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Eriksson, Leif A
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Publications (10 of 63) Show all publications
Czégény, G., Wu, M., Dér, A., Eriksson, L. A., Strid, Å. & Hideg, É. (2014). Hydrogen peroxide contributes to the ultraviolet-B (280-315 nm) induced oxidative stress of plant leaves through multiple pathways. FEBS Letters, 588(14), 2255-2261
Open this publication in new window or tab >>Hydrogen peroxide contributes to the ultraviolet-B (280-315 nm) induced oxidative stress of plant leaves through multiple pathways
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2014 (English)In: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 588, no 14, p. 2255-2261Article in journal (Refereed) Published
Abstract [en]

Solar UV-B (280-315 nm) radiation is a developmental signal in plants but may also cause oxidative stress when combined with other environmental factors. Using computer modelling and in solution experiments we show that UV-B is capable of photosensitizing hydroxyl radical production from hydrogen peroxide. We present evidence that the oxidative effect of UV-B in leaves is at least two-fold: (i) it increases cellular hydrogen peroxide concentrations, to a larger extent in pyridoxine antioxidant mutant pdx1.3-1 Arabidopsis and (ii) is capable of a partial photo-conversion of both ‘natural’ and ‘extra’ hydrogen peroxide to hydroxyl radicals. As stress conditions other than UV can increase cellular hydrogen peroxide levels, synergistic deleterious effects of various stresses may be expected already under ambient solar UV-B.

Keywords
Arabidopsis; Computer modeling; Hydrogen peroxide; Hydroxyl radical; Leaf; Oxygen radicals; Photosynthesis; Plant; Terephthalic acid; UV photobiology
National Category
Biochemistry and Molecular Biology
Research subject
Biochemistry
Identifiers
urn:nbn:se:oru:diva-34932 (URN)10.1016/j.febslet.2014.05.005 (DOI)000338401100011 ()24846142 (PubMedID)2-s2.0-84902662550 (Scopus ID)
Projects
UV Plant Photobiology
Funder
Knowledge FoundationCarl Tryggers foundation
Note

Funding Agencies:

COST Action FA0906

Hungarian Scientific Grant Agency OTKMNN-85349

Örebro University's Faculty for Business, Science and Technology

Available from: 2014-05-03 Created: 2014-05-03 Last updated: 2017-12-05Bibliographically approved
Wu, M., Strid, Å. & Eriksson, L. A. (2014). Photochemical reaction mechanism of UV-B-induced monomerization of UVR8 dimers as the first signaling event in UV-B-regulated gene expression in plants. Journal of Physical Chemistry B, 118, 951-965
Open this publication in new window or tab >>Photochemical reaction mechanism of UV-B-induced monomerization of UVR8 dimers as the first signaling event in UV-B-regulated gene expression in plants
2014 (English)In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 118, p. 951-965Article in journal (Refereed) Published
Abstract [en]

The Arabidopsis thaliana UV RESISTANCE LOCUS8 (UVR8) protein has been identified to specifically mediate photomorphogenic UV-B responses by acting as a UV-B photoreceptor. The dimeric structure of the UVR8 protein dissociates into signaling–active monomers upon UV-B exposure, and the monomers rapidly interact with downstream signaling components to regulate gene expression. UVR8 monomers revert to dimers in the absence of UV-B radiation, thereby reversing transcription activation. UVR8 amino acid residues W233 and W285 have been identified to play critical roles in the UVR8 dimer for the response to UV-B irradiation. In the present work, the photo-reaction mechanism for UVR8 monomerization is explored using quantum chemical cluster calculations, and evaluated by molecular dynamics simulations using the wild type UVR8 dimer and novel force field parameters developed for intermediate radicals formed in the photochemical process. Three different models are investigated, which show that the preferred mechanism for UVR8 monomerization involves electron transfer from residue W233 to W285 and onwards to R338 initiated by UV-B irradiation, coupled to simultaneous proton transfer from W233 to D129 leading to the formation of protonated D129, a deprotonated W233 radical and a neutral R338 radical.. Due to the formation of the neutral R338 radical, salt bridges involving this residue are disrupted together with the concomitant interruption of several other key salt bridges R286-D96, R286-D107, R338-D44, R354-E43 and R354-E53. The resulting large decrease in protein-protein interaction energy arising from this sequence of events lead to the monomerization of the UVR8 dimer. The mechanism presented is in accord with all experimental data available to date.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2014
Keywords
Amino acid residues; Arabidopsis thaliana; Force field parameters; Molecular dynamics simulations; Photochemical process; Protein-protein interactions; Sequence of events; Signaling components
National Category
Physical Chemistry Biochemistry and Molecular Biology
Research subject
Physical Chemistry; Biochemistry
Identifiers
urn:nbn:se:oru:diva-33022 (URN)10.1021/jp4104118 (DOI)000330610400011 ()24410443 (PubMedID)2-s2.0-84893504425 (Scopus ID)
Projects
ULTRAVIOLET RADIATION AS AN ENVIRONMENTAL STIMULI IN BIOLOGICAL SYSTEMS: PERCEPTION, SIGNALLING, MOLECULAR RESPONSES AND MORPHOGENESIS
Funder
Swedish Research CouncilCarl Tryggers foundation
Note

