Structural and Functional Characterization of Methicillin-Resistant Staphylococcus aureus’s Class IIb Fructose 1,6-Bisphosphate Aldolase
- Department of Chemistry and Biochemistry, University of Denver, Denver, Colorado 80208, United States
- Department of Pharmaceutical and Biomedical Sciences, University of Georgia, Athens, Georgia 30602, United States
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 Å allowing for a more direct structural analysis of SaFBA. Furthermore, we determined the KM for one of SaFBA’s substrates, fructose 1,6-bisphosphate, as well as performed mode of inhibition studies for an inhibitor that takes advantage of the Z-loop’s flexibility. Altogether 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.
- Research Organization:
- Univ. of Denver, Denver, CO (United States); Univ. of Georgia, Athens, GA (United States)
- Sponsoring Organization:
- USDOE Advanced Research Projects Agency - Energy (ARPA-E); USDOE Office of Science (SC), Basic Energy Sciences (BES)
- Grant/Contract Number:
- AC02-05CH11231
- OSTI ID:
- 1164331
- Alternate ID(s):
- OSTI ID: 1345591
- Journal Information:
- Biochemistry, Journal Name: Biochemistry Vol. 53 Journal Issue: 48; ISSN 0006-2960
- Publisher:
- American Chemical SocietyCopyright Statement
- Country of Publication:
- United States
- Language:
- English
Web of Science
Similar Records
Active Site Loop Dynamics of a Class IIa Fructose 1,6-Bisphosphate Aldolase from Mycobacterium tuberculosis
Crystal Structures of Wild-type and Mutant Methicillin-resistant Staphylococcus aureus Dihydrofolate Reductase Reveal an Alternative Conformation of NADPH that may be Linked to Trimethoprim Resistance