| Structural highlights
6fmd is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | , , , , , , |
| Gene: | DHODH (HUMAN) |
| Activity: | Dihydroorotate dehydrogenase (quinone), with EC number 1.3.5.2 |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Disease
[PYRD_HUMAN] Defects in DHODH are the cause of postaxial acrofacial dysostosis (POADS) [MIM:263750]; also known as Miller syndrome. POADS is characterized by severe micrognathia, cleft lip and/or palate, hypoplasia or aplasia of the posterior elements of the limbs, coloboma of the eyelids and supernumerary nipples. POADS is a very rare disorder: only 2 multiplex families, each consisting of 2 affected siblings born to unaffected, nonconsanguineous parents, have been described among a total of around 30 reported cases.[1]
Function
[PYRD_HUMAN] Catalyzes the conversion of dihydroorotate to orotate with quinone as electron acceptor.
Publication Abstract from PubMed
Human dihydroorotate dehydrogenase ( hDHODH) catalyzes the rate-limiting step in de novo pyrimidine biosynthesis, the conversion of dihydroorotate to orotate. hDHODH has recently been found to be associated with acute myelogenous leukemia, a disease for which the standard of intensive care has not changed over decades. This work presents a novel class of hDHODH inhibitors, which are based on an unusual carboxylic group bioisostere 2-hydroxypyrazolo[1,5- a]pyridine, that has been designed starting from brequinar, one of the most potent hDHODH inhibitors. A combination of structure-based and ligand-based strategies produced compound 4, which shows brequinar-like hDHODH potency in vitro and is superior in terms of cytotoxicity and immunosuppression. Compound 4 also restores myeloid differentiation in leukemia cell lines at concentrations that are one log digit lower than those achieved in experiments with brequinar. This Article reports the design, synthesis, SAR, X-ray crystallography, biological assays, and physicochemical characterization of the new class of hDHODH inhibitors.
Targeting Myeloid Differentiation Using Potent 2-Hydroxypyrazolo[1,5- a]pyridine Scaffold-Based Human Dihydroorotate Dehydrogenase Inhibitors.,Sainas S, Pippione AC, Lupino E, Giorgis M, Circosta P, Gaidano V, Goyal P, Bonanni D, Rolando B, Cignetti A, Ducime A, Andersson M, Jarva M, Friemann R, Piccinini M, Ramondetti C, Buccinna B, Al-Karadaghi S, Boschi D, Saglio G, Lolli ML J Med Chem. 2018 Jul 9. doi: 10.1021/acs.jmedchem.8b00373. PMID:29939742[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Ng SB, Buckingham KJ, Lee C, Bigham AW, Tabor HK, Dent KM, Huff CD, Shannon PT, Jabs EW, Nickerson DA, Shendure J, Bamshad MJ. Exome sequencing identifies the cause of a mendelian disorder. Nat Genet. 2010 Jan;42(1):30-5. doi: 10.1038/ng.499. Epub 2009 Nov 13. PMID:19915526 doi:10.1038/ng.499
- ↑ Sainas S, Pippione AC, Lupino E, Giorgis M, Circosta P, Gaidano V, Goyal P, Bonanni D, Rolando B, Cignetti A, Ducime A, Andersson M, Jarva M, Friemann R, Piccinini M, Ramondetti C, Buccinna B, Al-Karadaghi S, Boschi D, Saglio G, Lolli ML. Targeting Myeloid Differentiation Using Potent 2-Hydroxypyrazolo[1,5- a]pyridine Scaffold-Based Human Dihydroorotate Dehydrogenase Inhibitors. J Med Chem. 2018 Jul 9. doi: 10.1021/acs.jmedchem.8b00373. PMID:29939742 doi:http://dx.doi.org/10.1021/acs.jmedchem.8b00373
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