and/or approaches. Class D beta-lactamases, designated as OXA enzymes, are characterized by their activity specifically towards oxacillins. They are widely distributed among the ESKAPE bugs that are associated with antibiotic resistance and life-threatening hospital infections. The inadequacy of current beta-lactamase inhibitors for conventional treatments of \"OXA\" mediated infections confirms the necessity of new approaches. Here, the focus is on the mechanistic details of OXA-10, OXA-23, and OXA-48, commonly found in highly virulent and antibiotic-resistant pathogens Acinetobacter baumannii, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Enterobacter spp. to describe their similarities and differences. Furthermore, this review contains a specific emphasis on structural and computational perspectives, which will be valuable to guide efforts in the design/discovery of a common single-molecule drug against ESKAPE pathogens.Publication Open Access An evolutionarily conserved allosteric site modulates beta-lactamase activity(TAYLOR & FRANCIS LTD, 2016-11-03) SARIYAR AKBULUT, BERNA; Avci, Fatma Gizem; Altinisik, Fatma Ece; Vardar Ulu, Didem; Ozkirimli Olmez, Elif; Akbulut, Berna SariyarDeclining efficiency of antibiotic-inhibitor combinatorial therapies in treating beta-lactamase mediated resistance necessitates novel inhibitor development. Allosteric inhibition offers an alternative to conventional drugs that target the conserved active site. Here, we show that the evolutionarily conserved PWP triad located at the N-terminus of the H10 helix directly interacts with the allosteric site in TEM-1 beta-lactamase and regulates its activity. While point mutations in the PWP triad preserve the overall secondary structures around the allosteric site, they result in a more open and dynamic global structure with decreased chemical stability and increased aggregation propensity. These mutant enzymes with a less compact hydrophobic core around the allosteric site displayed significant activity loss. Detailed sequence and structure conservation analyses revealed that the PWP triad is an evolutionarily conserved motif unique to class A beta-lactamases aligning its allosteric site and hence is an effective potential target for enzyme regulation and selective drug design.