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Article ; Online: Bilateral Endogenous Methicillin-Resistant

Corredores, Jamel / Halpert, Michael / Cohen, Oren / Amer, Radgonde

2021 Volume 51, Issue 3, Page(s) 177–180

Abstract: Endogenous endophthalmitis (EE) is an ophthalmological emergency. We report the long-term outcome of bilateral methicillin- ... ...

Abstract	Endogenous endophthalmitis (EE) is an ophthalmological emergency. We report the long-term outcome of bilateral methicillin-resistant
MeSH term(s)	Anti-Bacterial Agents/therapeutic use ; Athletes ; Endophthalmitis/microbiology ; Endophthalmitis/physiopathology ; Endophthalmitis/therapy ; Eye Infections, Bacterial/physiopathology ; Eye Infections, Bacterial/therapy ; Humans ; Male ; Methicillin/pharmacology ; Methicillin-Resistant Staphylococcus aureus/isolation & purification ; Recovery of Function ; Staphylococcal Infections/microbiology ; Staphylococcal Infections/physiopathology ; Staphylococcal Infections/therapy ; Vancomycin/therapeutic use ; Vitrectomy/methods ; Young Adult
Chemical Substances	Anti-Bacterial Agents ; Vancomycin (6Q205EH1VU) ; Methicillin (Q91FH1328A)
Language	English
Publishing date	2021-06-29
Publishing country	Turkey
Document type	Case Reports ; Journal Article
ZDB-ID	2586160-8
ISSN	2149-8709 ; 2147-2661 ; 1300-0659 ; 1300-0659 ; 2149-8695
ISSN (online)	2149-8709 ; 2147-2661 ; 1300-0659
ISSN	1300-0659 ; 2149-8695
DOI	10.4274/tjo.galenos.2021.83809
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Article ; Online: Strategies in herbivory by mammals revisited: The role of liver metabolism in a juniper specialist (Neotoma stephensi) and a generalist (Neotoma albigula).

Orr, Teri J / Kitanovic, Smiljka / Schramm, Katharina M / Skopec, Michele M / Wilderman, P Ross / Halpert, James R / Dearing, M Denise

Molecular ecology

2020 Volume 29, Issue 9, Page(s) 1674–1683

Abstract: Although herbivory is widespread among mammals, few species have adopted a strategy of dietary specialization. Feeding on a single plant species often exposes herbivores to high doses of plant secondary metabolites (PSMs), which may exceed the animal's ... ...

Abstract	Although herbivory is widespread among mammals, few species have adopted a strategy of dietary specialization. Feeding on a single plant species often exposes herbivores to high doses of plant secondary metabolites (PSMs), which may exceed the animal's detoxification capacities. Theory predicts that specialists will have unique detoxification mechanisms to process high levels of dietary toxins. To evaluate this hypothesis, we compared liver microsomal metabolism of a juniper specialist, Neotoma stephensi (diet >85% juniper), to a generalist, N. albigula (diet ≤30% juniper). Specifically, we quantified the concentration of a key detoxification enzyme, cytochrome P450 2B (CYP2B) in liver microsomes, and the metabolism of α-pinene, the most abundant terpene in the juniper species consumed by the specialist woodrat. In both species, a 30% juniper diet increased the total CYP2B concentration (2-3×) in microsomes and microsomal α-pinene metabolism rates (4-fold). In N. stephensi, higher levels of dietary juniper (60% and 100%) further induced CYP2B and increased metabolism rates of α-pinene. Although no species-specific differences in metabolism rates were observed at 30% dietary juniper, total microsomal CYP2B concentration was 1.7× higher in N. stephensi than in N. albigula (p < .01), suggesting N. stephensi produces one or more variant of CYP2B that is less efficient at processing α-pinene. In N. stephensi, the rates of α-pinene metabolism increased with dietary juniper and were positively correlated with CYP2B concentration. The ability of N. stephensi to elevate CYP2B concentration and rate of α-pinene metabolism with increasing levels of juniper in the diet may facilitate juniper specialization in this species.
MeSH term(s)	Animals ; Herbivory ; Juniperus ; Liver/metabolism ; Sigmodontinae/classification ; Sigmodontinae/metabolism
Language	English
Publishing date	2020-04-22
Publishing country	England
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	1126687-9
ISSN	1365-294X ; 0962-1083
ISSN (online)	1365-294X
ISSN	0962-1083
DOI	10.1111/mec.15431
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Article ; Online: Use of Phenoxyaniline Analogues To Generate Biochemical Insights into the Interactio n of Polybrominated Diphenyl Ether with CYP2B Enzymes.

