Modulation of pantothenate kinase 3 activity by small molecules that interact with the substrate/allosteric regulatory domain.
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.
Leonardi
Roberta
R
Department of Infectious Diseases, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
Zhang
Yong-Mei
YM
Yun
Mi-Kyung
MK
Zhou
Ruobing
R
Zeng
Fu-Yue
FY
Lin
Wenwei
W
Cui
Jimmy
J
Chen
Taosheng
T
Rock
Charles O
CO
White
Stephen W
SW
Jackowski
Suzanne
S
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
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
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