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

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UDP-3-O-acyl-N-acetylglucosamine deacetylase
Identifiers
EC no. 3.5.1.108
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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. [1] [2] [3] [4] [5] [6]

Contents

This enzyme catalyses the chemical reaction:

UDP-3-O-[(3R)-3-hydroxymyristoyl]-N-acetylglucosamine + H2O UDP-3-O-[(3R)-3-hydroxymyristoyl]-D-glucosamine + acetate

Nomenclature

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

Inhibitors

Various inhibitors of LpxC have been developed as potential antibiotics, though none have yet reached clinical trials. [7] [8] [9]

References

  1. ↑ 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.
  2. ↑ 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.
  3. ↑ 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.
  4. ↑ 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.
  5. ↑ 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.
  6. ↑ 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.
  7. ↑ 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.
  8. ↑ 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.
  9. ↑ 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.
  10. ↑ 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.
  11. ↑ 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.
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