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]

Related Research Articles

Peptidoglycan or murein is a unique large macromolecule, a polysaccharide, consisting of sugars and amino acids that forms a mesh-like layer (sacculus) that surrounds the bacterial cytoplasmic membrane. The sugar component consists of alternating residues of β-(1,4) linked N-acetylglucosamine (NAG) and N-acetylmuramic acid (NAM). Attached to the N-acetylmuramic acid is an oligopeptide chain made of three to five amino acids. The peptide chain can be cross-linked to the peptide chain of another strand forming the 3D mesh-like layer. Peptidoglycan serves a structural role in the bacterial cell wall, giving structural strength, as well as counteracting the osmotic pressure of the cytoplasm. This repetitive linking results in a dense peptidoglycan layer which is critical for maintaining cell form and withstanding high osmotic pressures, and it is regularly replaced by peptidoglycan production. Peptidoglycan hydrolysis and synthesis are two processes that must occur in order for cells to grow and multiply, a technique carried out in three stages: clipping of current material, insertion of new material, and re-crosslinking of existing material to new material.

<span class="mw-page-title-main">Teicoplanin</span> Pharmaceutical drug

Teicoplanin is an semisynthetic glycopeptide antibiotic with a spectrum of activity similar to vancomycin. Its mechanism of action is to inhibit bacterial cell wall peptidoglycan synthesis. It is used in the prophylaxis and treatment of serious infections caused by Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus and Enterococcus faecalis.

<span class="mw-page-title-main">Heparan sulfate</span> Macromolecule

Heparan sulfate (HS) is a linear polysaccharide found in all animal tissues. It occurs as a proteoglycan in which two or three HS chains are attached in close proximity to cell surface or extracellular matrix proteins. In this form, HS binds to a variety of protein ligands, including Wnt, and regulates a wide range of biological activities, including developmental processes, angiogenesis, blood coagulation, abolishing detachment activity by GrB, and tumour metastasis. HS has also been shown to serve as cellular receptor for a number of viruses, including the respiratory syncytial virus. One study suggests that cellular heparan sulfate has a role in SARS-CoV-2 Infection, particularly when the virus attaches with ACE2.

<span class="mw-page-title-main">Tunicamycin</span> Chemical compound

Tunicamycin is a mixture of homologous nucleoside antibiotics that inhibits the UDP-HexNAc: polyprenol-P HexNAc-1-P family of enzymes. In eukaryotes, this includes the enzyme GlcNAc phosphotransferase (GPT), which catalyzes the transfer of N-acetylglucosamine-1-phosphate from UDP-N-acetylglucosamine to dolichol phosphate in the first step of glycoprotein synthesis. Tunicamycin blocks N-linked glycosylation (N-glycans) and treatment of cultured human cells with tunicamycin causes cell cycle arrest in G1 phase. It is used as an experimental tool in biology, e.g. to induce unfolded protein response. Tunicamycin is produced by several bacteria, including Streptomyces clavuligerus and Streptomyces lysosuperificus.

Uridine diphosphate <i>N</i>-acetylglucosamine Chemical compound

Uridine diphosphate N-acetylglucosamine or UDP-GlcNAc is a nucleotide sugar and a coenzyme in metabolism. It is used by glycosyltransferases to transfer N-acetylglucosamine residues to substrates. D-Glucosamine is made naturally in the form of glucosamine-6-phosphate, and is the biochemical precursor of all nitrogen-containing sugars. To be specific, glucosamine-6-phosphate is synthesized from fructose 6-phosphate and glutamine as the first step of the hexosamine biosynthesis pathway. The end-product of this pathway is UDP-GlcNAc, which is then used for making glycosaminoglycans, proteoglycans, and glycolipids.

<span class="mw-page-title-main">N-acetylglucosamine-6-phosphate deacetylase</span>

In enzymology, N-acetylglucosamine-6-phosphate deacetylase (EC 3.5.1.25), also known as GlcNAc-6-phosphate deacetylase or NagA, is an enzyme that catalyzes the deacetylation of N-acetylglucosamine-6-phosphate (GlcNAc-6-P) to glucosamine-6-phosphate (GlcN-6-P):

In enzymology, an acyl-[acyl-carrier-protein]-UDP-N-acetylglucosamine O-acyltransferase is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">UDP-N-acetylglucosamine 1-carboxyvinyltransferase</span> Class of enzymes

In enzymology, an UDP-N-acetylglucosamine 1-carboxyvinyltransferase is an enzyme that catalyzes the first committed step in peptidoglycan biosynthesis of bacteria:

<span class="mw-page-title-main">GNE (gene)</span> Protein-coding gene in humans

Bifunctional UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase is an enzyme that in humans is encoded by the GNE gene.

