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Albers, Michael Franz
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Publikasjoner (10 av 10) Visa alla publikasjoner
Moodie, L. W. K., Hubert, M., Zhou, X., Albers, M. F., Lundmark, R., Wanrooij, S. & Hedberg, C. (2019). Photoactivated Colibactin Probes Induce Cellular DNA Damage. Angewandte Chemie International Edition, 58(5), 1417-1421
Åpne denne publikasjonen i ny fane eller vindu >>Photoactivated Colibactin Probes Induce Cellular DNA Damage
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2019 (engelsk)Inngår i: Angewandte Chemie International Edition, ISSN 1433-7851, E-ISSN 1521-3773, Vol. 58, nr 5, s. 1417-1421Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Colibactin is a small molecule produced by certain bacterial species of the human microbiota that harbour the pks genomic island. Pks(+) bacteria induce a genotoxic phenotype in eukaryotic cells and have been linked with colorectal cancer progression. Colibactin is produced in a benign, prodrug form which, prior to export, is enzymatically matured by the producing bacteria to its active form. Although the complete structure of colibactin has not been determined, key structural features have been described including an electrophilic cyclopropane motif, which is believed to alkylate DNA. To investigate the influence of the putative "warhead" and the prodrug strategy on genotoxicity, a series of photolabile colibactin probes were prepared that upon irradiation induced a pks(+) like phenotype in HeLa cells. Furthermore, results from DNA cross-linking and imaging studies of clickable analogues enforce the hypothesis that colibactin effects its genotoxicity by directly targeting DNA.

Emneord
click chemistry, colibactin, DNA damage, microbiome, photochemistry
HSV kategori
Identifikatorer
urn:nbn:se:umu:diva-156892 (URN)10.1002/anie.201812326 (DOI)000458826100026 ()30506956 (PubMedID)
Tilgjengelig fra: 2019-03-11 Laget: 2019-03-11 Sist oppdatert: 2019-03-11bibliografisk kontrollert
Albers, M. F. (2016). Synthesis and investigation of bacterial effector molecules. (Doctoral dissertation). Umeå: Umeå University
Åpne denne publikasjonen i ny fane eller vindu >>Synthesis and investigation of bacterial effector molecules
2016 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
Abstract [en]

During infections, bacterial microorganisms initiate profound interactions with mammalian host cells. Usually defense mechanisms of the host destroy intruding bacteria in rapid manner. However, many bacterial pathogens have evolved in a way to avoid these mechanisms. By use of effector molecules, which can be small organic molecules or proteins with enzymatic activity, the host is manipulated on a molecular level. Effectors mediating post-translational modifications (PTMs) are employed by many pathogens to influence the biological activity of host proteins. In the presented thesis, two related PTMs are investigated in detail: Adenylylation, the covalent transfer of an adenosine monophosphate group from adenosine triphosphate onto proteins, and phosphocholination, the covalent transfer of a phosphocholine moiety onto proteins. Over the past years, enzymes mediating these modifications have been discovered in several pathogens, especially as a mechanism to influence the signaling of eukaryotic cells by adenylylating or phosphocholinating small GTPases. However, the development of reliable methods for the isolation and identification of adenylylated and phosphocholinated proteins remains a vehement challenge in this field of research. This thesis presents general procedures for the synthesis of peptides carrying adenylylated or phosphocholinated tyrosine, threonine and serine residues. From the resulting peptides, mono-selective polyclonal antibodies against adenylylated tyrosine and threonine have been raised. The antibodies were used as tools for proteomic research to isolate unknown substrates of adenylyl transferases from eukaryotic cells. Mass spectrometric fragmentation techniques have been investigated to ease the identification of adenylylated proteins. Furthermore, this work presents a new strategy to identify adenylylated proteins. Additionally, small effector molecules are involved in the regulation of infection mechanisms. In this work, the small molecule LAI-1 (Legionella autoinducer 1) from the pathogen Legionella pneumophila, the causative agent of the Legionnaire’s disease, was synthesised together with its amino-derivatives. LAI-1 showed are a clear pharmacological effect on the regulation of the life cycle of L. pneumophila, initiating transmissive traits like motility and virulence. Furthermore, LAI-1 was shown to have an effect on eukaryotic cells as well. Directed motility of the eukaryotic cells was significantly reduced and the cytoskeletal architecture was reorganised, probably by interfering with the small GTPase Cdc42.

