title: Modulation of pantothenate kinase 3 activity by small molecules that interact with the substrate/allosteric regulatory domain.
abstract: Pantothenate kinase (PanK) catalyzes the rate-controlling step in coenzyme A (CoA) biosynthesis. PanK3 is stringently regulated by acetyl-CoA and uses an ordered kinetic mechanism with ATP as the leading substrate. Biochemical analysis of site-directed mutants indicates that pantothenate binds in a tunnel adjacent to the active site that is occupied by the pantothenate moiety of the acetyl-CoA regulator in the PanK3acetyl-CoA binary complex. A high-throughput screen for PanK3 inhibitors and activators was applied to a bioactive compound library. Thiazolidinediones, sulfonylureas and steroids were inhibitors, and fatty acyl-amides and tamoxifen were activators. The PanK3 activators and inhibitors either stimulated or repressed CoA biosynthesis in HepG2/C3A cells. The flexible allosteric acetyl-CoA regulatory domain of PanK3 also binds the substrates, pantothenate and pantetheine, and small molecule inhibitors and activators to modulate PanK3 activity.
authors.affiliation: Department of Infectious Diseases, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
authors.forename: Roberta
authors.initials: R
authors.lastname: Leonardi
authors.forename: Yong-Mei
authors.initials: YM
authors.lastname: Zhang
authors.forename: Mi-Kyung
authors.initials: MK
authors.lastname: Yun
authors.forename: Ruobing
authors.initials: R
authors.lastname: Zhou
authors.forename: Fu-Yue
authors.initials: FY
authors.lastname: Zeng
authors.forename: Wenwei
authors.initials: W
authors.lastname: Lin
authors.forename: Jimmy
authors.initials: J
authors.lastname: Cui
authors.forename: Taosheng
authors.initials: T
authors.lastname: Chen
authors.forename: Charles O
authors.initials: CO
authors.lastname: Rock
authors.forename: Stephen W
authors.initials: SW
authors.lastname: White
authors.forename: Suzanne
authors.initials: S
authors.lastname: Jackowski
mesh_terms: D000105:Acetyl Coenzyme A / Q000378:metabolism; D000494:Allosteric Regulation / Q000187:drug effects; D001665:Binding Sites; D003065:Coenzyme A / Q000096:biosynthesis; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D056945:Hep G2 Cells; D057166:High-Throughput Screening Assays; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D054852:Small Molecule Libraries / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D013379:Substrate Specificity; D013453:Sulfonylurea Compounds / Q000378:metabolism; D045162:Thiazolidinediones / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D007527:Isoenzymes; D054852:Small Molecule Libraries; D013453:Sulfonylurea Compounds; D045162:Thiazolidinediones; D000105:Acetyl Coenzyme A; C089946:2,4-thiazolidinedione; D017853:Phosphotransferases (Alcohol Group Acceptor); C023088:pantothenate kinase; D003065:Coenzyme A
references.citation: J Biomol Screen. 1999;4(2):67-73
references.pmid: 10838414
references.citation: Lancet. 2001 Jun 9;357(9271):1870-5
references.pmid: 11410214
references.citation: J Biol Chem. 2005 Feb 4;280(5):3314-22
references.pmid: 15548531
references.citation: Infect Disord Drug Targets. 2010 Jun;10(3):200-16
references.pmid: 20334619
references.citation: Chem Biol. 2007 Mar;14(3):291-302
references.pmid: 17379144
references.citation: Annu Rev Med. 2001;52:239-57
references.pmid: 11160777
references.citation: Proc Natl Acad Sci U S A. 2007 Jan 30;104(5):1494-9
references.pmid: 17242360
references.citation: Biochem Pharmacol. 2002 Jul 1;64(1):151-8
references.pmid: 12106615
references.citation: Bioorg Med Chem Lett. 2003 May 5;13(9):1517-21
references.pmid: 12699745
references.citation: Prog Lipid Res. 2005 Mar-May;44(2-3):125-53
references.pmid: 15893380
references.citation: Br Med J. 1980 Jun 21;280(6230):1495-8
references.pmid: 7388562
references.citation: J Biol Chem. 2000 Sep 8;275(36):28093-9
references.pmid: 10862768
references.citation: Am J Med. 1990 Aug 20;89(2A):3S-10S; discussion 51S-53S
references.pmid: 2117388
references.citation: Hum Mol Genet. 2003 Feb 1;12(3):321-7
references.pmid: 12554685
references.citation: J Biol Chem. 1995 Jun 2;270(22):12953-6
references.pmid: 7768881
references.citation: Nat Genet. 2001 Aug;28(4):345-9
references.pmid: 11479594
references.citation: Cell Metab. 2008 Oct;8(4):281-288
references.pmid: 18840358
references.citation: Biochem Pharmacol. 2009 Sep 15;78(6):553-60
references.pmid: 19413995
references.citation: J Biol Chem. 1998 Dec 4;273(49):32679-84
references.pmid: 9830009
references.citation: Bioorg Med Chem. 2006 Feb 15;14(4):1007-20
references.pmid: 16213731
references.citation: Clin Ther. 2004 Nov;26(11):1714-27
references.pmid: 15639686
references.citation: J Biol Chem. 2005 Sep 23;280(38):32594-601
references.pmid: 16040613
references.citation: Structure. 2006 Aug;14(8):1251-61
references.pmid: 16905099
references.citation: J Biol Chem. 2007 Aug 31;282(35):25395-405
references.pmid: 17581817
references.citation: J Biol Chem. 1994 Oct 28;269(43):27051-8
references.pmid: 7929447
references.citation: FEBS Lett. 2007 Oct 2;581(24):4639-44
references.pmid: 17825826
references.citation: Gene. 2002 May 29;291(1-2):35-43
references.pmid: 12095677
references.citation: Nat Genet. 2009 Jan;41(1):35-46
references.pmid: 19060910
references.citation: J Biomol Screen. 2009 Jul;14(6):679-89
references.pmid: 19470716
references.citation: J Bacteriol. 2003 Jun;185(11):3410-5
references.pmid: 12754240
references.citation: Brain Res Brain Res Rev. 2001 Nov;37(1-3):301-12
references.pmid: 11744095
references.citation: PLoS One. 2010 Jun 14;5(6):e11107
references.pmid: 20559429
references.citation: J Biol Chem. 2009 Jun 26;284(26):17527-39
references.pmid: 19398560
references.citation: J Biol Chem. 2007 Sep 21;282(38):27984-93
references.pmid: 17631502
references.citation: Pharmacol Biochem Behav. 2006 Aug;84(4):555-67
references.pmid: 17023038