UDP-3-O-acyl-N-acetylglucosamine deacetylase

UDP-3-O-acyl-N-acetylglucosamine deacetylase (EC 3.5.1.108), also known as LpxC, is a zinc-dependent enzyme involved in bacterial lipid A biosynthesis, catalyzing the removal of the acetyl group from UDP-3-O-acyl-N-acetylglucosamine, a key step in the production of lipopolysaccharides in the outer membrane of gram-negative bacteria.

This enzyme catalyses the chemical reaction:

UDP-3-O--N-acetylglucosamine + H₂O

\rightleftharpoons

UDP-3-O--D-glucosamine + acetate

Nomenclature

UDP-3-O-acyl-N-acetylglucosamine deacetylase is also known as:

UDP-3-O-((3R)-3-hydroxymyristoyl)-N-acetylglucosamine amidohydrolase
LpxC enzyme
LpxC deacetylase
deacetylase LpxC
UDP-3-O-acyl-GlcNAc deacetylase
UDP-3-O-((R)-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase
UDP-(3-O-acyl)-N-acetylglucosamine deacetylase
UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase
UDP-(3-O-(R-3-hydroxymyristoyl))-N-acetylglucosamine deacetylase)

Inhibitors

Various inhibitors of LpxC have been developed as potential antibiotics, though none have yet reached clinical trials.

ACHN-975
CHIR-090
CS250
LPC-233
PF-5081090
TP0586532

References

Hernick M, Gennadios HA, Whittington DA, Rusche KM, Christianson DW, Fierke CA (April 2005). "UDP-3-O-((R)-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase functions through a general acid–base catalyst pair mechanism". The Journal of Biological Chemistry. 280 (17): 16969–78. doi:10.1074/jbc.M413560200. PMID 15705580.
Jackman JE, Raetz CR, Fierke CA (February 1999). "UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase of Escherichia coli is a zinc metalloenzyme". Biochemistry. 38 (6): 1902–11. doi:10.1021/bi982339s. PMID 10026271.
Hyland SA, Eveland SS, Anderson MS (March 1997). "Cloning, expression, and purification of UDP-3-O-acyl-GlcNAc deacetylase from Pseudomonas aeruginosa: a metalloamidase of the lipid A biosynthesis pathway". Journal of Bacteriology. 179 (6): 2029–37. doi:10.1128/jb.179.6.2029-2037.1997. PMC 178929. PMID 9068651.
Wang W, Maniar M, Jain R, Jacobs J, Trias J, Yuan Z (March 2001). "A fluorescence-based homogeneous assay for measuring activity of UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase". Analytical Biochemistry. 290 (2): 338–46. doi:10.1006/abio.2000.4973. PMID 11237337.
Whittington DA, Rusche KM, Shin H, Fierke CA, Christianson DW (July 2003). "Crystal structure of LpxC, a zinc-dependent deacetylase essential for endotoxin biosynthesis". Proceedings of the National Academy of Sciences of the United States of America. 100 (14): 8146–50. Bibcode:2003PNAS..100.8146W. doi:10.1073/pnas.1432990100. PMC 166197. PMID 12819349.
Mochalkin I, Knafels JD, Lightle S (March 2008). "Crystal structure of LpxC from Pseudomonas aeruginosa complexed with the potent BB-78485 inhibitor". Protein Science. 17 (3): 450–7. doi:10.1110/ps.073324108. PMC 2248309. PMID 18287278.
Kalinin DV, Holl R (2016). "Insights into the Zinc-Dependent Deacetylase LpxC: Biochemical Properties and Inhibitor Design". Current Topics in Medicinal Chemistry. 16 (21): 2379–2430. doi:10.2174/1568026616666160413135835. PMID 27072691.
Kalinin DV, Holl R (November 2017). "LpxC inhibitors: a patent review (2010-2016)". Expert Opinion on Therapeutic Patents. 27 (11): 1227–1250. doi:10.1080/13543776.2017.1360282. PMID 28742403.
Niu Z, Lei P, Wang Y, Wang J, Yang J, Zhang J (May 2023). "Small molecule LpxC inhibitors against gram-negative bacteria: Advances and future perspectives". European Journal of Medicinal Chemistry. 253: 115326. doi:10.1016/j.ejmech.2023.115326. PMID 37023679.
Zoghlami M, Oueslati M, Basharat Z, Sadfi-Zouaoui N, Messaoudi A (February 2023). "Inhibitor Assessment against the LpxC Enzyme of Antibiotic-resistant Acinetobacter baumannii Using Virtual Screening, Dynamics Simulation, and in vitro Assays". Molecular Informatics. 42 (2): e2200061. doi:10.1002/minf.202200061. PMID 36289054.
Fujita K, Takata I, Yoshida I, Okumura H, Otake K, Takashima H, et al. (February 2022). "TP0586532, a non-hydroxamate LpxC inhibitor, has in vitro and in vivo antibacterial activities against Enterobacteriaceae". The Journal of Antibiotics. 75 (2): 98–107. doi:10.1038/s41429-021-00486-3. PMID 34837061.

External links

UDP-3-O-acyl-N-acetylglucosamine+deacetylase at the U.S. National Library of Medicine Medical Subject Headings (MeSH)

v t e Hydrolases: carbon-nitrogen non-peptide (EC 3.5)
3.5.1: Linear amides / Amidohydrolases	Asparaginase Glutaminase Urease Biotinidase Aminoacylase ACY1 Aspartoacylase(ACY2) ACY3 Ceramidase Aspartylglucosaminidase Fatty acid amide hydrolase Histone deacetylase Sirtuin
3.5.2: Cyclic amides/ Amidohydrolases	Barbiturase Beta-lactamase Dihydroorotase
3.5.3: Linear amidines/ Ureohydrolases	Arginase Agmatinase Protein-arginine deiminase
3.5.4: Cyclic amidines/ Aminohydrolases	Guanine deaminase Adenosine deaminase AMP deaminase Inosine monophosphate synthase DCMP deaminase GTP cyclohydrolase I Cytidine deaminase AICDA Activation-induced cytidine deaminase
3.5.5: Nitriles/ Aminohydrolases	Nitrilase
3.5.99: Other	Riboflavinase Thiaminase II

v t e Enzymes
Activity	Active site Binding site Catalytic triad Oxyanion hole Enzyme promiscuity Diffusion-limited enzyme Cofactor Enzyme catalysis
Regulation	Allosteric regulation Cooperativity Enzyme inhibitor Enzyme activator
Classification	EC number Enzyme superfamily Enzyme family List of enzymes
Kinetics	Enzyme kinetics Eadie–Hofstee diagram Hanes–Woolf plot Lineweaver–Burk plot Michaelis–Menten kinetics
Types	EC1 Oxidoreductases (list) EC2 Transferases (list) EC3 Hydrolases (list) EC4 Lyases (list) EC5 Isomerases (list) EC6 Ligases (list) EC7 Translocases (list)

Portal:

Biology

Category:

EC 3.5.1