Chloroquine Binding Reveals Flavin Redox Switch Function of Quinone Reductase 2

Leung, Kevin; Shilton, Brian H.

doi:10.1074/jbc.m113.457002

Cited by 37 publications

(55 citation statements)

References 52 publications

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“…Thus, the decrease in the space group symmetry of the OXA-58 crystal soaked in the solution of either compound must be presumed to result from their binding to the enzyme (whether covalently or noncovalently), effecting a structural change to the protein. An example of ligand binding reducing the space group symmetry of the protein crystal, which is linked to the induction of conformational changes in the protein structure, is found in the literature: the flavin adenine dinucleotide (FAD)-linked quinone reductase 2 enzyme gave a reduction in the space group symmetry and structural change upon the binding of chloroquinone (35).…”

Section: Resultsmentioning

confidence: 99%

Active-Site Plasticity Is Essential to Carbapenem Hydrolysis by OXA-58 Class D β-Lactamase of Acinetobacter baumannii

Pratap

Katiki

Gill

et al. 2016

Antimicrob Agents Chemother

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Carbapenem-hydrolyzing class D ␤-lactamases (CHDLs) are a subgroup of class D ␤-lactamases, which are enzymes that hydrolyze ␤-lactams. They have attracted interest due to the emergence of multidrug-resistant Acinetobacter baumannii, which is not responsive to treatment with carbapenems, the usual antibiotics of choice for this bacterium. Unlike other class D ␤-lactamases, these enzymes efficiently hydrolyze carbapenem antibiotics. To explore the structural requirements for the catalysis of carbapenems by these enzymes, we determined the crystal structure of the OXA-58 CHDL of A. baumannii following acylation of its active-site serine by a 6␣-hydroxymethyl penicillin derivative that is a structural mimetic for a carbapenem. In addition, several point mutation variants of the active site of OXA-58, as identified by the crystal structure analysis, were characterized kinetically. These combined studies confirm the mechanistic relevance of a hydrophobic bridge formed over the active site. This structural feature is suggested to stabilize the hydrolysis-productive acyl-enzyme species formed from the carbapenem substrates of this enzyme. Furthermore, our structural studies provide strong evidence that the hydroxyethyl group of carbapenems samples different orientations in the active sites of CHDLs, and the optimum orientation for catalysis depends on the topology of the active site allowing proper closure of the active site. We propose that CHDLs use the plasticity of the active site to drive the mechanism of carbapenem hydrolysis toward efficiency.

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Section: Resultsmentioning

confidence: 99%

Active-Site Plasticity Is Essential to Carbapenem Hydrolysis by OXA-58 Class D β-Lactamase of Acinetobacter baumannii

Pratap

Katiki

Gill

et al. 2016

Antimicrob Agents Chemother

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“…Quinone reductase 2 enzymes are one of known human targets for antimalarial drugs, primaquine and chloroquine. 59,60 The most well-characterised quinone reductase 2 enzyme is human quinone reductase 2 (Nqo2) (PDB 2FGL, 2FGI), which is unique in that it uses dihydronicotinamide riboside (NRH) as a reducing coenzyme rather than NADH or NADPH. 59,60 The structural and sequence alignment of Th-Fre with human quinone reductase 2 shows that Th-Fre is a shorter protein and there is a 30 amino acid insertion at the N terminal of human quinone reductase 2 that forms an extended helix above the flavin domain of opposite monomer (Fig.…”

Section: Crystal Structure and Amino Acid Variability Of Th-halmentioning

confidence: 99%

Structure and biocatalytic scope of thermophilic flavin-dependent halogenase and flavin reductase enzymes

et al. 2016

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Flavin-dependent halogenase (Fl-Hal) enzymes have been shown to halogenate a range of synthetic as well as natural aromatic compounds. The exquisite regioselectively of Fl-Hal enzymes can provide halogenated building blocks which are inaccessible using standard halogenation chemistries. Consequently, Fl-Hal are potentially useful biocatalysts for the chemoenzymatic synthesis of pharmaceuticals and other valuable products, which are derived from haloaromatic precursors. However, the application of Fl-Hal enzymes, in vitro, has been hampered by their poor catalytic activity and lack of stability. To overcome these issues, we identified a thermophilic tryptophan halogenase (Th-Hal), which has significantly improved catalytic activity and stability, compared with other Fl-Hal characterised to date. When used in combination with a thermostable flavin reductase, Th-Hal can efficiently halogenate a number of aromatic substrates. X-ray crystal structures of Th-Hal, and the reductase partner (Th-Fre), provide insights into the factors that contribute to enzyme stability, which could guide the discovery and engineering of more robust and productive halogenase biocatalysts.

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“…The modulation of the proteasome has also been shown in a yeast homolog quinone reductase Lot6p, which binds to the 20S proteasome and forms a ternary complex with transcriptional factor Yap4p [74, 75]. When binding to a specific inhibitor, the reduction of FAD leads to global changes in the NQO2 structure and stabilization of the active site in an alternate conformation [76], and the conformational switch is consistent with the observation of NQO1 in the redox-dependent regulation of p53 [77]. …”

Section: Puta Is a Flavin Switch Proteinmentioning

confidence: 99%

Structure, function, and mechanism of proline utilization A (PutA)

Liu

Becker

Tanner

2017

Archives of Biochemistry and Biophysics

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Proline has important roles in multiple biological processes such as cellular bioenergetics, cell growth, oxidative and osmotic stress response, protein folding and stability, and redox signaling. The proline catabolic pathway, which forms glutamate, enables organisms to utilize proline as a carbon, nitrogen, and energy source. FAD-dependent proline dehydrogenase (PRODH) and NAD+-dependent glutamate semialdehyde dehydrogenase (GSALDH) convert proline to glutamate in two sequential oxidative steps. Depletion of PRODH and GSALDH in humans leads to hyperprolinemia, which is associated with mental disorders such as schizophrenia. Also, some pathogens require proline catabolism for virulence. A unique aspect of proline catabolism is the multifunctional proline utilization A (PutA) enzyme found in Gram-negative bacteria. PutA is a large (> 1000 residues) bifunctional enzyme that combines PRODH and GSALDH activities into one polypeptide chain. In addition, some PutAs function as a DNA-binding transcriptional repressor of proline utilization genes. This review describes several attributes of PutA that make it a remarkable flavoenzyme: (1) diversity of oligomeric state and quaternary structure; (2) substrate channeling and enzyme hysteresis; (3) DNA-binding activity and transcriptional repressor function; and (4) flavin redox dependent changes in subcellular location and function in response to proline (functional switching).

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Chloroquine Binding Reveals Flavin Redox Switch Function of Quinone Reductase 2

Cited by 37 publications

References 52 publications

Active-Site Plasticity Is Essential to Carbapenem Hydrolysis by OXA-58 Class D β-Lactamase of Acinetobacter baumannii

Active-Site Plasticity Is Essential to Carbapenem Hydrolysis by OXA-58 Class D β-Lactamase of Acinetobacter baumannii

Structure and biocatalytic scope of thermophilic flavin-dependent halogenase and flavin reductase enzymes

Structure, function, and mechanism of proline utilization A (PutA)

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