Sami Ullah Khan

In the realm of cellular energy production, there exists a remarkable and essential protein known as Electron Transfer Flavoprotein (ETF). This protein plays a crucial role in the transfer of electrons, ultimately contributing to the generation of adenosine triphosphate (ATP) – the cell's primary energy currency. ETF acts as a bridge between two vital metabolic processes, connecting fatty acid oxidation and the electron transport chain. In this article, we will explore the fascinating world of ETF and its significance in cellular energy production.

ETF acts as an electron carrier protein, capable of accepting electrons from various enzymes involved in fatty acid oxidation. Its structure includes a flavin adenine dinucleotide (FAD) cofactor, enabling it to bind and transport electrons. Once ETF accepts electrons, it shuttles them to the electron transport chain, specifically to an enzyme complex called electron-transferring flavoprotein dehydrogenase (ETFdh). This transfer is essential because it allows the electrons to enter the electron transport chain, where they can be further processed and contribute to ATP synthesis.

Through ETF's involvement, the electrons derived from fatty acid oxidation bypass the initial steps of the electron transport chain, avoiding potential inefficiencies. This direct entry optimizes the utilization of these electrons for ATP production, enhancing the overall efficiency of cellular energy generation.

The significance of ETF extends beyond its role in fatty acid oxidation. ETF also participates in the metabolism of certain amino acids, such as lysine, tryptophan, and valine. These amino acids undergo degradation, generating electrons that can be transferred to ETF. This versatility showcases the protein's ability to adapt and contribute to energy production from various metabolic pathways.

Moreover, dysfunction or mutations in ETF can lead to severe metabolic disorders such as multiple acyl-CoA dehydrogenase deficiency (MADD) or glutaric aciduria type II, diabetes, and certain types of cancers.

Therefore, the focus of our research is to achieve a deeper understanding of the functional role of amino acids in the active site of EFT protein with regard to substrate recognition and stereo- and regiospecificity of the chemical transformation. In addition, we are also interested in substrate-triggered conformational changes and how enzymes utilize cofactors (flavin) to achieve catalysis.

To achieve our aims we employ a multidisciplinary approach encompassing kinetic, thermodynamic, spectroscopic and structural techniques. In addition, we use site-directed mutagenesis to generate enzyme variants to probe their functional role in the mentioned processes. Furthermore, we collaborate with our partners in academia and industry to develop inhibitors for enzymes, which can yield important new insights into enzyme mechanisms and can be useful as potential lead compounds in the design of new drugs.