Funding Agency:

Faculty of Science at the University of Gothenburg

Available from: 2014-01-11 Created: 2014-01-11 Last updated: 2017-10-18Bibliographically approved
Wu, M., Strid, Å. & Eriksson, L. A. (2013). Interactions and Stabilities of the UV RESISTANCE LOCUS8 (UVR8) protein dimer and its key mutants. Journal of Chemical Information and Modeling, 53(7), 1736-1746
Open this publication in new window or tab >>Interactions and Stabilities of the UV RESISTANCE LOCUS8 (UVR8) protein dimer and its key mutants
2013 (English)In: Journal of Chemical Information and Modeling, ISSN 1549-9596, E-ISSN 1549-960X, Vol. 53, no 7, p. 1736-1746Article in journal (Refereed) Published
Abstract [en]

The dimeric UVR8 protein is a ultraviolet-B radiation (280-315 nm) photoreceptor responsible for the first step in UV-B regulation of gene expression in plants. Its action comprises the actual absorption of the UV quanta by a tryptophan array at the protein-protein interface, followed by monomerisation, and subsequent aggregation with downstream signaling components. A crystal structure of the Arabidopsis thaliana tryptophan-rich wild type UVR8 protein dimer was recently published, showing the presence of several salt bridges involving arginines R146, R286, R338 and R354. In this work, molecular dynamics simulations in conjunction with umbrella sampling was used to calculate the binding free energy for the wild type UVR8 dimer and three of its mutants (R286A, R338A and R286A/R338A), in order to verify whether the key mutants are able to disrupt the dimeric structure as indicated experimentally.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2013
National Category
Theoretical Chemistry Physical Chemistry Biochemistry and Molecular Biology
Research subject
Biochemistry
Identifiers
urn:nbn:se:oru:diva-29389 (URN)10.1021/ci4001822 (DOI)000322345400018 ()23745796 (PubMedID)2-s2.0-84880534992 (Scopus ID)
Projects
Plant UV-B photbiology
Funder
Swedish Research Council
Note

Funding agency:

University of Gothenburg 

Available from: 2013-06-09 Created: 2013-06-09 Last updated: 2018-05-18Bibliographically approved
Gao, L., Tu, Y., Wegman [Palmebäck-Wegman], P., Wingren, S. & Eriksson, L. A. (2011). Conformational enantiomerization and estrogen receptor alpha binding of anti-cancer drug tamoxifen and its derivatives. Journal of Chemical Information and Modeling, 51(2), 306-314
Open this publication in new window or tab >>Conformational enantiomerization and estrogen receptor alpha binding of anti-cancer drug tamoxifen and its derivatives
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2011 (English)In: Journal of Chemical Information and Modeling, ISSN 1549-9596, E-ISSN 1549-960X, Vol. 51, no 2, p. 306-314Article in journal (Refereed) Published
Abstract [en]

The anticancer drug tamoxifen (TAM) displays two chiral vinyl propeller structures, which interconvert so rapidly that the process is undetectable on the NMR time scale. In the present work, the enantiomerization processes were investigated with molecular modeling techniques. The threshold mechanisms probed at the different rings were shown to be identical, i.e., involving a synchronous three-ring flip, with a correlated rotation of the rings. In order to reveal the pharmacological profiles of the two chiral forms, we performed structural studies on the ligand binding domain of estrogen receptor alpha. (ER alpha LBD) and associated ligands. The enantiomers, with opposite torsional twist, were found to be discriminated by ER alpha. For TAM and its main metabolites, the effects of the stereoselectivity of ER alpha are overcome by the low energy cost for helical inversion between the two torsional enantiomers, estimated to be similar to 3 kcal/mol.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2011
National Category
Medical and Health Sciences
Research subject
Medicine
Identifiers
urn:nbn:se:oru:diva-17124 (URN)10.1021/ci100401t (DOI)000287685700012 ()21194224 (PubMedID)2-s2.0-79952139350 (Scopus ID)
Available from: 2011-09-05 Created: 2011-09-02 Last updated: 2017-12-08Bibliographically approved
Musa, K. A. K., Palwai, V. R. & Eriksson, L. A. (2011). New nonsteroidal anti-inflammatory molecules with reduced photodegradation side effects and enhanced COX-2 selectivity. International Journal of Quantum Chemistry, 111(6), 1184-1195
Open this publication in new window or tab >>New nonsteroidal anti-inflammatory molecules with reduced photodegradation side effects and enhanced COX-2 selectivity
2011 (English)In: International Journal of Quantum Chemistry, ISSN 0020-7608, E-ISSN 1097-461X, Vol. 111, no 6, p. 1184-1195Article in journal (Refereed) Published
Abstract [en]