Chen, Chao / Liu, Jingbao / Halpert, James R / Wilderman, P Ross

Biochemistry

2017 Volume 57, Issue 5, Page(s) 817–826

Abstract: Human hepatic cytochromes P450 (CYP) are integral to xenobiotic metabolism. CYP2B6 is a major catalyst of biotransformation of environmental toxicants, including polybrominated diphenyl ethers (PBDEs). CYP2B substrates tend to contain halogen atoms, but ... ...

Abstract	Human hepatic cytochromes P450 (CYP) are integral to xenobiotic metabolism. CYP2B6 is a major catalyst of biotransformation of environmental toxicants, including polybrominated diphenyl ethers (PBDEs). CYP2B substrates tend to contain halogen atoms, but the biochemical basis for this selectivity and for species specific determinants of metabolism has not been identified. Spectral binding titrations and inhibition studies were performed to investigate interactions of rat CYP2B1, rabbit CYP2B4, and CYP2B6 with a series of phenoxyaniline (POA) congeners that are analogues of PBDEs. For most congeners, there was a <3-fold difference between the spectral binding constants (K
MeSH term(s)	Alkylation/drug effects ; Amino Acid Substitution ; Aniline Compounds ; Animals ; Aryl Hydrocarbon Hydroxylases/antagonists & inhibitors ; Aryl Hydrocarbon Hydroxylases/chemistry ; Aryl Hydrocarbon Hydroxylases/genetics ; Aryl Hydrocarbon Hydroxylases/metabolism ; Benzene Derivatives/pharmacology ; Cytochrome P-450 CYP2B1/antagonists & inhibitors ; Cytochrome P-450 CYP2B1/chemistry ; Cytochrome P-450 CYP2B1/genetics ; Cytochrome P-450 CYP2B1/metabolism ; Cytochrome P-450 CYP2B6/chemistry ; Cytochrome P-450 CYP2B6/drug effects ; Cytochrome P-450 CYP2B6/genetics ; Cytochrome P-450 CYP2B6/metabolism ; Cytochrome P-450 CYP2B6 Inhibitors/metabolism ; Cytochrome P-450 CYP2B6 Inhibitors/pharmacology ; Cytochrome P-450 Enzyme Inhibitors/metabolism ; Cytochrome P-450 Enzyme Inhibitors/pharmacology ; Cytochrome P450 Family 2/antagonists & inhibitors ; Cytochrome P450 Family 2/chemistry ; Cytochrome P450 Family 2/genetics ; Cytochrome P450 Family 2/metabolism ; Cytochromes b5/metabolism ; Environmental Pollutants/metabolism ; Halogenated Diphenyl Ethers/metabolism ; Halogenated Diphenyl Ethers/pharmacology ; Humans ; Hydrocarbons, Halogenated/metabolism ; Inhibitory Concentration 50 ; Molecular Structure ; Mutagenesis, Site-Directed ; NADPH Oxidases/metabolism ; Oxidation-Reduction ; Rabbits ; Rats ; Recombinant Proteins/metabolism ; Structure-Activity Relationship ; Substrate Specificity
Chemical Substances	Aniline Compounds ; Benzene Derivatives ; Cytochrome P-450 CYP2B6 Inhibitors ; Cytochrome P-450 Enzyme Inhibitors ; Environmental Pollutants ; Halogenated Diphenyl Ethers ; Hydrocarbons, Halogenated ; Recombinant Proteins ; Cytochromes b5 (9035-39-6) ; Aryl Hydrocarbon Hydroxylases (EC 1.14.14.1) ; CYP2B6 protein, human (EC 1.14.14.1) ; Cytochrome P-450 CYP2B1 (EC 1.14.14.1) ; Cytochrome P-450 CYP2B6 (EC 1.14.14.1) ; Cytochrome P450 Family 2 (EC 1.14.14.1) ; cytochrome P-450 CYP2B4 (rabbit) (EC 1.14.14.1) ; NADPH Oxidases (EC 1.6.3.-) ; cumene hydroperoxide (PG7JD54X4I)
Language	English
Publishing date	2017-12-19
Publishing country	United States
Document type	Comparative Study ; Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1108-3
ISSN	1520-4995 ; 0006-2960
ISSN (online)	1520-4995
ISSN	0006-2960
DOI	10.1021/acs.biochem.7b01024
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Article ; Online: Controlled decongestion by Reprieve therapy in acute heart failure: results of the TARGET-1 and TARGET-2 studies.

