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Flentie, K., Harrison, G. A., Tükenmez, H., Livny, J., Good, J. A. D., Sarkar, S., . . . Stallings, C. L. (2019). Chemical disarming of isoniazid resistance in Mycobacterium tuberculosis. Proceedings of the National Academy of Sciences of the United States of America, 116(21), 10510-10517
Öppna denna publikation i ny flik eller fönster >>Chemical disarming of isoniazid resistance in Mycobacterium tuberculosis
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2019 (Engelska)Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 116, nr 21, s. 10510-10517Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Mycobacterium tuberculosis (Mtb) killed more people in 2017 than any other single infectious agent. This dangerous pathogen is able to withstand stresses imposed by the immune system and tolerate exposure to antibiotics, resulting in persistent infection. The global tuberculosis (TB) epidemic has been exacerbated by the emergence of mutant strains of Mtb that are resistant to frontline antibiotics. Thus, both phenotypic drug tolerance and genetic drug resistance are major obstacles to successful TB therapy. Using a chemical approach to identify compounds that block stress and drug tolerance, as opposed to traditional screens for compounds that kill Mtb, we identified a small molecule, C10, that blocks tolerance to oxidative stress, acid stress, and the frontline antibiotic isoniazid (INH). In addition, we found that C10 prevents the selection for INH-resistant mutants and restores INH sensitivity in otherwise INH-resistant Mtb strains harboring mutations in the katG gene, which encodes the enzyme that converts the prodrug INH to its active form. Through mechanistic studies, we discovered that C10 inhibits Mtb respiration, revealing a link between respiration homeostasis and INH sensitivity. Therefore, by using C10 to dissect Mtb persistence, we discovered that INH resistance is not absolute and can be reversed.

Ort, förlag, år, upplaga, sidor
The National Academy of Scionces of the United States of America, 2019
Nyckelord
Mycobacterium tuberculosis, drug tolerance, antibiotic resistance, isoniazid, respiration
Nationell ämneskategori
Infektionsmedicin
Identifikatorer
urn:nbn:se:umu:diva-159857 (URN)10.1073/pnas.1818009116 (DOI)000468403400054 ()31061116 (PubMedID)
Forskningsfinansiär
VetenskapsrådetKnut och Alice Wallenbergs StiftelseStiftelsen för strategisk forskning (SSF)KempestiftelsernaNIH (National Institute of Health)
Tillgänglig från: 2019-06-10 Skapad: 2019-06-10 Senast uppdaterad: 2019-06-10Bibliografiskt granskad
Tükenmez, H., Edström, I., Kalsum, S., Braian, C., Ummanni, R., Lindberg, S., . . . Larsson, C. (2019). Corticosteroids protect infected cells against mycobacterial killing in vitro. Biochemical and Biophysical Research Communications - BBRC, 511(1), 117-121
Öppna denna publikation i ny flik eller fönster >>Corticosteroids protect infected cells against mycobacterial killing in vitro
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2019 (Engelska)Ingår i: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 511, nr 1, s. 117-121Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

The effect of corticosteroids on human physiology is complex and their use in tuberculosis patients remains controversial. In a high-throughput screening approach designed to discover virulence inhibitors, several corticosteroids were found to prevent cytolysis of fibroblasts infected with mycobacteria. Further experiments with Mycobacterium tuberculosis showed anti-cytolytic activity in the 10 nM range, but no effect on bacterial growth or survival in the absence of host cells at 20 mu M. The results from a panel of corticosteroids with various affinities to the glucocorticoid- and mineralocorticoid receptors indicate that the inhibition of cytolysis most likely is mediated through the glucocorticoid receptor. Using live-imaging of M. tuberculosis-infected human monocyte-derived macrophages, we also show that corticosteroids to some extent control intracellular bacteria. In vitro systems with reduced complexity are to further study and understand the interactions between bacterial infection, immune defense and cell signaling. (C) 2019 The Authors. Published by Elsevier Inc.