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used as antipyretic, analgesic, and anti-inflammatory agents. However, they are also associated with a range of side effects, from phototoxicity due to excited state induced decarboxylation to severe conditions in the gastrointestinal tract caused by inhibition of the COX-1 isoform of the target cyclooxygenase enzyme. In the current work, new derivatives of the three NSAIDs ketoprofen, ibuprofen, and naproxen were designed. Their photochemistry was explored using hybrid-density functional theory (B3LYP/6-31G(d,p)) and time-dependent (TD) DFT, showing that the compounds will have significantly reduced propensity to decarboxylate from the first excited triplet state. In addition, docking studies were carried out for these new molecules to explore their activity and selectivity toward the two isoforms of the COX enzyme. The results show that most compounds have increased activity toward the COX enzymes, and in general are more selective toward the COX-2 target isoform. The results from this study suggest that the new modified molecules could be used in the future as NSAIDs with considerably reduced side effects.

Place, publisher, year, edition, pages
Wiley-Blackwell, 2011
Keywords
NSAIDs, phototoxicity, docking, cyclooxygenase, interaction energy, selectivity
National Category
Physical Chemistry
Research subject
Chemistry
Identifiers
urn:nbn:se:oru:diva-17073 (URN)10.1002/qua.22649 (DOI)000288096500007 ()2-s2.0-79952179045 (Scopus ID)
Note

4th International Theoretical Biophysics Symposium, Roscoff, FRANCE, JUN 29-JUL 03, 2009

Available from: 2011-09-06 Created: 2011-09-02 Last updated: 2017-12-08Bibliographically approved
Bushnell, E. A. C., Erdtman, E., Llano, J., Eriksson, L. A. & Gauld, J. W. (2011). The first branching point in porphyrin biosynthesis: a systematic docking, molecular dynamics and quantum mechanical/molecular mechanical study of substrate binding and mechanism of uroporphyrinogen-III decarboxylase. Journal of Computational Chemistry, 32(5), 822-834
Open this publication in new window or tab >>The first branching point in porphyrin biosynthesis: a systematic docking, molecular dynamics and quantum mechanical/molecular mechanical study of substrate binding and mechanism of uroporphyrinogen-III decarboxylase
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2011 (English)In: Journal of Computational Chemistry, ISSN 0192-8651, E-ISSN 1096-987X, Vol. 32, no 5, p. 822-834Article in journal (Refereed) Published
Abstract [en]

In humans, uroporphyrinogen decarboxylase is intimately involved in the synthesis of heme, where the decarboxylation of the uroporphyrinogen-III occurs in a single catalytic site. Several variants of the mechanistic proposal exist; however, the exact mechanism is still debated. Thus, using an ONIOM quantum mechanical/molecular mechanical approach, the mechanism by which uroporphyrinogen decarboxylase decarboxylates ring D of uroporphyrinogen-III has been investigated. From the study performed, it was found that both Arg37 and Arg50 are essential in the decarboxylation of ring D, where experimentally both have been shown to be critical to the catalytic behavior of the enzyme. Overall, the reaction was found to have a barrier of 10.3 kcal mol−1 at 298.15 K. The rate-limiting step was found to be the initial protontransfer from Arg37 to the substrate before the decarboxylation. In addition, it has been found that several key interactions exist between the substrate carboxylate groups and backbone amides of various activesite residues as well as several other functional groups.