sted, utgiver, år, opplag, sider
Umeå: Umeå University, 2016. s. 110
Emneord
bacterial effectors, organic synthesis, Legionella, PTM, peptide synthesis, nucleotide chemistry
HSV kategori
Forskningsprogram
bioorganisk kemi
Identifikatorer
urn:nbn:se:umu:diva-114698 (URN)978-91-7601-411-0 (ISBN)
Disputas
2016-02-19, KB3A9, KBC-huset, Umeå University, Umeå, 10:00 (engelsk)
Opponent
Veileder
Tilgjengelig fra: 2016-01-29 Laget: 2016-01-26 Sist oppdatert: 2018-06-07bibliografisk kontrollert
Schell, U., Simon, S., Sahr, T., Hager, D., Albers, M. F., Kessler, A., . . . Hilbi, H. (2016). The α-hydroxyketone LAI-1 regulates motility, Lqs-dependent phosphorylation signaling and gene expression of Legionella pneumophila. Molecular Microbiology, 99(4), 778-793
Åpne denne publikasjonen i ny fane eller vindu >>The α-hydroxyketone LAI-1 regulates motility, Lqs-dependent phosphorylation signaling and gene expression of Legionella pneumophila
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2016 (engelsk)Inngår i: Molecular Microbiology, ISSN 0950-382X, E-ISSN 1365-2958, Vol. 99, nr 4, s. 778-793Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

The causative agent of Legionnaires' disease, Legionella pneumophila, employs the autoinducer compound LAI-1 (3-hydroxypentadecane-4-one) for cell–cell communication. LAI-1 is produced and detected by the Lqs (Legionella quorum sensing) system, comprising the autoinducer synthase LqsA, the sensor kinases LqsS and LqsT, as well as the response regulator LqsR. Lqs-regulated processes include pathogen–host interactions, production of extracellular filaments and natural competence for DNA uptake. Here we show that synthetic LAI-1 promotes the motility of L. pneumophila by signalling through LqsS/LqsT and LqsR. Upon addition of LAI-1, autophosphorylation of LqsS/LqsT by [γ-32P]-ATP was inhibited in a dose-dependent manner. In contrast, the Vibrio cholerae autoinducer CAI-1 (3-hydroxytridecane-4-one) promoted the phosphorylation of LqsS (but not LqsT). LAI-1 did neither affect the stability of phospho-LqsS or phospho-LqsT, nor the dephosphorylation by LqsR. Transcriptome analysis of L. pneumophila treated with LAI-1 revealed that the compound positively regulates a number of genes, including the non-coding RNAs rsmY and rsmZ, and negatively regulates the RNA-binding global regulator crsA. Accordingly, LAI-1 controls the switch from the replicative to the transmissive growth phase of L. pneumophila. In summary, the findings indicate that LAI-1 regulates motility and the biphasic life style of L. pneumophila through LqsS- and LqsT-dependent phosphorylation signalling.

sted, utgiver, år, opplag, sider
Wiley-Blackwell, 2016
HSV kategori
Identifikatorer
urn:nbn:se:umu:diva-114331 (URN)10.1111/mmi.13265 (DOI)000370338900012 ()26538361 (PubMedID)
Merknad

Article first published online: 27 NOV 2015

Tilgjengelig fra: 2016-01-18 Laget: 2016-01-18 Sist oppdatert: 2018-06-07bibliografisk kontrollert
Heller, K., Ochtrop, P., Albers, M. F., Zauner, F. B., Itzen, A. & Hedberg, C. (2015). Covalent Protein Labeling by Enzymatic Phosphocholination. Angewandte Chemie International Edition, 54(35), 10327-10330
Åpne denne publikasjonen i ny fane eller vindu >>Covalent Protein Labeling by Enzymatic Phosphocholination
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2015 (engelsk)Inngår i: Angewandte Chemie International Edition, ISSN 1433-7851, E-ISSN 1521-3773, Vol. 54, nr 35, s. 10327-10330Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

We present a new protein labeling method based on the covalent enzymatic phosphocholination of a specific octapeptide amino acid sequence in intact proteins. The bacterial enzyme AnkX from Legionella pneumophila has been established to transfer functional phosphocholine moieties from synthetically produced CDP-choline derivatives to N-termini, C-termini, and internal loop regions in proteins of interest. Furthermore, the covalent modification can be hydrolytically removed by the action of the Legionella enzyme Lem3. Only a short peptide sequence (eight amino acids) is required for efficient protein labeling and a small linker group (PEG-phosphocholine) is introduced to attach the conjugated cargo.

