Exploring the Active Site of the Antibacterial Target MraY by Modified Tunicamycins.

Hering, JennyGothenburg University,Göteborgs universitet,Institutionen för kemi och molekylärbiologi,Department of Chemistry and Molecular Biology (författare)

The alarming growth of antibiotic resistance that is currently ongoing is a serious threat to human health. One of the most promising novel antibiotic targets is MraY (phospho-MurNAc-pentapeptide-transferase), an essential enzyme in bacterial cell wall synthesis. Through recent advances in biochemical research, there is now structural information available for MraY, and for its human homologue GPT (GlcNAc-1-P-transferase), that opens up exciting possibilities for structure-based drug design. The antibiotic compound tunicamycin is a natural product inhibitor of MraY that is also toxic to eukaryotes through its binding to GPT. In this work, we have used tunicamycin and modified versions of tunicamycin as tool compounds to explore the active site of MraY and to gain further insight into what determines inhibitor potency. We have investigated tunicamycin variants where the following motifs have been modified: the length and branching of the tunicamycin fatty acyl chain, the saturation of the fatty acyl chain, the 6″-hydroxyl group of the GlcNAc ring, and the ring structure of the uracil motif. The compounds are analyzed in terms of how potently they bind to MraY, inhibit the activity of the enzyme, and affect the protein thermal stability. Finally, we rationalize these results in the context of the protein structures of MraY and GPT.

Dunevall, Elin,1986Gothenburg University,Göteborgs universitet,Institutionen för kemi och molekylärbiologi,Department of Chemistry and Molecular Biology(Swepub:gu)xjelix (författare)
Snijder, Arjan (författare)
Eriksson, Per-Olof (författare)
Jackson, Michael A (författare)
Hartman, Trina M (författare)
Ting, Ran (författare)
Chen, Hongming (författare)
Price, Neil P J (författare)
Brändén, Gisela,1975Gothenburg University,Göteborgs universitet,Institutionen för kemi och molekylärbiologi,Department of Chemistry and Molecular Biology(Swepub:gu)xbragi (författare)
Ek, Margareta (författare)
Göteborgs universitetInstitutionen för kemi och molekylärbiologi (creator_code:org_t)

Ingår i:ACS chemical biology: American Chemical Society (ACS)15:11, s. 2885-28951554-89371554-8929

Av författaren/redakt...: Hering, Jenny; Dunevall, Elin, ...; Snijder, Arjan; Eriksson, Per-Ol ...; Jackson, Michael ...; Hartman, Trina M; visa fler...; Ting, Ran; Chen, Hongming; Price, Neil P J; Brändén, Gisela, ...; Ek, Margareta; visa färre...

Om ämnet

Kungliga biblioteket hanterar dina personuppgifter i enlighet med EU:s dataskyddsförordning (2018), GDPR. Läs mer om hur det funkar här.
Så här hanterar KB dina uppgifter vid användning av denna tjänst.