Structural and Functional Characterization of Methicillin-Resistant Staphylococcus aureus鈥檚 Class IIb Fructose 1,6-Bisphosphate Aldolase

详细信息    查看全文

• 作者：Glenn C. Capodagli ; Stephen A. Lee ; Kyle J. Boehm ; Kristin M. Brady ; Scott D. Pegan
• 刊名：Biochemistry
• 出版年：2014
• 出版时间：December 9, 2014
• 年：2014
• 卷：53
• 期：48
• 页码：7604-7614
• 全文大小：787K
• ISSN：1520-4995

文摘

Staphylococcus aureus is one of the most common nosocomial sources of soft-tissue and skin infections and has more recently become prevalent in the community setting as well. Since the use of penicillins to combat S. aureus infections in the 1940s, the bacterium has been notorious for developing resistances to antibiotics, such as methicillin-resistant Staphylococcus aureus (MRSA). With the persistence of MRSA as well as many other drug resistant bacteria and parasites, there is a growing need to focus on new pharmacological targets. Recently, class II fructose 1,6-bisphosphate aldolases (FBAs) have garnered attention to fill this role. Regrettably, scarce biochemical data and no structural data are currently available for the class II FBA found in MRSA (SaFBA). With the recent finding of a flexible active site zinc-binding loop (Z-Loop) in class IIa FBAs and its potential for broad spectrum class II FBA inhibition, the lack of information regarding this feature of class IIb FBAs, such as SaFBA, has been limiting for further Z-loop inhibitor development. Therefore, we elucidated the crystal structure of SaFBA to 2.1 脜 allowing for a more direct structural analysis of SaFBA. Furthermore, we determined the K_M for one of SaFBA鈥檚 substrates, fructose 1,6-bisphosphate, as well as performed mode of inhibition studies for an inhibitor that takes advantage of the Z-loop鈥檚 flexibility. Together the data offers insight into a class IIb FBA from a pervasively drug resistant bacterium and a comparison of Z-loops and other features between the different subtypes of class II FBAs.