Emneord
enzymes, nucleotides, phosphocholination, protein modifications
HSV kategori
Identifikatorer
urn:nbn:se:umu:diva-109454 (URN)10.1002/anie.201502618 (DOI)000360216800050 ()26147231 (PubMedID)
Forskningsfinansiär
German Research Foundation (DFG)Knut and Alice Wallenberg FoundationMax Planck Society
Tilgjengelig fra: 2015-10-08 Laget: 2015-09-28 Sist oppdatert: 2018-06-07bibliografisk kontrollert
Heller, K., Ochtrop, P., Albers, M., Hedberg, C. & Itzen, A. (2015). Enzymatic phosphocholination as a tool for protein labeling. Paper presented at 40th Congress of the Federation-of-European-Biochemical-Societies (FEBS) - The Biochemical Basis of Life, Berlin, July 4-9, 2015. The FEBS Journal, 282, 12-12
Åpne denne publikasjonen i ny fane eller vindu >>Enzymatic phosphocholination as a tool for protein labeling
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2015 (engelsk)Inngår i: The FEBS Journal, ISSN 1742-464X, E-ISSN 1742-4658, Vol. 282, s. 12-12Artikkel i tidsskrift, Meeting abstract (Annet vitenskapelig) Published
Abstract [en]

Posttranslational modification (PTM) of proteins is a versatile cellular process to regulate the activities of proteins. The high regioselectivity and catalysis rate of posttranslationally modifying enzymes utilizing high-energy precursors can potentially be exploited to equip proteins or peptide sequences with a label of choice site selectively and efficiently. We and others have recently described and analyzed a new reversible PTM called phosphocholination in which a phosphocholine group is transferred from a cytidine diphosphate choline (CDP-choline) to a serine residue of the small GTPase Rab1 [1–3]. The enzymes AnkX and Lem3 catalyze the modification and the corresponding demodification reactions, respectively. Interestingly, we could demonstrate that the modifying enzyme AnkX only requires a short amino acid sequence for substrate recognition. Therefore, we envision AnkX as a tool for the site directed labeling of target proteins. Here we report on the progress of developing a novel reversible protein labeling strategy based on the enzymes AnkX and Lem3 and on derivatives of CDP-choline. We demonstrate the optimization of AnkX and Lem3 enzyme activities and the identification of optimal and minimal peptide target sequences. Results indicate that indeed arbitrary proteins of interest can be functionalized with phosphocholine derivatives. In summary, this work yields first insights into the development of a CDP-choline based fully reversible protein labeling strategy.

HSV kategori
Identifikatorer
urn:nbn:se:umu:diva-111160 (URN)10.1111/febs.13320 (DOI)000362570600031 ()
Konferanse
40th Congress of the Federation-of-European-Biochemical-Societies (FEBS) - The Biochemical Basis of Life, Berlin, July 4-9, 2015
Merknad