<span class="mw-page-title-main">DPAGT1</span> Protein-coding gene in the species Homo sapiens

UDP-N-acetylglucosamine—dolichyl-phosphate N-acetylglucosaminephosphotransferase is an enzyme that in humans is encoded by the DPAGT1 gene.

<span class="mw-page-title-main">Ribostamycin</span> Aminoglycoside antibiotic

Ribostamycin is an aminoglycoside-aminocyclitol antibiotic isolated from a streptomycete, Streptomyces ribosidificus, originally identified in a soil sample from Tsu City of Mie Prefecture in Japan. It is made up of 3 ring subunits: 2-deoxystreptamine (DOS), neosamine C, and ribose. Ribostamycin, along with other aminoglycosides with the DOS subunit, is an important broad-spectrum antibiotic with important use against human immunodeficiency virus and is considered a critically important antimicrobial by the World Health Organization., Resistance against aminoglycoside antibiotics, such as ribostamycin, is a growing concern. The resistant bacteria contain enzymes that modify the structure through phosphorylation, adenylation, and acetylation and prevent the antibiotic from being able to interact with the bacterial ribosomal RNAs.

<span class="mw-page-title-main">Bacillithiol</span> Chemical compound

Bacillithiol is a thiol compound found in Bacillus species. It is likely involved in maintaining cellular redox balance and plays a role in microbial resistance to the antibiotic fosfomycin.

<span class="mw-page-title-main">UDP-3-O-N-acetylglucosamine deacetylase</span> Enzyme

In molecular biology, UDP-3-O-N-acetylglucosamine deacetylase, EC 3.5.1.-, is a bacterial enzyme involved in lipid A biosynthesis.

UDP-3-O-(3-hydroxymyristoyl)glucosamine N-acyltransferase is an enzyme with systematic name (3R)-3-hydroxymyristoyl-(acyl-carrier protein):UDP-3-O-( -3-hydroxymyristoyl)-alpha-D-glucosamine N-acetyltransferase. This enzyme catalyses the following chemical reaction

Protein <i>O</i>-GlcNAc transferase Protein-coding gene in the species Homo sapiens

Protein O-GlcNAc transferase also known as OGT or O-linked N-acetylglucosaminyltransferase is an enzyme that in humans is encoded by the OGT gene. OGT catalyzes the addition of the O-GlcNAc post-translational modification to proteins.

UDP-GlcNAc:ribostamycin N-acetylglucosaminyltransferase is an enzyme with systematic name UDP-N-acetyl-alpha-D-glucosamine:ribostamycin N-acetylglucosaminyltransferase. This enzyme catalyses the following chemical reaction

The alpha-D-phosphohexomutases are a large superfamily of enzymes, with members in all three domains of life. Enzymes from this superfamily are ubiquitous in organisms from E. coli to humans, and catalyze a phosphoryl transfer reaction on a phosphosugar substrate. Four well studied subgroups in the superfamily are:

  1. Phosphoglucomutase (PGM)
  2. Phosphoglucomutase/Phosphomannomutase (PGM/PMM)
  3. Phosphoglucosamine mutase (PNGM)
  4. Phosphoaceytlglucosamine mutase (PAGM)

UDP-N-acetylglucosamine—undecaprenyl-phosphate N-acetylglucosaminephosphotransferase is an enzyme with systematic name UDP-N-acetyl-alpha-D-glucosamine:ditrans,octacis-undecaprenyl phosphate N-acetyl-alpha-D-glucosaminephosphotransferase. This enzyme catalyses the following chemical reaction

<span class="mw-page-title-main">Epimerox</span> Chemical compound

Epimerox is an experimental broad-spectrum antibiotic compound being developed by scientists at the Rockefeller University and Astex Pharmaceuticals. It is a small molecule inhibitor compound that blocks the activity of the enzyme UDP-N-acetylglucosamine 2-epimerase, an epimerase enzyme that is called 2-epimerase for short.

<span class="mw-page-title-main">LPC-233</span> Chemical compound

LPC-233 is an experimental antibiotic drug. It acts as a potent and selective inhibitor of the bacterial enzyme UDP-3-O-acyl-N-acetylglucosamine deacetylase (LpxC), which is important for the production of Lipid A, a key component of the cell membrane of Gram-negative bacteria. Various inhibitors of LpxC have been developed but none have yet progressed into clinical trials in humans, mostly because of off-target cardiovascular toxicity. LPC-233 is one of the most advanced drugs of this type in preclinical testing, showing activity against several pathogens of concern such as multidrug-resistant Pseudomonas aeruginosa and carbapenem resistant Enterobacter strains, and with no cardiovascular toxicity evident in testing on mice and dogs.

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.