Biegus, Jan / Zymlinski, Robert / Siwolowski, Pawel / Testani, Jeffrey / Szachniewicz, Joanna / Tycińska, Agnieszka / Banasiak, Waldemar / Halpert, Andrew / Levin, Howard / Ponikowski, Piotr

European journal of heart failure

2019 Volume 21, Issue 9, Page(s) 1079–1087

Abstract: Aims: Safe and effective decongestion is the main goal of therapy in acute heart failure (AHF). In the non-randomized, prospective TARGET-1 and TARGET-2 studies (NCT03897842), we investigated whether adding the Reprieve System® (which continuously ... ...

Abstract	Aims: Safe and effective decongestion is the main goal of therapy in acute heart failure (AHF). In the non-randomized, prospective TARGET-1 and TARGET-2 studies (NCT03897842), we investigated whether adding the Reprieve System® (which continuously monitors urine output and delivers a matched volume of hydration fluid sufficient to maintain the set fluid balance rate) to standard diuretic-based regimen improves decongestion in AHF. Methods and results: The population consisted of 19 patients hospitalized with AHF (mean age 67 ± 10 years, 18 male, ejection fraction 34 ± 15%, median N-terminal pro-B-type natriuretic peptide 4492 pg/mL). Patients served as their own controls: each patient underwent 24 h of standard diuretic therapy followed by 24 h of diuretics with Reprieve therapy (with normal saline used for matched volume replacement). The primary efficacy endpoint of actual fluid loss not exceeding the target fluid loss at the end of therapy was met in all 19 (100%) patients. The mean diuresis during Reprieve therapy was 6284 ± 2679 mL (vs. 1966 ± 1057 mL 24 h before therapy) and 2053 ± 888 mL (24 h after therapy) (both P < 0.0001). At the end of therapy, patient global assessment improved from 7.7 ± 1.1 to 3.0 ± 1.3 points (P < 0.001), central venous pressure decreased from 15.5 ± 5.3 mmHg to 12.8 ± 4.8 mmHg (P < 0.05) and the median urine sodium loss was 9.7 [3-13] mmol/h. The Reprieve therapy was safe, systolic blood pressure remained stable, mean creatinine dropped from 1.45 ± 0.4 mg/dL to 1.26 ± 0.4 mg/dL (P < 0.001) and biomarkers of renal injury did not change during treatment. Conclusions: The Reprieve System in conjunction with diuretic therapy supports safe and controlled decongestion in AHF.
MeSH term(s)	Acute Disease ; Aged ; Central Venous Pressure ; Creatinine/metabolism ; Diuretics/therapeutic use ; Edema, Cardiac/metabolism ; Edema, Cardiac/therapy ; Equipment and Supplies ; Female ; Fluid Therapy/instrumentation ; Fluid Therapy/methods ; Furosemide/therapeutic use ; Heart Failure/metabolism ; Heart Failure/therapy ; Humans ; Male ; Middle Aged ; Natriuretic Peptide, Brain/metabolism ; Peptide Fragments/metabolism ; Saline Solution/therapeutic use ; Urine ; Water-Electrolyte Balance
Chemical Substances	Diuretics ; Peptide Fragments ; Saline Solution ; pro-brain natriuretic peptide (1-76) ; Natriuretic Peptide, Brain (114471-18-0) ; Furosemide (7LXU5N7ZO5) ; Creatinine (AYI8EX34EU)
Language	English
Publishing date	2019-08-29
Publishing country	England
Document type	Controlled Clinical Trial ; Journal Article
ZDB-ID	1483672-5
ISSN	1879-0844 ; 1388-9842
ISSN (online)	1879-0844
ISSN	1388-9842
DOI	10.1002/ejhf.1533
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Article ; Online: Automated optimized parameters for T-distributed stochastic neighbor embedding improve visualization and analysis of large datasets.