Supplement: 1

Special Issue: SI

Meeting Abstract: P14-004-SH

Tilgjengelig fra: 2015-11-10 Laget: 2015-11-06 Sist oppdatert: 2018-06-07bibliografisk kontrollert
Simon, S., Schell, U., Heuer, N., Hager, D., Albers, M. F., Matthias, J., . . . Hilbi, H. (2015). Inter-kingdom Signaling by the Legionella Quorum Sensing Molecule LAI-1 Modulates Cell Migration through an IQGAP1-Cdc42-ARHGEF9-Dependent Pathway. PLoS Pathogens, 11(12), Article ID e1005307.
Åpne denne publikasjonen i ny fane eller vindu >>Inter-kingdom Signaling by the Legionella Quorum Sensing Molecule LAI-1 Modulates Cell Migration through an IQGAP1-Cdc42-ARHGEF9-Dependent Pathway
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2015 (engelsk)Inngår i: PLoS Pathogens, ISSN 1553-7366, E-ISSN 1553-7374, Vol. 11, nr 12, artikkel-id e1005307Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Small molecule signaling promotes the communication between bacteria as well as between bacteria and eukaryotes. The opportunistic pathogenic bacterium Legionella pneumophila employs LAI-1 (3-hydroxypentadecane-4-one) for bacterial cell-cell communication. LAI-1 is produced and detected by the Lqs (Legionella quorum sensing) system, which regulates a variety of processes including natural competence for DNA uptake and pathogen-host cell interactions. In this study, we analyze the role of LAI-1 in inter-kingdom signaling. L. pneumophila lacking the autoinducer synthase LqsA no longer impeded the migration of infected cells, and the defect was complemented by plasmid-borne lqsA. Synthetic LAI-1 dose-dependently inhibited cell migration, without affecting bacterial uptake or cytotoxicity. The forward migration index but not the velocity of LAI-1-treated cells was reduced, and the cell cytoskeleton appeared destabilized. LAI-1-dependent inhibition of cell migration involved the scaffold protein IQGAP1, the small GTPase Cdc42 as well as the Cdc42-specific guanine nucleotide exchange factor ARHGEF9, but not other modulators of Cdc42, or RhoA, Rac1 or Ran GTPase. Upon treatment with LAI-1, Cdc42 was inactivated and IQGAP1 redistributed to the cell cortex regardless of whether Cdc42 was present or not. Furthermore, LAI-1 reversed the inhibition of cell migration by L. pneumophila, suggesting that the compound and the bacteria antagonistically target host signaling pathway(s). Collectively, the results indicate that the L. pneumophila quorum sensing compound LAI-1 modulates migration of eukaryotic cells through a signaling pathway involving IQGAP1, Cdc42 and ARHGEF9.

Emneord
Legionella, Microbial Interactions
HSV kategori
Identifikatorer
urn:nbn:se:umu:diva-114332 (URN)10.1371/journal.ppat.1005307 (DOI)000368332800029 ()26633832 (PubMedID)
Tilgjengelig fra: 2016-01-18 Laget: 2016-01-18 Sist oppdatert: 2018-06-07bibliografisk kontrollert
Hansen, T., Albers, M., Hedberg, C. & Sickmann, A. (2013). Adenylylation, MS, and proteomics-Introducing a "new" modification to bottom-up proteomics. Proteomics, 13(6), 955-963
Åpne denne publikasjonen i ny fane eller vindu >>Adenylylation, MS, and proteomics-Introducing a "new" modification to bottom-up proteomics
2013 (engelsk)Inngår i: Proteomics, ISSN 1615-9853, E-ISSN 1615-9861, Vol. 13, nr 6, s. 955-963Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Although the addition of a 5'-adenosine phosphodiester group to proteins, called adenylylation, has been known for decades, the possibility that adenylylation could be a molecular switch in cellular signaling pathways has emerged recently. The distinct mass shift upon adenylation of threonine or tyrosine residues renders it a good target for MS detection and identification; however, the fragmentation of adenylylated peptides derived from proteolytic digestion of adenylylated proteins has not yet been systematically investigated. Here, we demonstrate that adenylylated peptides show loss of parts of the adenosine monophosphate (AMP) upon different fragmentation techniques. As expected, causing the least fragmentation of the AMP group, electron transfer dissociation yields less complicated spectra. In contrast, CID and higher energy collision (HCD) fragmentation caused AMP to fragment, generating characteristic ions that could be utilized in the specific identification of adenylylated peptides. The characteristic ions and losses upon CID and higher energy collision fragmentation from the AMP group turned out to be highly dependent on which amino acid was adenylylated, with different reporter ions for adenylylated threonine and tyrosine. We also investigated how adenylylation is best incorporated into search engines, exemplified by Mascot and showed that it is possible to identify adenylylation by search engines.

