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* Residue conservation analysis
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Enzyme class:
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E.C.3.2.1.52
- Beta-N-acetylhexosaminidase.
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Reaction:
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Hydrolysis of terminal non-reducing N-acetyl-D-hexosamine residues in N-acetyl-beta-D-hexosaminides.
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Gene Ontology (GO) functional annotation
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Cellular component
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cytoplasm
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1 term
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Biological process
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metabolic process
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7 terms
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Biochemical function
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hydrolase activity
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4 terms
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J Biol Chem
282:21382-21391
(2007)
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PubMed id:
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Small molecule inhibitors of a glycoside hydrolase attenuate inducible AmpC-mediated beta-lactam resistance.
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K.A.Stubbs,
M.Balcewich,
B.L.Mark,
D.J.Vocadlo.
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ABSTRACT
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The increasing spread of plasmid-borne ampC-ampR operons is of considerable
medical importance, since the AmpC beta-lactamases they encode confer high level
resistance to many third generation cephalosporins. Induction of AmpC
beta-lactamase from endogenous or plasmid-borne ampC-ampR operons is mediated by
a catabolic inducer molecule, 1,6-anhydro-N-acetylmuramic acid (MurNAc)
tripeptide, an intermediate of the cell wall recycling pathway derived from the
peptidoglycan. Here we describe a strategy for attenuating the antibiotic
resistance associated with the ampC-ampR operon by blocking the formation of the
inducer molecule using small molecule inhibitors of NagZ, the glycoside
hydrolase catalyzing the formation of this inducer molecule. The structure of
the NagZ-inhibitor complex provides insight into the molecular basis for
inhibition and enables the development of inhibitors with 100-fold selectivity
for NagZ over functionally related human enzymes. These PUGNAc-derived
inhibitors reduce the minimal inhibitory concentration (MIC) values for several
clinically relevant cephalosporins in both wild-type and AmpC-hyperproducing
strains lacking functional AmpD.
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Literature references that cite this PDB file's key reference
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PubMed id
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Reference
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E.Yoshida,
M.Hidaka,
S.Fushinobu,
T.Koyanagi,
H.Minami,
H.Tamaki,
M.Kitaoka,
T.Katayama,
and
H.Kumagai
(2010).
Role of a PA14 domain in determining substrate specificity of a glycoside hydrolase family 3 β-glucosidase from Kluyveromyces marxianus.
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Biochem J, 431,
39-49.
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PDB codes:
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L.Zamorano,
T.M.Reeve,
L.Deng,
C.Juan,
B.Moyá,
G.Cabot,
D.J.Vocadlo,
B.L.Mark,
and
A.Oliver
(2010).
NagZ inactivation prevents and reverts beta-lactam resistance, driven by AmpD and PBP 4 mutations, in Pseudomonas aeruginosa.
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Antimicrob Agents Chemother, 54,
3557-3563.
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M.S.Macauley,
Y.He,
T.M.Gloster,
K.A.Stubbs,
G.J.Davies,
and
D.J.Vocadlo
(2010).
Inhibition of O-GlcNAcase using a potent and cell-permeable inhibitor does not induce insulin resistance in 3T3-L1 adipocytes.
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Chem Biol, 17,
937-948.
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PDB code:
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A.Asgarali,
K.A.Stubbs,
A.Oliver,
D.J.Vocadlo,
and
B.L.Mark
(2009).
Inactivation of the glycoside hydrolase NagZ attenuates antipseudomonal beta-lactam resistance in Pseudomonas aeruginosa.
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Antimicrob Agents Chemother, 53,
2274-2282.
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M.D.Balcewich,
K.A.Stubbs,
Y.He,
T.W.James,
G.J.Davies,
D.J.Vocadlo,
and
B.L.Mark
(2009).
Insight into a strategy for attenuating AmpC-mediated beta-lactam resistance: structural basis for selective inhibition of the glycoside hydrolase NagZ.
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Protein Sci, 18,
1541-1551.
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PDB codes:
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J.T.Park,
and
T.Uehara
(2008).
How bacteria consume their own exoskeletons (turnover and recycling of cell wall peptidoglycan).
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Microbiol Mol Biol Rev, 72,
211.
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S.K.Sarkar,
and
A.S.Ghosh
(2008).
Involvement of O8-antigen in altering beta-lactam antibiotic susceptibilities in Escherichia coli.
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FEMS Microbiol Lett, 282,
59-64.
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A.Scaffidi,
K.A.Stubbs,
R.J.Dennis,
E.J.Taylor,
G.J.Davies,
D.J.Vocadlo,
and
R.V.Stick
(2007).
A 1-acetamido derivative of 6-epi-valienamine: an inhibitor of a diverse group of beta-N-acetylglucosaminidases.
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Org Biomol Chem, 5,
3013-3019.
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PDB code:
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The most recent references are shown first.
Citation data come partly from CiteXplore and partly
from an automated harvesting procedure. Note that this is likely to be
only a partial list as not all journals are covered by
either method. However, we are continually building up the citation data
so more and more references will be included with time.
Where a reference describes a PDB structure, the PDB
codes are
shown on the right.
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Links