Belkina, Anna C / Ciccolella, Christopher O / Anno, Rina / Halpert, Richard / Spidlen, Josef / Snyder-Cappione, Jennifer E

Nature communications

2019 Volume 10, Issue 1, Page(s) 5415

Abstract: Accurate and comprehensive extraction of information from high-dimensional single cell datasets necessitates faithful visualizations to assess biological populations. A state-of-the-art algorithm for non-linear dimension reduction, t-SNE, requires ... ...

Abstract	Accurate and comprehensive extraction of information from high-dimensional single cell datasets necessitates faithful visualizations to assess biological populations. A state-of-the-art algorithm for non-linear dimension reduction, t-SNE, requires multiple heuristics and fails to produce clear representations of datasets when millions of cells are projected. We develop opt-SNE, an automated toolkit for t-SNE parameter selection that utilizes Kullback-Leibler divergence evaluation in real time to tailor the early exaggeration and overall number of gradient descent iterations in a dataset-specific manner. The precise calibration of early exaggeration together with opt-SNE adjustment of gradient descent learning rate dramatically improves computation time and enables high-quality visualization of large cytometry and transcriptomics datasets, overcoming limitations of analysis tools with hard-coded parameters that often produce poorly resolved or misleading maps of fluorescent and mass cytometry data. In summary, opt-SNE enables superior data resolution in t-SNE space and thereby more accurate data interpretation.
MeSH term(s)	Algorithms ; Animals ; Automation ; Computational Biology ; Data Visualization ; Datasets as Topic ; Flow Cytometry ; Gene Expression Profiling ; Humans ; Machine Learning ; Mice ; Nonlinear Dynamics ; Principal Component Analysis
Language	English
Publishing date	2019-11-28
Publishing country	England
Document type	Journal Article
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-019-13055-y
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Article: Endogenous fungal endophthalmitis: risk factors, clinical course, and visual outcome in 13 patients.

Corredores, Jamel / Hemo, Itzhak / Jaouni, Tareq / Habot-Wilner, Zohar / Kramer, Michal / Shulman, Shiri / Jabaly-Habib, Haneen / Al-Talbishi, Ala'a / Halpert, Michael / Averbukh, Edward / Levy, Jaime / Deitch-Harel, Iris / Amer, Radgonde

International journal of ophthalmology

2021 Volume 14, Issue 1, Page(s) 97–105

Abstract: Aim: To analyze the risk factors, ophthalmological features, treatment modalities and their effect on the visual outcome in patients with endogenous fungal endophthalmitis (EFE).: Methods: Data retrieved from the medical files included age at ... ...

