Complexed Crystal Structure of the Dihydroorotase Domain of Human CAD Protein with the Anticancer Drug 5-Fluorouracil.
5-fluorouracil
CAD
anticancer drug
crystal structure
dihydroorotase
dihydropyrimidinase
dynamic loop
fluorescence quenching
pyrimidine biosynthesis
Journal
Biomolecules
ISSN: 2218-273X
Titre abrégé: Biomolecules
Pays: Switzerland
ID NLM: 101596414
Informations de publication
Date de publication:
11 Jan 2023
11 Jan 2023
Historique:
received:
29
11
2022
revised:
05
01
2023
accepted:
09
01
2023
entrez:
21
1
2023
pubmed:
22
1
2023
medline:
25
1
2023
Statut:
epublish
Résumé
Dihydroorotase (DHOase) is the third enzyme in the pathway used for the biosynthesis of pyrimidine nucleotides. In mammals, DHOase is active in a trifunctional enzyme, CAD, which also carries out the activities of carbamoyl phosphate synthetase and aspartate transcarbamoylase. Prior to this study, it was unknown whether the FDA-approved clinical drug 5-fluorouracil (5-FU), which is used as an anticancer therapy, could bind to the DHOase domain of human CAD (huDHOase). Here, we identified huDHOase as a new 5-FU binding protein, thereby extending the 5-FU interactome to this human enzyme. In order to investigate where 5-FU binds to huDHOase, we solved the complexed crystal structure at 1.97 Å (PDB ID 8GVZ). The structure of huDHOase complexed with malate was also determined for the sake of comparison (PDB ID 8GW0). These two nonsubstrate ligands were bound at the active site of huDHOase. It was previously established that the substrate
Identifiants
pubmed: 36671534
pii: biom13010149
doi: 10.3390/biom13010149
pmc: PMC9856072
pii:
doi:
Substances chimiques
Dihydroorotase
EC 3.5.2.3
malic acid
817L1N4CKP
Malates
0
Ligands
0
Fluorouracil
U3P01618RT
Antineoplastic Agents
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : National Science and Technology Council, Taiwan
ID : NSTC 111-2622-E-025-002
Références
Pharmacogenetics. 1997 Feb;7(1):35-43
pubmed: 9110360
J Biol Chem. 2006 May 12;281(19):13762-13776
pubmed: 16517602
J Mol Biol. 2005 May 6;348(3):535-47
pubmed: 15826652
Acta Crystallogr D Biol Crystallogr. 2008 Jan;64(Pt 1):61-9
pubmed: 18094468
Methods Enzymol. 1997;276:307-26
pubmed: 27754618
Biochimie. 2020 Apr - May;171-172:124-135
pubmed: 32147511
Pharmaceuticals (Basel). 2022 Aug 28;15(9):
pubmed: 36145292
Biochimie. 2014 Jun;101:113-22
pubmed: 24418229
Clin Pharmacokinet. 1989 Apr;16(4):215-37
pubmed: 2656050
Acta Crystallogr D Biol Crystallogr. 2012 Apr;68(Pt 4):431-40
pubmed: 22505263
J Biol Chem. 2018 Dec 7;293(49):18903-18913
pubmed: 30315107
Acta Crystallogr D Biol Crystallogr. 2011 Apr;67(Pt 4):235-42
pubmed: 21460441
Nat Rev Mol Cell Biol. 2019 Jul;20(7):436-450
pubmed: 30976106
