Manuel Orozco

Manuel Orozco

Doctoral Student

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I hold a Bachelor's degree in Bioprocess Engineering from the Monterrey Institute of Technology (Mexico) and a Master's degree in Biotechnology from Lund University. I started my doctoral studies in November 2017 under the supervision of Wolfgang Knecht. We are interested in the structural biology of membrane proteins. Integral membrane proteins that interact with lipophilic substrates are particularly difficult to study. An example of this type of proteins is human dihydroorotate dehydrogenase (DHODH). DHODH is a flavoenzyme found in the inner mitochondrial membrane (IMM) that catalyses the oxidation of dihydroorotic acid with the concomitant reduction of ubiquinone Q10, thus acting as a link between pyrimidine nucleotide biosynthesis and the respiratory chain. Human DHODH is a well validated target for anti-inflammatory drugs and antiproliferative compounds that act as inhibitors. However, the mechanism by which DHODH interacts with lipids found in the IMM, with ubiquinone and with inhibitors are not well understood. Furthermore, certain mutations found in DHODH have been found to be the cause of Miller syndrome, a genetic disorder characterised by head and limb abnormalities. To answer these questions, we intend to reconstitute DHODH into supported lipid bilayers mimicking the composition and structure of the IMM, and to use neutron reflectometry and selective deuterium labelling to investigate the interactions between DHODH with ubiquinone and with known inhibitors. In addition, we will also investigate how certain mutations found in Miller syndrome affect those interactions.

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