Staff Profile
Dr Sabrina Mackinnon
Research Associate
- Email: sabrina.mackinnon@ncl.ac.uk
- Personal Website: https://www.ncl.ac.uk/medical-sciences/research/institutes/biosciences/
- Address: Biosciences Institute
Catherine Cookson Building
Faculty of Medical Sciences
Newcastle University
Framlington Place
NE2 4HH
I am a Research Associate in Wyatt Yue’s lab where we aim to advance the understanding and treatment of rare metabolic disorders through the discovery of novel binding sites on disease-related enzymes, looking at how such enzymes interact with themselves and with other proteins, and by studying enzymes in a more native environment to explore their non-canonical – ‘moonlighting’ – functions.
Within the university, I am a member of the following:
- Biosciences Institute
- Discovery of Medicines research theme
- Molecular Mechanisms of Life research theme
- Centre for Rare Disease NUCoRE
My research to date has focussed on using fragment screening by X-ray crystallography, paired with enzyme activity and binding assays, to identify and improve small molecule inhibitors for the treatment of inborn errors of metabolism for which the pathogenic driver is accumulation of a toxic substrate.
Qualifications
D. Phil in Clinical Medicine 2015 - 2020
Nuffield Department of Medicine, University of Oxford
- Thesis title: Development of small molecule therapies for inborn errors of metabolism.
- Supervised by Associate Professor Wyatt Yue and Professor Paul Brennan
- Brief synopsis: Fragment screening by X-ray crystallography to identify, optimise and characterise small molecule inhibitors of metabolic enzymes for the treatment of metabolic disorders.
- Funded by the Nuffield Department of Medicine Prize Studentship.
- Maintained research blog: https://openlabnotebooks.org/category/scientist/sabrina-mackinnon/
- Awards: ‘Best scored’ poster at Study of Inborn Errors of Metabolism (SSIEM) annual conference (2016). Travel scholarship (€760 plus registration fee) for oral presentation at SSIEM annual conference (2018).
Pass with minor corrections 16th April 2020. Received Leave to Supplicate 3rd August 2020.
BSc (Hons) Bioscience with Biomedical Sciences 2011 - 2014
Robert Gordon University, Aberdeen.
- Dissertation: Influence of Cytochrome P450s in metabolic disease.
- Final year research project: A 16S rDNA fingerprinting assay for identification of unknown microorganisms.
- Nominated for Top Biology Student in Scotland Society of Biology award.
First Class Honours degree with Society of Biology 'Top Biology Student in University' prize.
Previous Positions
Postdoctoral Research Scientist - Metabolic Enzymes and Disorders 2019 - 2021
Centre for Medicines Discovery, University of Oxford. Collaboration with Evotec, funded by Lab282 grant.
- Large-scale expression, purification, and crystallisation of target protein
- Determination of X-ray crystal structures with inhibitor compounds
- Development of activity and solution binding assays for target protein
- Characterisation of inhibitor kinetics and binding
- Regular communication of results and plans to industrial collaborators.
Current Work
During my PhD, I worked on optimising approaches to protein production, crystallisation, biochemical and biophysical assays, fragment screening by X-ray crystallography and structure-guided drug design and applying them to develop inhibitors for two drug candidate targets. As a Research Associate here at Newcastle University, I am currently working on improving the potency of the molecules that I had developed in my PhD, to advance them towards clinical candidates. In a broader sense, my research interests lie in developing methodology for early drug discovery in rare metabolic disorders with the aim of developing first-in-class drug candidates and de-risking new drug discovery targets.
Expertise
Specialist knowledge in metabolic enzymes and disorders
X-ray crystallography for hit finding and hit validation
Luminescence and fluorescence-based assays to characterise potency, selectivity and mechanism of enzyme inhibitors
Structure-guided compound design and in silico docking of designed compounds
Structure-guided prediction of mutation effects
- Mackinnon SR, Krojer T, Foster WR, Diaz-Saez L, Tang M, Huber KVM, von Delft F, Lai K, Brennan PE, Arruda Bezerra G, Yue WW. Fragment Screening Reveals Starting Points for Rational Design of Galactokinase 1 Inhibitors to Treat Classic Galactosemia. ACS Chemical Biology 2021, 16(4), 586-595.
