Ongoing Projects
TUBITAK 2515 – COST Action 21162: “Computational Reengineering of Catalytically Promiscuous Lipases to Steer the Morita- Baylis-Hillman and Aldol Product Distribution” (Project No: 122Z506)
The development of high efficiency and selective eco-friendly catalysts that can selectively accelerate C-C coupling reactions, such as Morita-Baylis-Hillman (MBH) and aldol, which stand out especially in the acquisition of pharmaceutically important compounds, is of great importance in the synthesis of prominent pharmaceutical chemicals. Remarkably, the catalytic mechanism required for these C-C coupling reactions of industrial importance is present in natural enzymes. However, in order to repurpose these enzymes, information on binding site and catalytic elements is essential, that can only be investigated by computational methods. Burkholderia cepicia lipase gives 2 different reaction products (Aldol and MBH) from the same substrates, in other words, the enzyme shows promiscuous activity for 2 different reactions in an intriguing way. It is not clear how the enzyme catalysed the path to both products, whether it uses the same catalytic elements and region, and how it directs product distribution. Given the importance of C-C coupling reactions such as MBH and aldol in the synthesis of pharmaceuticals, the development of eco-friendly biocatalysts that can selectively direct product distribution from the same pair of substrates to MBH product and also selectively to aldol product is a prominent goal. In this project, it is aimed to illuminate how the same enzyme gives two different products with the same pair of substrates, the catalytic mechanism leading to these products and to redesign the enzyme to direct the product distribution in the direction of each product. For this purpose, a computational approach using different levels of calculations and protein design tools will be used.
TUBITAK 1001: “Development of Green Catalysts for Decontamination of Nerve Agents” (Project No: 123Z592)
Although organophosphorus (OP) compounds have been developed as pesticides and insecticides, they have been posing a serious threat as chemical warfare agents since their deadly effects on humans have been detected in years. These compounds, called nerve agents, inhibit acetylcholinesterase (AChE) by forming a covalent bond with the serine residue in the active region. This, in turn, leads to overstimulation of the nervous system, followed by respiratory failure and death. For this reason, development of catalysts that will bind nerve agents stronger than AChE and will break them down is still a very active area of research. This project aims to develop green catalysts for the decontamination of nerve agents. The insights to be obtained from high level computational methods within the scope of the project will constitute a very important basis for the studies in this field and greatly increases the widespread impact of the project.
“Allosteric Modification of Transaminases Using Evolutionary Footprints” Collaborative Study – Prof. Türkan Haliloğlu, Boğaziçi University
Transaminases are attractive enzymes to produce enantiopure amines. In the last decade, they are increasingly used to synthesize optically pure chiral amines, which are important intermediates in the synthesis of pharmaceuticals and other fine chemicals. However, the limited activity of these enzymes often causes a bottleneck of their application in biocatalysis. For this reason, the design of new enzymes with improved activity and also operability under industrial process conditions is a significant issue. Although a variety of studies focus on the development of new variants by mutations in the active site of the enzymes, it remains inadequately understood how beneficial the mutations far from the active site confer improved catalytic properties. Getting an insight into this issue would aid the design of new enzymes with higher catalytic activities. Moreover, for natural evolution, it is also shrouded in mystery how mutations far from the active site affect the active sites’ functions and also stability. Thus, the current challenge is to figure out how nature alters the function and biophysical properties of the enzymes by amino acid substitutions in both allosteric sites and active sites during evolution. In this study, the objective is to develop an understanding of the mutations that occurred during the natural evolution of a member of the omega-transaminases family, using computational tools and developing a new design conception. With this study, it is also possible to understand the role of cooperativity between allosteric sites and active sites of the enzymes in functionality.
NC Research 