Abstract	Aim: To analyze the risk factors, ophthalmological features, treatment modalities and their effect on the visual outcome in patients with endogenous fungal endophthalmitis (EFE). Methods: Data retrieved from the medical files included age at presentation to the uveitis clinic, gender, ocular symptoms and their duration before presentation, history of fever, eye affected, anatomical diagnosis and laboratory evidence of fungal infection. Medical therapy recorded included systemic antifungal therapy and its duration, use of intravitreal antifungal agents and use of oral/intravitreal steroids. Surgical procedures and the data of ophthalmologic examination at presentation and at last follow-up were also collected. Results: Included were 13 patients (20 eyes, mean age 58y). Ten patients presented after gastrointestinal or urological interventions and two presented after organ transplantation. In one patient, there was no history of previous intervention. Diagnostic vitrectomy was performed in 16 eyes (80%) and vitreous cultures were positive in 10 of the vitrectomized eyes (62.5%). In only 4 patients (31%), blood cultures were positive. All patients received systemic antifungal therapy. Sixteen eyes (80%) received intravitreal antifungal agent with voriconazole being the most commonly used. Visual acuity (VA) improved from 0.9±0.9 at initial exam to 0.5±0.8 logMAR at last follow-up ( Conclusion: High index of suspicion in patients with inciting risk factors is essential because of the low yield of blood cultures and the good general condition of patients at presentation. Visual prognosis is improved with the prompt institution of systemic and intravitreal pharmacotherapy and the immediate surgical intervention. Oral±local steroids could be considered in cases of prolonged or marked inflammatory responses in order to hasten control of inflammation and limit ocular complications.
Language	English
Publishing date	2021-01-18
Publishing country	China
Document type	Journal Article
ZDB-ID	2663246-9
ISSN	2227-4898 ; 2222-3959
ISSN (online)	2227-4898
ISSN	2222-3959
DOI	10.18240/ijo.2021.01.14
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Article ; Online: AutoSpill is a principled framework that simplifies the analysis of multichromatic flow cytometry data.

Roca, Carlos P / Burton, Oliver T / Gergelits, Václav / Prezzemolo, Teresa / Whyte, Carly E / Halpert, Richard / Kreft, Łukasz / Collier, James / Botzki, Alexander / Spidlen, Josef / Humblet-Baron, Stéphanie / Liston, Adrian

Nature communications

2021 Volume 12, Issue 1, Page(s) 2890

Abstract: Compensating in flow cytometry is an unavoidable challenge in the data analysis of fluorescence-based flow cytometry. Even the advent of spectral cytometry cannot circumvent the spillover problem, with spectral unmixing an intrinsic part of such systems. ...

Abstract	Compensating in flow cytometry is an unavoidable challenge in the data analysis of fluorescence-based flow cytometry. Even the advent of spectral cytometry cannot circumvent the spillover problem, with spectral unmixing an intrinsic part of such systems. The calculation of spillover coefficients from single-color controls has remained essentially unchanged since its inception, and is increasingly limited in its ability to deal with high-parameter flow cytometry. Here, we present AutoSpill, an alternative method for calculating spillover coefficients. The approach combines automated gating of cells, calculation of an initial spillover matrix based on robust linear regression, and iterative refinement to reduce error. Moreover, autofluorescence can be compensated out, by processing it as an endogenous dye in an unstained control. AutoSpill uses single-color controls and is compatible with common flow cytometry software. AutoSpill allows simpler and more robust workflows, while reducing the magnitude of compensation errors in high-parameter flow cytometry.
Language	English
Publishing date	2021-05-17
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-021-23126-8
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Article ; Online: Role of cytochrome P450 2B sequence variation and gene copy number in facilitating dietary specialization in mammalian herbivores.

Kitanovic, Smiljka / Orr, Teri J / Spalink, Daniel / Cocke, Granger B / Schramm, Katharina / Wilderman, P Ross / Halpert, James R / Dearing, M Denise

Molecular ecology

2018 Volume 27, Issue 3, Page(s) 723–736

Abstract: Theory postulates that dietary specialization in mammalian herbivores is enabled by a specialized set of liver enzymes that process the high concentrations of similar plant secondary metabolites (PSMs) in the diets of specialists. To investigate whether ... ...

