Dihydroorotate dehydrogenase in oxidative phosphorylation and cancer.

Stepana Boukalova, Sona Hubackova, Mirko Milosevic, Zuzana Ezrova, Jiri Neuzil, Jakub Rohlena

Journal: Biochimica et biophysica acta. Molecular basis of disease 2020;1866(6):165759

PMID: 32151633

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Abstract

Dihydroorotate dehydrogenase (DHODH) is an enzyme of the de novo pyrimidine synthesis pathway that provides nucleotides for RNA/DNA synthesis essential for proliferation. In mammalian cells, DHODH is localized in mitochondria, linked to the respiratory chain via the coenzyme Q pool. Here we discuss the role of DHODH in the oxidative phosphorylation system and in the initiation and progression of cancer. We summarize recent findings on DHODH biology, the progress made in the development of new, specific inhibitors of DHODH intended for cancer therapy, and the mechanistic insights into the consequences of DHODH inhibition.

Address: Institute of Biotechnology, Czech Academy of Sciences, BIOCEV, 252 50 Vestec, Prague-West, Czech Republic.; Institute of Biotechnology, Czech Academy of Sciences, BIOCEV, 252 50 Vestec, Prague-West, Czech Republic; Faculty of Science, Charles University, Prague, Czech Republic.; Institute of Biotechnology, Czech Academy of Sciences, BIOCEV, 252 50 Vestec, Prague-West, Czech Republic; School of Medical Science, Griffith University, Southport, 4222, Qld, Australia.; Institute of Biotechnology, Czech Academy of Sciences, BIOCEV, 252 50 Vestec, Prague-West, Czech Republic. Electronic address: [email protected].

DOI: 10.1016/j.bbadis.2020.165759

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MeSH Terms: Cell Proliferation, Dihydroorotate Dehydrogenase, Electron Transport, Enzyme Inhibitors, Humans, Mitochondria, Neoplasms, Oxidative Phosphorylation, Oxidoreductases Acting on CH-CH Group Donors, Ubiquinone