- Grünert SC, Foster W, Schumann A, Lund A, Pontes C, Roloff S, Weinhold N, Yue WW, AlAsmari A, Obaid OA, Faqeih EA, Stübbe L, Yamamoto R, Gemperle-Britschgi C, Walter M, Spiekerkoetter U, Mackinnon S, Sass JO. Succinyl-CoA:3-oxoacid coenzyme A transferase (SCOT) deficiency: A rare and potentially fatal metabolic disease. Biochimie 2021, 183, 55-62.
- Sokolovskaya OM, Plessl T, Bailey H, Mackinnon S, Baumgartner MR, Yue WW, Froese DS, Taga ME. Naturally occurring cobalamin (B12) analogs can function as cofactors for human methylmalonyl-CoA mutase. Biochimie 2020, 183, 35-43.
- Knerr I, Colombo R, Urquhart J, Morais A, Merinero B, Oyarzabal A, Pérez B, Jones SA, Perveen R, Preece MA, Rogers Y, Treacy EP, Mayne P, Zampino G, MacKinnon S, Wassmer E, Yue WW, Robinson I, Rodríguez-Pombo P, Olpin SE, Banka S. Expanding the genetic and phenotypic spectrum of branched-chain amino acid transferase 2 deficiency. Journal of Inherited Metabolic Disease 2019, 42(5), 809-817.
- Yue WW, Mackinnon S, Bezerra GA. Substrate reduction therapy for inborn errors of metabolism. Emerging topics in life sciences 2019, 3(1), 63-73.
- Haskovic M, Derks B, van der Ploeg L, Trommelen J, Nyakayiru J, van Loon LJC, Mackinnon S, Yue WW, Peake RWA, Zha L, Demirbas D, Qi W, Huang X, Berry GT, Achten J, Bierau J, Rubio-Gozalbo ME, Coelho AI. Arginine does not rescue p.Q188R mutation deleterious effect in classic galactosemia. Orphanet Journal of Rare Diseases 2018, 13(1), 212.
- Arruda Bezerra G, MacKinnon S, McCorvie T, Zhang M, Foster W, Fairhead M, Tumber A, Strain-Damerell C, Kopec J, Fitzpatrick F, Tang M, Whitby F, Lai K, Hill CP, Yue WW. Human Galactose-1-phosphate Uridylyltransferase (GALT), Galactokinase 1 (GALK1); A Target Enabling Package. Geneva: Zenodo, 2018. Available at: https://doi.org/10.5281/zenodo.3234909.
- MacKinnon S, Arruda Bezerra G, Krojer T, Bradley AR, Talon R, Brandao-Neto J, Douangamath A, Oppermann U, von Delft F, Brennan PE, Yue WW. Human Hydroxyacid Oxidase (HAO1); A Target Enabling Package. Geneva: Zenodo, 2018. Available at: https://doi.org/10.5281/zenodo.4153603.
- Demain LAM, Urquhart JE, O'Sullivan J, Williams SG, Bhaskar SS, Jenkinson EM, Lourenco CM, Heiberg A, Pearce SH, Shalev SA, Yue WW, Mackinnon S, Munro KJ, Newbury-Ecob R, Becker K, Kim MJ, O' Keefe RT, Newman WG. Expanding the genotypic spectrum of Perrault syndrome. Clinical Genetics 2017, 91(2), 302-312.
- Kopec J, Pena I, Rembeza E, McLaughlin M, Fedorov O, Strain-Damerell C, Goubin S, MacKinnon S, Burgess-Brown N, Brennan P, MacKenzie A, Arruda P, Yue WW. Human alpha-aminoadipic semialdehyde synthase (AASS); A Target Enabling Package. Geneva: Zenodo, 2017. Available at: https://doi.org/10.5281/zenodo.1219674.
- Ghosh A, Mercer J, Mackinnon S, Yue WW, Church H, Beesley CE, Broomfield A, Jones SA, Tylee K. IDUA mutational profile and genotype-phenotype relationships in UK patients with Mucopolysaccharidosis Type I. Human Mutation 2017, 38(11), 1555-1568.