Abstract	Theory postulates that dietary specialization in mammalian herbivores is enabled by a specialized set of liver enzymes that process the high concentrations of similar plant secondary metabolites (PSMs) in the diets of specialists. To investigate whether qualitative and quantitative differences in detoxification mechanisms distinguish dietary specialists from generalists, we compared the sequence diversity and gene copy number of detoxification enzymes in two woodrat species: a generalist, the white-throated woodrat (Neotoma albigula) and a juniper specialist, Stephens' woodrat (N. stephensi). We focused on enzymes in the cytochrome P450 subfamily 2B (CYP2B), because previous research suggests this subfamily plays a key role in the processing of PSMs. For both woodrat species, we obtained and sequenced CYP2B cDNA, generated CYP2B phylogenies, estimated CYP2B gene copy number and created a homology model of the active site. We found that the specialist possessed on average ~5 more CYP2B gene copies than the generalist, but the specialist's CYP2B sequences were less diverse. Phylogenetic analysis of putative CYP2B homologs resolved woodrat species as reciprocally monophyletic and suggested evolutionary convergence of distinct homologs on similar key amino acid residues in both species. Homology modelling of the CYP2B enzyme suggests that interspecific differences in substrate preference and function likely result from amino acid differences in the enzyme active site. The characteristics of CYP2B in the specialist, that is greater gene copy number coupled with less sequence variation, are consistent with specialization to a narrow range of dietary toxins.
MeSH term(s)	Animals ; Base Sequence ; Cytochrome P-450 Enzyme System/genetics ; Diet ; Evolution, Molecular ; Gene Dosage ; Genetic Variation ; Haploidy ; Herbivory/physiology ; Mutation/genetics ; Phylogeny ; Sigmodontinae/genetics ; Structural Homology, Protein
Chemical Substances	Cytochrome P-450 Enzyme System (9035-51-2)
Language	English
Publishing date	2018-01-29
Publishing country	England
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	1126687-9
ISSN	1365-294X ; 0962-1083
ISSN (online)	1365-294X
ISSN	0962-1083
DOI	10.1111/mec.14480
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Article ; Online: Rational Re-Engineering of the O-Dealkylation of 7-Alkoxycoumarin Derivatives by Cytochromes P450 2B from the Desert Woodrat Neotoma lepida.

Huo, Lu / Liu, Jingbao / Dearing, M Denise / Szklarz, Grazyna D / Halpert, James R / Wilderman, P Ross

Biochemistry

2017 Volume 56, Issue 16, Page(s) 2238–2246

Abstract: On the basis of recent functional and structural characterization of cytochromes P450 2B from the desert woodrat (Neotoma lepida), the 7-alkoxycoumarin and 7-alkoxy-4-(trifluoromethyl)coumarin O-dealkylation profiles of CYP2B35 and CYP2B37 were re- ... ...

