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Results 1 - 10 of 13 > >>
EC Number General Information Commentary Reference
Display the word mapDisplay the reaction diagram Show all sequences 2.7.1.190evolution aminoglycoside phosphotransferases (APHs) are one of three families of aminoglycoside-modifying enzymes that confer high-level resistance to the aminoglycoside antibiotics via enzymatic modification, the APH(2'') family comprises four distinct members 760284
Display the word mapDisplay the reaction diagram Show all sequences 2.7.1.190evolution Streptomyces rimosus ATCC 10970 contains 14 genes annotated as aminoglycoside phosphotransferases in its genome: aphSR1-aphSR14 -, 762393
Display the word mapDisplay the reaction diagram Show all sequences 2.7.1.190malfunction if the enzyme's binding mode is made impossible because of additional substitutions to the standard 4,5- or 4,6-disubstituted aminoglycoside architecture, as in lividomycin A or the N1-substituted aminoglycosides, it is still possible for these aminoglycosides to bind to the antibiotic binding site by using alternate binding modes, which explains the low rates of noncanonical phosphorylation activities seen in enzyme assays. A clinically observed arbekacin-resistant mutant of APH(2'')-Ia reveals an altered aminoglycoside binding site that can stabilize an alternative binding mode for N1-substituted aminoglycosides. This mutation may alter and expand the aminoglycoside resistance spectrum of the wild-type enzyme in response to developed aminoglycosides 760355
Display the word mapDisplay the reaction diagram Show all sequences 2.7.1.190more APH(2'')-Ia maintains a preferred mode of binding aminoglycosides by using the conserved neamine rings when possible, with flexibility that allows it to accommodate additional rings 760355
Display the word mapDisplay the reaction diagram Show all sequences 2.7.1.190more coexpression of aphSR2 gene and genes pkSR1 and pkSR2, encoding serine-threonine protein kinases, causes a 2fold increase in resistance to neomycin -, 762393
Display the word mapDisplay the reaction diagram Show all sequences 2.7.1.190more structural basis for the diversity of the mechanism of nucleotide hydrolysis by the aminoglycoside-2''-phosphotransferases. Structure comparisons of the ternary complex of APH(2'')-IIIa with GDP and kanamycin with substrate-bound structures of APH(2'')-Ia, APH(2'')-IIa and APH(2'')-IVa. In contrast to the case for APH(2'')-Ia, where it was proposed that the enzyme-mediated hydrolysis of GTP is regulated by conformational changes in its N-terminal domain upon GTP binding, APH(2'')-IIa, APH(2'')-IIIa and APH(2'')-IVa show no such regulatory mechanism, primarily owing to structural differences in the N-terminal domains of these enzymes. The ternary complex between APH(2'')-IIIa, GDP and kanamycin can be regarded as an inactive abortive complex, since the gamma-phosphate group which would normally be transferred to the 2''-hydroxyl of the substrate is absent. The cofactor binding in the ternary complex is similar in detail to that in the previously described binary complex 760284
Display the word mapDisplay the reaction diagram Show all sequences 2.7.1.190more the open-closed transition in APH(2'')-Ia brings distal regions of the protein into contact. The enzyme also exhibits a novel phenomenon: a switch between two welldefined triphosphate conformations. Interactions between the helical subdomain and N lobe loops connect enzyme closure to triphosphate activation. APH(2'')-Ia open-closed transition links aminoglycoside binding to catalysis through the Gly loop. In the stabilized conformation, the enzyme does not form most of the interactions that are required for catalysis in kinases. The gamma-phosphate does not coordinate between the two catalytic magnesium ions. There is no catalytic base in position to activate the incoming nucleophile, and no positively charged residue in place to stabilize the leaving group. To hydrogen bonds are formed between the triphosphate and residues S214 of the Gly oop and Y237. Aminoglycoside molecules bind in the cleft between the core (residues 280-322 and 366-432) and helical (residues 322-365 and 433-479) subdomains of the C lobe, the nucleoside cosubstrates bind in the cleft between the N lobe (residues 180-279) and C lobe (residues 280-479), and two magnesium ions, Mg1 and Mg2, are consistently resolved with coordinating water molecules. Aminoglycosides bind to APH(2'')-Ia via conserved rings, while variable rings Dictate reactivity 762483
Display the word mapDisplay the reaction diagram Show all sequences 2.7.1.190physiological function APH(2'')-Ia is a widely disseminated resistance factor frequently found in clinical isolates of Staphylococcus aureus and pathogenic enterococci, where it is constitutively expressed. APH(2'')-Ia confers high-level resistance to gentamicin and related aminoglycosides through phosphorylation of the antibiotic using GTP as phosphate donor 762483
Display the word mapDisplay the reaction diagram Show all sequences 2.7.1.190physiological function change in the level of resistance to aminoglycoside antibiotics upon combined expression of the aphSR2, pkSR1, and pkSR2 genes in Escherichia coli strain BL21(DE3), overview -, 762393
Display the word mapDisplay the reaction diagram Show all sequences 2.7.1.190physiological function enzyme phosphorylates 4,6-disubstituted aminoglycosides with high efficiency. Despite this proficiency, no resistance is conferred to some of these antibiotics by the enzyme in vivo. Phosphorylation of 4,5-disubstituted and atypical aminoglycosides are negligible and these antibiotics are not substrates. Instead, these aminoglycosides tend to stimulate an intrinsic GTPase activity of the enzyme 734204
Results 1 - 10 of 13 > >>