Place, publisher, year, edition, pages
New York: John Wiley & Sons, 2011
Keywords
uroporphyrinogen decarboxylase III, uroporphyrinogen III, porphyrin biosynthesis, quantum mechanics/molecular mechanics and density functional theory
National Category
Natural Sciences Physical Chemistry Physical Chemistry Theoretical Chemistry Theoretical Chemistry
Research subject
Biochemistry
Identifiers
urn:nbn:se:oru:diva-13964 (URN)10.1002/jcc.21661 (DOI)000288400600007 ()20941734 (PubMedID)2-s2.0-79951968121 (Scopus ID)
Note

Leif A. Eriksson is also affiliated to School of Chemistry, National University of Ireland, Galway, Ireland

Available from: 2011-01-14 Created: 2011-01-14 Last updated: 2018-05-02Bibliographically approved
Jarikote, D. V., Li, W., Jiang, T., Eriksson, L. A. & Murphy, P. V. (2011). Towards echinomycin mimetics by grafting quinoxaline residues on glycophane scaffolds. Bioorganic & Medicinal Chemistry, 19(2), 826-835
Open this publication in new window or tab >>Towards echinomycin mimetics by grafting quinoxaline residues on glycophane scaffolds
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2011 (English)In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 19, no 2, p. 826-835Article in journal (Refereed) Published
Abstract [en]

Echinomycin is a natural depsipeptide, which is a bisintercalator, inserting quinoxaline units preferentially adjacent to CG base pairs of DNA. Herein the design and synthesis of echinomycin mimetics based on grafting of two quinoxaline residues onto a macrocyclic scaffold (glycophane) is addressed. Binding of the compounds to calf-thymus DNA was studied using UV-vis and steady state fluorescence spectroscopy, as well as thermal denaturation. An interesting observation was enhancement of fluorescence emission for the peptidomimetics on binding to DNA, which contrasted with observations for echinomycin. Molecular dynamics simulations were exploited to explore in more detail if bis-intercalation to DNA was possible for one of the glycophanes. Bis-intercalating echinomycin complexes with DNA were found to be stable during 20 ns simulations at 298 K. However, the MD simulations of a glycophane complexed with a DNA octamer displayed very different behaviour to echinomycin and its quinoxaline units were found to rapidly migrate out from the intercalation site. Release of bis-intercalation strain occurred with only one of the quinoxaline chromophores remaining intercalated throughout the simulation. The distance between the quinoxaline residues in the glycophane at the end of the MD simulation was 7.3-7.5 angstrom, whereas in echinomycin, the distance between the residues was similar to 11 angstrom, suggesting that longer glycophane scaffolds would be required to generate bis-intercalating echinomycin mimetics. (C) 2010 Elsevier Ltd. All rights reserved.

National Category
Theoretical Chemistry
Research subject
Chemistry
Identifiers
urn:nbn:se:oru:diva-18797 (URN)10.1016/j.bmc.2010.12.009 (DOI)000287590500013 ()
Available from: 2011-09-29 Created: 2011-09-29 Last updated: 2017-12-08Bibliographically approved
Wu, M. & Eriksson, L. A. (2010). Absorption spectra of riboflavin: A difficult case for computational chemistry. Journal of Physical Chemistry A, 114(37), 10234-10242
Open this publication in new window or tab >>Absorption spectra of riboflavin: A difficult case for computational chemistry
2010 (English)In: Journal of Physical Chemistry A, ISSN 1089-5639, E-ISSN 1520-5215, Vol. 114, no 37, p. 10234-10242Article in journal (Refereed) Published
Abstract [en]

Computing accurate absorption spectra of riboflavin (RBF) has proven a difficult task for computational chemistry. Time-dependent density functional theory have herein been employed using a wide range of recent range-separated and hybrid meta functionals to investigate ultraviolet and visible spectra of RBF to determine if any progress has been made through recent developments. It is concluded that B3LYP and PBE0 perform the best throughout the entire test set. However, since all methods deviate from experimental results by at least 40 nm when computing the spectra in vacuum, two approaches to describe aqueous solution are implemented together with the MPWB1K, B3LYP, and PBE0 functionals: implicitly using integral equation formulation of the polarized continuum model (minor improvement) and explicitly through molecular dynamics (MD) simulations of the molecule embedded in a water cluster whereafter snapshots of RBF-water clusters are extracted and time-dependent density functional theory calculations performed. The resulting averaged spectra from the MD-simulated clusters show a constant blue-shift for all peaks by similar to 20 nm compared to experimental data at the TD-B3LYP/6-31+G(d,p) level.

