7kr9

From Proteopedia

Bifunctional enzyme GlmU bound to Zn(II)

Structural highlights

7kr9 is a 1 chain structure with sequence from Streptococcus pneumoniae D39. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.9Å
Ligands:	, , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

GLMU_STRP2 Catalyzes the last two sequential reactions in the de novo biosynthetic pathway for UDP-N-acetylglucosamine (UDP-GlcNAc). The C-terminal domain catalyzes the transfer of acetyl group from acetyl coenzyme A to glucosamine-1-phosphate (GlcN-1-P) to produce N-acetylglucosamine-1-phosphate (GlcNAc-1-P), which is converted into UDP-GlcNAc by the transfer of uridine 5-monophosphate (from uridine 5-triphosphate), a reaction catalyzed by the N-terminal domain.

Publication Abstract from PubMed

Streptococcus pneumoniae is the primary cause of community-acquired bacterial pneumonia with rates of penicillin and multidrug-resistance exceeding 80% and 40%, respectively. The innate immune response generates a variety of antimicrobial agents to control infection, including zinc stress. Here, we characterize the impact of zinc intoxication on S. pneumoniae, observing disruptions in central carbon metabolism, lipid biogenesis, and peptidoglycan biosynthesis. Characterization of the pivotal peptidoglycan biosynthetic enzyme GlmU indicates a sensitivity to zinc inhibition. Disruption of the sole zinc efflux pathway, czcD, renders S. pneumoniae highly susceptible to beta-lactam antibiotics. To dysregulate zinc homeostasis in the wild-type strain, we investigated the safe-for-human-use ionophore 5,7-dichloro-2-[(dimethylamino)methyl]quinolin-8-ol (PBT2). PBT2 rendered wild-type S. pneumoniae strains sensitive to a range of antibiotics. Using an invasive ampicillin-resistant strain, we demonstrate in a murine pneumonia infection model the efficacy of PBT2 + ampicillin treatment. These findings present a therapeutic modality to break antibiotic resistance in multidrug-resistant S. pneumoniae.

Dysregulation of Streptococcus pneumoniae zinc homeostasis breaks ampicillin resistance in a pneumonia infection model.,Brazel EB, Tan A, Neville SL, Iverson AR, Udagedara SR, Cunningham BA, Sikanyika M, De Oliveira DMP, Keller B, Bohlmann L, El-Deeb IM, Ganio K, Eijkelkamp BA, McEwan AG, von Itzstein M, Maher MJ, Walker MJ, Rosch JW, McDevitt CA Cell Rep. 2022 Jan 11;38(2):110202. doi: 10.1016/j.celrep.2021.110202. PMID:35021083^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Brazel EB, Tan A, Neville SL, Iverson AR, Udagedara SR, Cunningham BA, Sikanyika M, De Oliveira DMP, Keller B, Bohlmann L, El-Deeb IM, Ganio K, Eijkelkamp BA, McEwan AG, von Itzstein M, Maher MJ, Walker MJ, Rosch JW, McDevitt CA. Dysregulation of Streptococcus pneumoniae zinc homeostasis breaks ampicillin resistance in a pneumonia infection model. Cell Rep. 2022 Jan 11;38(2):110202. doi: 10.1016/j.celrep.2021.110202. PMID:35021083 doi:http://dx.doi.org/10.1016/j.celrep.2021.110202