hrvatski jezikClear Cookie - decide language by browser settings

The mechanism behind the selection of two different cleavage sites in NAG-NAM polymers

Mihelič, Marko; Vlahoviček-Kahlina, Kristina; Renko, Miha; Mesnage, Stephane; Doberšek, Andreja; Taler-Verčič, Ajda; Jakas, Andreja; Turk, Dušan (2017) The mechanism behind the selection of two different cleavage sites in NAG-NAM polymers. IUCrJ, 4 (2). pp. 185-198. ISSN 2052-2525

[img]
Preview
PDF - Published Version - article
Download (2MB) | Preview

Abstract

Peptidoglycan is a giant molecule that forms the cell wall that surrounds bacterial cells. It is composed of alternating N-acetylglucosamine (NAG) and N-acetylmuramic acid (NAM) residues connected by β-(1, 4)-glycosidic bonds and cross-linked with short polypeptide chains. Owing to the increasing antibiotic resistance against drugs targeting peptidoglycan synthesis, studies of enzymes involved in the degradation of peptidoglycan, such as N-acetylglucosaminidases, may expose new, valuable drug targets. The scientific challenge addressed here is how lysozymes, muramidases which are likely to be the most studied enzymes ever, and bacterial N-acetylglucosaminidases discriminate between two glycosidic bonds that are different in sequence yet chemically equivalent in the same NAG-NAM polymers. In spite of more than fifty years of structural studies of lysozyme, it is still not known how the enzyme selects the bond to be cleaved. Using macromolecular crystallography, chemical synthesis and molecular modelling, this study explains how these two groups of enzymes based on an equivalent structural core exhibit a difference in selectivity. The crystal structures of Staphylococcus aureus N-acetylglucosaminidase autolysin E (AtlE) alone and in complex with fragments of peptidoglycan revealed that N-acetylglucosaminidases and muramidases approach the substrate at alternate glycosidic bond positions from opposite sides. The recognition pocket for NAM residues in the active site of N-acetylglucosaminidases may make them a suitable drug target.

Item Type: Article
Additional Information: Funding for this research was provided by: Slovenian Research Agency (award Nos. P1-0048, IO-0005, IO-0048); European Regional Development Fund (85%)/Slovenian Ministry of Education, Science and Sport (15%) (development of CIPKeBiP funding) (award No. OP13.1.1.2.02.0005); Ministry of Science and Education of the Republic of Croatia (award No. 098-0982933- 2936); Biotechnology and Biological Sciences Research Council (award No. BBSRC BB/N00095 1/1); Medical Research Council (award No. MR/N002679/1).
Uncontrolled Keywords: Staphylococcus aureus ; autolysins ; substrate specificity ; N-acetylglucosaminidase ; muramidases ; lysozyme.
Subjects: NATURAL SCIENCES > Chemistry
Divisions: Division of Organic Chemistry and Biochemistry
Projects:
Project titleProject leaderProject codeProject type
Kemijske preobrazbe prirodnih spojeva-Lidija Varga-Defterdarović098-0982933-2936MZOS
Depositing User: Andreja Jakas
Date Deposited: 30 Apr 2020 06:31
Last Modified: 30 Apr 2020 06:31
URI: http://fulir.irb.hr/id/eprint/5601
DOI: 10.1107/S2052252517000367

Actions (login required)

View Item View Item

Downloads

Downloads per month over past year

Contrast
Increase Font
Decrease Font
Dyslexic Font
Accessibility