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Literature summary for 2.7.1.136 extracted from

  • Fong, D.H.; Burk, D.L.; Blanchet, J.; Yan, A.Y.; Berghuis, A.M.
    Structural basis for kinase-mediated macrolide antibiotic resistance (2017), Structure, 25, 750-761.e5 .
    View publication on PubMed

Crystallization (Commentary)

Crystallization (Comment) Organism
purified isozyme MPH(2')-I in apoform and in complex with GTP analogues and six different macrolides (guanosine 5'-[beta,gamma-imido]triphosphate (GMPPNP) or guanosine diphosphate (GDP) and either a 14-membered lactone macrolide: erythromycin, oleandomycin, or clarithromycin, or the 15-membered lactone macrolide azithromycin), X-ray diffraction structure determination analysis at 1.2-1.6 A resolution, molecular replacement method, modeling. Despite the inclusion of MgCl2 in the crystallization experiments, no evidence of magnesium ions is observed in any of the MPH(2')-I electron density maps Escherichia coli
purified isozyme MPH(2')-II in apoform and in complex with GTP analogues and six different macrolides (guanosine diphosphate (GDP) or GDP or GTPgS (guanosine 5'-O-[gamma-thio]triphosphate) and either a 14-membered lactone macrolide: erythromycin, oleandomycin, or clarithromycin, or the 15-membered lactone macrolide azithromycin), X-ray diffraction structure determination analysis at 1.31-1.65 A resolution, molecular replacement method, modeling. At least one divalent metal ion (either Mg2+ or Ca2+, based on the geometry and bond distances) from the crystallization solution is observed in the nucleotide binding pocket Escherichia coli

Metals/Ions

Metals/Ions Comment Organism Structure
Mg2+ required Escherichia coli

Natural Substrates/ Products (Substrates)

Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
ATP + oleandomycin Escherichia coli
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ADP + oleandomycin 2'-O-phosphate
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?

Organism

Organism UniProt Comment Textmining
Escherichia coli O32553
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-
Escherichia coli Q9EVJ6
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-

Substrates and Products (Substrate)

Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
ATP + oleandomycin
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Escherichia coli ADP + oleandomycin 2'-O-phosphate
-
?
additional information structure-based substrate specificity, macrolide binding analysis, overview. Although erythromycin, clarithromycin, oleandomycin, and azithromycin differ in the size of the lactone ring and varying substitutions, the 14- and 15-membered ring substrates bind to the two MPH enzymes in a similar location, adopt similar conformations, and interact with the enzymes in a similar manner. MPH(2')-I cannot modify 16-membered macrolides, in contrast to MPH(2')-II Escherichia coli ?
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additional information structure-based substrate specificity, macrolide binding analysis, overview. Although erythromycin, clarithromycin, oleandomycin, and azithromycin differ in the size of the lactone ring and varying substitutions, the 14- and 15-membered ring substrates bind to the two MPH enzymes in a similar location, adopt similar conformations, and interact with the enzymes in a similar manner. Unlike MPH(2')-I, MPH(2')-II can efficiently modify 16-membered macrolides. The 16-membered rings are more ovoid in shape compared with the rounded shape of the 14- and 15-membered macrolides. The interactions between MPH(2')-II and the 16-membered macrolides, spiramycin and josamycin, are similar to those of the 14- and 15-membered macrolides, involving many of the same amino acid side chains Escherichia coli ?
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Synonyms

Synonyms Comment Organism
macrolide 2'-phosphotransferase type I
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Escherichia coli
macrolide 2'-phosphotransferase type II
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Escherichia coli
MPH(2')-I
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Escherichia coli
MPH(2')-II
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Escherichia coli
mphA
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Escherichia coli
mphB
-
Escherichia coli

Cofactor

Cofactor Comment Organism Structure
ATP
-
Escherichia coli

General Information

General Information Comment Organism
evolution the macrolide phosphotransferase structures show that the enzymes are related to the aminoglycoside phosphotransferases, but are distinguished from them by the presence of a large interdomain linker that contributes to an expanded antibiotic binding pocket Escherichia coli
additional information the large interdomain linker contributes to an expanded antibiotic binding pocket. This pocket is largely hydrophobic, with a negatively charged patch located at a conserved aspartate residue. Comparison of the enzyme-macrolide complex structure with the structures of macrolides bound to their natural target, the 50S ribosome, overview. Nucleotides bind to MPH(2')-I in a cleft between the N-terminal lobe and the core subdomain of the C-terminal lobe, binding site structure analysis Escherichia coli
additional information the large interdomain linker contributes to an expanded antibiotic binding pocket. This pocket is largely hydrophobic, with a negatively charged patch located at a conserved aspartate residue. Comparison of the enzyme-macrolide complex structure with the structures of macrolides bound to their natural target, the 50S ribosome, overview. Nucleotides bind to MPH(2')-II in a cleft between the N-terminal lobe and the core subdomain of the C-terminal lobe, binding site structure analysis Escherichia coli
physiological function macrolide phosphotransferase enzymes can inactivate the macrolides, a class of antibiotic, characterized by a large macrocyclic lactone ring. Broad-spectrum resistance is conferred by the enzymes Escherichia coli