National Category
Chemical Sciences
Research subject
Chemistry
Identifiers
urn:nbn:se:oru:diva-12879 (URN)10.1021/jp104127r (DOI)000281753800034 ()
Available from: 2011-01-05 Created: 2011-01-03 Last updated: 2018-04-23Bibliographically approved
Tian, B., Eriksson, E. S. E. & Eriksson, L. A. (2010). Can range-separated and hybrid DFT functionals predict low-lying excitations?: a tookad case study. Journal of Chemical Theory and Computation, 6(7), 2086-2094
Open this publication in new window or tab >>Can range-separated and hybrid DFT functionals predict low-lying excitations?: a tookad case study
2010 (English)In: Journal of Chemical Theory and Computation, ISSN 1549-9618, E-ISSN 1549-9626, Vol. 6, no 7, p. 2086-2094Article in journal (Refereed) Published
Abstract [en]

The spectral properties of Tookad (Pd-bacteriopheophorbide, Pd-BPheid), an effective photosensitizer that targets mainly prostate tumors, and metal-free BPheid have been studied using time-dependent density functional theory (TD-DFT). The well-established B3LYP functional, which is known to overestimate excitation energies, was included in the study along with recently introduced range-separated and meta hybrid DFT functionals CAM-B3LYP, M06, M06-2X, MO6HF, omega B97XD, omega B97X, omega B97, LC-wPBE, and PBE0 (PBE1PBE). The main focus is the performance of the new functionals in predicting low-lying excitations (>600 nm), to explore their potential roles in drug development for photodynamic therapy. The data suggests that wB97XD overall performs best for the Q(y) transition band (the red-most absorption), followed by CAM-B3LYP. LC-wPBE, wB97, B3LYP, and PBE1PBE all generated the Qy band far from the experimental position. The error in absorption energy for the Q. band was found to be at most 0.05 eV for omega 1397XD, compared to 0.15-0.19 eV for B3LYP. The use of different basis sets used in excited-state calculations was shown to be of less importance as was the use of either B3LYP or M06 in geometry optimizations.

National Category
Chemical Sciences
Research subject
Chemistry
Identifiers
urn:nbn:se:oru:diva-12921 (URN)10.1021/ct100148h (DOI)000279751500017 ()
Available from: 2011-01-04 Created: 2011-01-03 Last updated: 2018-04-23Bibliographically approved
Elmabsout, A., Kumawat, A. K., Karlsson, M., Krivospitskaya, O., Sävenstrand, H., Hans, T., . . . Sirsjö, A. (2010). Cloning and functional studies of a splice variant of CYP26B1: a cellular storage protein for all-trans retinoic acid. In Vivo, 24(3), 345-346
Open this publication in new window or tab >>Cloning and functional studies of a splice variant of CYP26B1: a cellular storage protein for all-trans retinoic acid
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2010 (English)In: In Vivo, ISSN 0258-851X, E-ISSN 1791-7549, Vol. 24, no 3, p. 345-346Article in journal, Meeting abstract (Refereed) Published
Abstract [en]

Background

All-trans retinoic acid (atRA) plays an essential role in the regulation of gene expression, cell growth and differentiation and is also important for normal cardiovascular development but may in turn be involved in cardiovascular diseases, i.e. atherosclerosis and restenosis. The cellular atRA levels are under strict control involving several cytochromes P450 isoforms (CYPs). CYP26 may be the most important regulator of atRA catabolism in vascular cells. The present study describes the molecular cloning, characterization and function of atRA-induced expression of a spliced variant of the CYP26B1 gene.

Methodology/Principal Findings

The coding region of the spliced CYP26B1 lacking exon 2 was amplified from cDNA synthesized from atRA-treated human aortic smooth muscle cells and sequenced. Both the spliced variant and full length CYP26B1 was found to be expressed in cultured human endothelial and smooth muscle cells, and in normal and atherosclerotic vessel. atRA induced both variants of CYP26B1 in cultured vascular cells. Furthermore, the levels of spliced mRNA transcript were 4.5 times higher in the atherosclerotic lesion compared to normal arteries and the expression in the lesions was increased 20-fold upon atRA treatment. The spliced CYP26B1 still has the capability to degrade atRA, but at an initial rate one-third that of the corresponding full length enzyme. Transfection of COS-1 and THP-1 cells with the CYP26B1 spliced variant indicated either an increase or a decrease in the catabolism of atRA, probably depending on the expression of other atRA catabolizing enzymes in the cells.

Conclusions/Significance

Vascular cells express the spliced variant of CYP26B1 lacking exon 2 and it is also increased in atherosclerotic lesions. The spliced variant displays a slower and reduced degradation of atRA as compared to the full-length enzyme. Further studies are needed, however, to clarify the substrate specificity and role of the CYP26B1 splice variant in health and disease.

National Category
Medical and Health Sciences Chemical Sciences
Research subject
Biomedicine; Biochemistry
Identifiers
urn:nbn:se:oru:diva-14227 (URN)
Note

Abstracts of the 3rd Swedish-Hellenic life sciences research conference

Available from: 2012-08-06 Created: 2011-01-25 Last updated: 2018-04-23Bibliographically approved
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