Abstract	On the basis of recent functional and structural characterization of cytochromes P450 2B from the desert woodrat (Neotoma lepida), the 7-alkoxycoumarin and 7-alkoxy-4-(trifluoromethyl)coumarin O-dealkylation profiles of CYP2B35 and CYP2B37 were re-engineered. Point mutants interchanging residues at seven positions in the enzyme active sites were created and purified from an Escherichia coli expression system. In screens for O-dealkylation activity, wild-type CYP2B35 metabolized long-chain 7-alkoxycoumarins but not 7-alkoxy-4-(trifluoromethyl)coumarins or short-chain 7-alkoxycoumarins. Wild-type CYP2B37 metabolized short-chain substrates from both series of compounds. CYP2B35 A367V showed maximal activity with 7-butoxycoumarin as opposed to 7-heptoxycoumarin in the parental enzyme, and CYP2B35 A363I/A367V produced an activity profile like that generated by CYP2B37. CYP2B35 A363I/A367V/I477F showed 7-ethoxycoumarin and 7-ethoxy-4-(trifluoromethyl)coumarin O-dealkylation rates similar to those of CYP2B37 and higher than those of the double mutant. A CYP2B35 septuple mutant retained a CYP2B37-like activity profile. In contrast, the CYP2B37 septuple mutant produced very low rates of O-dealkylation of all substrates. As mutating residue 108 in either enzyme was detrimental, this change was removed from both septuple mutants. Remarkably, the CYP2B35 sextuple mutant produced an activity profile that was a hybrid of that of CYP2B35 and CYP2B37, whereas the CYP2B37 sextuple mutant had almost no O-dealkylation activity. Docking of 7-substituted coumarin derivatives into a model of the CYP2B35 sextuple mutant based on a previous crystal structure of the 4-(4-chlorophenyl)imidazole wild-type complex revealed how the mutant can exhibit activities of both CYP2B35 and CYP2B37.
MeSH term(s)	Alkylation ; Animals ; Coumarins/metabolism ; Cytochrome P-450 Enzyme System/chemistry ; Cytochrome P-450 Enzyme System/genetics ; Cytochrome P-450 Enzyme System/isolation & purification ; Cytochrome P-450 Enzyme System/metabolism ; Mutagenesis, Site-Directed ; Sigmodontinae
Chemical Substances	Coumarins ; Cytochrome P-450 Enzyme System (9035-51-2)
Language	English
Publishing date	2017-04-25
Publishing country	United States
Document type	Journal Article
ZDB-ID	1108-3
ISSN	1520-4995 ; 0006-2960
ISSN (online)	1520-4995
ISSN	0006-2960
DOI	10.1021/acs.biochem.7b00097
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Article ; Online: Halogen-π Interactions in the Cytochrome P450 Active Site: Structural Insights into Human CYP2B6 Substrate Selectivity.

Shah, Manish B / Liu, Jingbao / Zhang, Qinghai / Stout, C David / Halpert, James R

ACS chemical biology

2017 Volume 12, Issue 5, Page(s) 1204–1210

Abstract: Numerous cytochrome P450 (CYP) 2B6 substrates including drugs and environmental chemicals are halogenated. To assess the role of halogen-π bonds in substrate selectivity and orientation in the active site, structures of four CYP2B6 monoterpenoid ... ...

Abstract	Numerous cytochrome P450 (CYP) 2B6 substrates including drugs and environmental chemicals are halogenated. To assess the role of halogen-π bonds in substrate selectivity and orientation in the active site, structures of four CYP2B6 monoterpenoid complexes were solved by X-ray crystallography. Bornyl bromide exhibited dual orientations in the active site with the predominant orientation revealing a bromine-π bond with the Phe108 side chain. Bornane demonstrated two orientations with equal occupancy; in both, the C2 atom that bears the bromine in bornyl bromide was displaced by more than 2.5 Å compared with the latter complex. The bromine in myrtenyl bromide π-bonded with Phe297 in CYP2B6, whereas the two major orientations in the active site mutant I114V exhibited bromine-π interactions with two additional residues, Phe108 and Phe115. Analysis of existing structures suggests that halogen-π interactions may be unique to the CYP2B enzymes within CYP family 2 but are also important for CYP3A enzymes.
MeSH term(s)	Binding Sites ; Catalytic Domain ; Crystallography, X-Ray ; Cytochrome P-450 CYP2B6/chemistry ; Halogens/chemistry ; Humans ; Monoterpenes/chemistry ; Protein Binding ; Substrate Specificity
Chemical Substances	Halogens ; Monoterpenes ; Cytochrome P-450 CYP2B6 (EC 1.14.14.1)
Language	English
Publishing date	2017-05-19
Publishing country	United States
Document type	Journal Article
ISSN	1554-8937
ISSN (online)	1554-8937
DOI	10.1021/acschembio.7b00056
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