Emneord
Adenylylation, Adenylation, AMPylation, MS, Technology
HSV kategori
Identifikatorer
urn:nbn:se:umu:diva-114329 (URN)10.1002/pmic.201200344 (DOI)000316150500007 ()23335384 (PubMedID)
Tilgjengelig fra: 2016-01-18 Laget: 2016-01-18 Sist oppdatert: 2018-06-07bibliografisk kontrollert
Albers, M. F. & Hedberg, C. (2013). Amino acid building blocks for Fmoc solid-phase synthesis of peptides phosphocholinated at serine, threonine, and tyrosine. Journal of Organic Chemistry, 78(6), 2715-2719
Åpne denne publikasjonen i ny fane eller vindu >>Amino acid building blocks for Fmoc solid-phase synthesis of peptides phosphocholinated at serine, threonine, and tyrosine
2013 (engelsk)Inngår i: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 78, nr 6, s. 2715-2719Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Phosphocholination of eukaryotic host cell proteins has recently been identified as a novel post-translational modification important for bacterial pathogenesis. Here, we describe the first straightforward synthetic strategy for peptides containing phosphocholinated serine, threonine, or tyrosine residues using preformed functional amino acid building blocks, fully compatible with standard Fmoc solid-phase peptide synthesis.

Emneord
enzymes, nucleotides, phosphocholination, protein modifications
HSV kategori
Forskningsprogram
bioorganisk kemi
Identifikatorer
urn:nbn:se:umu:diva-114327 (URN)10.1021/jo302587g (DOI)000316375300057 ()23373758 (PubMedID)
Tilgjengelig fra: 2016-01-18 Laget: 2016-01-18 Sist oppdatert: 2018-06-07bibliografisk kontrollert
Albers, M. F., van Vliet, B. & Hedberg, C. (2011). Amino acid building blocks for efficient Fmoc solid-phase synthesis of peptides adenylylated at serine or threonine. Organic Letters, 13(22), 6014-6017
Åpne denne publikasjonen i ny fane eller vindu >>Amino acid building blocks for efficient Fmoc solid-phase synthesis of peptides adenylylated at serine or threonine
2011 (engelsk)Inngår i: Organic Letters, ISSN 1523-7060, E-ISSN 1523-7052, Vol. 13, nr 22, s. 6014-6017Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

The first straightforward building block based (non-interassembly) synthesis of peptides containing adenylylated serine and threonine residues is described. Key features include final global acidolytic protective group removal as well as full compatibility with standard Fmoc solid-phase peptide synthesis (SPPS). The described Thr-AMP SPPS-building block has been employed in the synthesis of the Thr-adenylylated sequence of human GTPase CDC42 (Ac-SEYVP-T(AMP)-VFDNYGC-NH(2)). Further, we demonstrate proof-of-concept for the synthesis of an Ser-adenylylated peptide (Ac-GSGA-S(AMP)-AGSGC-NH(2)) from the corresponding adenylylated serine building block.

HSV kategori
Forskningsprogram
bioorganisk kemi
Identifikatorer
urn:nbn:se:umu:diva-114328 (URN)10.1021/ol2024696 (DOI)000296756600021 ()22029258 (PubMedID)
Tilgjengelig fra: 2016-01-18 Laget: 2016-01-18 Sist oppdatert: 2018-06-07bibliografisk kontrollert
Smit, C., Blümer, J., Eerland, M. F., Albers, M. F., Müller, M. P., Goody, R. S., . . . Hedberg, C. (2011). Efficient synthesis and applications of peptides containing adenylylated tyrosine residues. Angewandte Chemie International Edition, 50(39), 9200-9204
Åpne denne publikasjonen i ny fane eller vindu >>Efficient synthesis and applications of peptides containing adenylylated tyrosine residues
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2011 (engelsk)Inngår i: Angewandte Chemie International Edition, ISSN 1433-7851, E-ISSN 1521-3773, Vol. 50, nr 39, s. 9200-9204Artikkel i tidsskrift (Fagfellevurdert) Published
Emneord
adenylylation, antibodies, peptides, post-translational modifications, Rab proteins
HSV kategori
Identifikatorer
urn:nbn:se:umu:diva-114333 (URN)10.1002/anie.201103203 (DOI)000296104300037 ()21919157 (PubMedID)
Tilgjengelig fra: 2016-01-18 Laget: 2016-01-18 Sist oppdatert: 2018-06-07bibliografisk kontrollert
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