Grote Dakota, Stewart Christopher G, Daraji Drashti G, Enayati Parisa, Braverman Kristina N, Romanaggi CeAnn, Bolejack Madison J, Yano Jason K, Abendroth Jan, Dranow David M, Pierce Phillip G, Lorimer Donald D, Horanyi Peter S, Staker Bart L, Edwards Thomas E, Myler Peter J, Horn James R, Hagen Timothy J
Department of Chemistry and Biochemistry, Northern Illinois University, 1425 Lincoln Highway, DeKalb, IL 60115, USA.
Seattle Structural Genomics Center for Infectious Disease (SSGCID), Seattle, WA 98109, USA.
Acta Crystallogr F Struct Biol Commun. 2025 Apr 1;81(Pt 4):138-145. doi: 10.1107/S2053230X25001414. Epub 2025 Mar 4.
The methylerythritol phosphate (MEP) pathway is a metabolic pathway that produces the isoprenoids isopentyl pyrophosphate and dimethylallyl pyrophosphate. Notably, the MEP pathway is present in bacteria and not in mammals, which makes the enzymes of the MEP pathway attractive targets for the discovery of new anti-infective agents due to the reduced chances of off-target interactions leading to side effects. There are seven enzymes in the MEP pathway, the fifth of which is IspF. Crystal structures of Burkholderia pseudomallei IspF were determined with five different sulfonamide ligands bound. The sulfonamide-containing ligands were ethoxzolamide, acetazolamide, sulfapyridine and sulfamonomethoxine. The fifth bound ligand was a synthetic analog of acetazolamide. All ligands coordinated to the active-site Zn ion through the sulfonamide group, although sulfapyridine and sulfamonomethoxine, both of which are known antibacterial agents, possess similar binding interactions that are distinct from the other three sulfonamides. These structural data will aid in the discovery of new IspF inhibitors.
甲基赤藓糖醇磷酸（MEP）途径是一条产生类异戊二烯焦磷酸异戊烯酯和二甲基烯丙基焦磷酸的代谢途径。值得注意的是，MEP途径存在于细菌中，而不存在于哺乳动物中，这使得MEP途径的酶成为发现新型抗感染药物的有吸引力的靶点，因为脱靶相互作用导致副作用的可能性降低。MEP途径中有七种酶，其中第五种是IspF。测定了与五种不同磺酰胺配体结合的伯克霍尔德菌IspF的晶体结构。含磺酰胺的配体是乙氧唑胺、乙酰唑胺、磺胺吡啶和磺胺间甲氧嘧啶。第五种结合配体是乙酰唑胺的合成类似物。所有配体均通过磺酰胺基团与活性位点的锌离子配位，尽管磺胺吡啶和磺胺间甲氧嘧啶这两种已知的抗菌剂具有与其他三种磺酰胺不同的类似结合相互作用。这些结构数据将有助于发现新的IspF抑制剂。