Protein Sci. 2021 Oct;30(10):1995-2008
pubmed: 34288185
J Biol Chem. 2004 Dec 17;279(51):53136-44
pubmed: 15381710
Acta Crystallogr D Biol Crystallogr. 2009 Jun;65(Pt 6):582-601
pubmed: 19465773
Gene. 1989 Jun 30;79(1):59-70
pubmed: 2570735
Plants (Basel). 2022 Jun 23;11(13):
pubmed: 35807620
Proc Natl Acad Sci U S A. 2022 Sep 27;119(39):e2202157119
pubmed: 36122209
Biochemistry. 2002 Jul 30;41(30):9410-7
pubmed: 12135362
Acta Crystallogr D Biol Crystallogr. 2010 Jan;66(Pt 1):12-21
pubmed: 20057044
Int J Mol Sci. 2021 Jun 25;22(13):
pubmed: 34202294
Structure. 2014 Feb 4;22(2):185-98
pubmed: 24332717
Bioinorg Chem Appl. 2022 Feb 14;2022:1817745
pubmed: 35198016
Clin Cancer Res. 2003 Oct 1;9(12):4363-7
pubmed: 14555507
Adv Protein Chem Struct Biol. 2020;122:63-96
pubmed: 32951816
Biochem Biophys Res Commun. 2021 Apr 30;551:33-37
pubmed: 33714757
J Mol Biol. 2007 Jul 27;370(5):812-25
pubmed: 17550785
J Mol Biol. 2002 Jun 28;320(1):143-56
pubmed: 12079340
Science. 2003 Mar 14;299(5613):1694-7
pubmed: 12637735
J Mol Biol. 2009 Apr 17;387(5):1067-74
pubmed: 19248789
Cancers (Basel). 2021 Feb 11;13(4):
pubmed: 33670206
Nucleic Acids Res. 2003 Mar 15;31(6):1683-92
pubmed: 12626710
Am J Med Genet. 1998 Jul 24;78(4):336-40
pubmed: 9714435
J Mol Biol. 2007 Sep 21;372(3):774-97
pubmed: 17681537
Biochemistry. 2001 Jun 19;40(24):6989-97
pubmed: 11401542
Biochem Biophys Res Commun. 2002 Oct 4;297(4):1027-32
pubmed: 12359259
J Biol Chem. 2004 Aug 6;279(32):33035-8
pubmed: 15096496
Annu Rev Biochem. 2001;70:209-46
pubmed: 11395407
PLoS One. 2015 May 19;10(5):e0127634
pubmed: 25993634
Bioinorg Chem Appl. 2021 Sep 30;2021:2572844
pubmed: 34630544
BMC Biochem. 2013 Dec 09;14:36
pubmed: 24314009
Nat Rev Cancer. 2003 May;3(5):330-8
pubmed: 12724731
Cancers (Basel). 2021 Sep 15;13(18):
pubmed: 34572850
Protein Pept Lett. 2015;22(12):1117-22
pubmed: 26446564
J Bacteriol. 2003 Jan;185(1):126-34
pubmed: 12486048
Acta Crystallogr D Biol Crystallogr. 2010 Feb;66(Pt 2):125-32
pubmed: 20124692
Recent Pat Biotechnol. 2008;2(1):35-46
pubmed: 19075851
Biochem Biophys Res Commun. 2019 Oct 29;519(1):160-165
pubmed: 31481233
Biochem Biophys Res Commun. 2003 Dec 12;312(2):467-72
pubmed: 14637160
Int J Mol Sci. 2021 Sep 23;22(19):
pubmed: 34638594
Bioorg Med Chem. 2016 Oct 1;24(19):4536-4543
pubmed: 27499369
J Biol Chem. 1984 Mar 10;259(5):3293-8
pubmed: 6142052
Cancer Res. 1987 Apr 15;47(8):2203-6
pubmed: 3829006
Nat Rev Gastroenterol Hepatol. 2017 Jun;14(6):356-365
pubmed: 28270698
Subcell Biochem. 2019;93:505-538
pubmed: 31939163
Molecules. 2021 Nov 29;26(23):
pubmed: 34885830
Nat Rev Clin Oncol. 2014 May;11(5):282-98
pubmed: 24732946
Biochemistry. 2007 Sep 18;46(37):10538-50
pubmed: 17711307
Cancers (Basel). 2022 Jun 30;14(13):
pubmed: 35804978