{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Dihydroorotate dehydrogenase (DHODH) is a mitochondrial enzyme that catalyzes the oxidation of dihydroorotate to orotate—a key and rate‐limiting step in the de novo pyrimidine biosynthesis pathway. Through this reaction, DHODH links mitochondrial respiration (via its connection with electron transport chain complexes) to the production of pyrimidine nucleotides that are essential for DNA and RNA synthesis and thus for cell proliferation and development."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Mutations in the DHODH gene have been implicated in developmental disorders such as Miller syndrome, highlighting its critical role during embryogenesis. In several studies, genetic defects in DHODH were shown to reduce enzyme activity yet allow residual function, suggesting that even partial disruption of pyrimidine synthesis can have profound developmental consequences."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In cancer biology, DHODH has emerged as a pivotal metabolic regulator. Its activity underpins the rapid proliferation of tumor cells by supplying the necessary pyrimidine pools for DNA replication. Pharmacologic inhibition of DHODH, for instance with leflunomide or teriflunomide, disrupts pyrimidine biosynthesis. This not only induces cell-cycle arrest and apoptosis but also interferes with transcriptional processes critical for neural crest development and melanoma growth."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": " In addition, studies have shown that DHODH‐dependent pyrimidine biosynthesis is required to overcome metabolic cell‐cycle checkpoints during tumor formation, and its inhibition can directly impair tumorigenesis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n At the molecular level, DHODH has been found to interact physically with components of the respiratory chain (notably complexes II and III), thereby coupling mitochondrial function to nucleotide production. The disruption of this coupling can lead to mitochondrial dysfunction, altered reactive oxygen species generation, and abnormal cell-cycle progression."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Structural and pharmacologic studies have advanced the development of selective DHODH inhibitors, which are being explored for therapeutic applications in cancers as well as autoimmune diseases, such as rheumatoid arthritis. Furthermore, genetic polymorphisms in DHODH have been associated with differences in treatment outcomes, underscoring the enzyme’s clinical relevance."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "9", "end_ref": "12"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In summary, DHODH is central to linking mitochondrial respiration to nucleotide biosynthesis, a function that is crucial for normal embryonic development, tumor cell proliferation, and immune cell function. Its inhibition or mutation disrupts these processes and thereby represents both a pathogenic mechanism in developmental disorders and a promising therapeutic target in cancer and autoimmune conditions."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}, {"type": "fg_f", "ref": "3"}, {"type": "fg_f", "ref": "5"}, {"type": "fg_f", "ref": "7"}, {"type": "fg_f", "ref": "9"}, {"type": "fg_f", "ref": "6"}, {"type": "fg_f", "ref": "10"}, {"type": "fg_f", "ref": "8"}, {"type": "fg_f", "ref": "12"}, {"type": "fg_f", "ref": "2"}, {"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Sarah B Ng, Kati J Buckingham, Choli Lee, et al. 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