Ort, förlag, år, upplaga, sidor
ACADEMIC PRESS INC ELSEVIER SCIENCE, 2019
Nyckelord
Mycobacterium, Tuberculosis, Corticosteroids, Cell death, Drug discovery
Nationell ämneskategori
Immunologi
Identifikatorer
urn:nbn:se:umu:diva-157508 (URN)10.1016/j.bbrc.2019.02.044 (DOI)000460849800019 ()30773257 (PubMedID)
Tillgänglig från: 2019-04-05 Skapad: 2019-04-05 Senast uppdaterad: 2019-04-05Bibliografiskt granskad
Tükenmez, H. (2016). Influence of wobble uridine modifications on eukaryotic translation. (Doctoral dissertation). Umeå: Umeå University
Öppna denna publikation i ny flik eller fönster >>Influence of wobble uridine modifications on eukaryotic translation
2016 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

Elongator is a conserved six subunit protein (Elp1p-Elp6p) complex that is required for the formation of ncm5 and mcm5 side chains at wobble uridines in transfer RNAs (tRNAs). Moreover, loss-of-function mutations in any gene encoding an Elongator subunit results in translational defects and a multitude of phenotypic effects. This thesis is based on investigations of effects of wobble uridine modifications on translation.

In Saccharomyces cerevisiae, ncm5U34-, mcm5U34- and mcm5s2U34- modified wobble nucleosides in tRNAs are important for proper codonanticodon interactions. My colleagues and I (hereafter we) showed that mcm5 and s2 groups at wobble uridine in tRNAs are vital for maintaining the reading frame during translation, as absence of these modifications increases the frequency of +1 frameshifting. We also showed that +1 frameshifting events at lysine AAA codons in Elongator mutants are due to slow entry of the hypomodified tRNA Lyss2UUU to the ribosomal A-site.

Ixr1p is a protein that plays a key role in increasing production of deoxynucleotides (dNTPs) in responses to DNA damage, via induction of Ribonucleotide reductase 1 (Rnr1p), in S. cerevisiae. We showed that expression of Ixr1p is reduced in elp3Δ mutants due to a post-transcriptional defect, which results in lower levels of Rnr1p in responses to DNA damage. Collectively, these results suggest that high sensitivity of Elongator mutants to DNA damaging agents might be partially due to reductions in Ixr1p expression and hence Rnr1p levels.

Elongator mutant phenotypes are linked to several cellular processes. To probe the mechanisms involved we investigated the metabolic perturbations associated with absence of a functional ELP3 gene in S. cerevisiae. We found that its absence results in widespread metabolic perturbations under both optimal (30°C) and semi-permissive (34°C) growth conditions. We also found that changes in levels of certain metabolites (but not others) were ameliorated by elevated levels of hypomodified tRNAs, suggesting that amelioration of perturbations of these metabolites might be sufficient for suppression of the Elongator mutant phenotypes.

A mutation in the IKBKAP (hELP1) gene results in lower levels of the full-length hELP1 protein, which causes a neurodegenerative disease in humans called familial dysautonomia (FD). We showed that the levels of mcm5s2U-modified wobble nucleoside in tRNAs are lower in both brain tissues and fibroblast cell lines derived from FD patients than in corresponding materials derived from healthy individuals. This suggests that FD may result from inefficient translation due to partial loss of mcm5s2U-modified nucleosides in tRNAs.

Ort, förlag, år, upplaga, sidor
Umeå: Umeå University, 2016. s. 53
Nationell ämneskategori
Genetik
Identifikatorer
urn:nbn:se:umu:diva-125663 (URN)978-91-7601-540-7 (ISBN)
Disputation
2016-10-13, N200, Naturvetarhuset, Umeå, 09:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2016-09-22 Skapad: 2016-09-14 Senast uppdaterad: 2018-06-07Bibliografiskt granskad
Tükenmez, H., Magnussen, H., Kovermann, M., Byström, A. & Wolf-Watz, M. (2016). Linkage between Fitness of Yeast Cells and Adenylate Kinase Catalysis. PLoS ONE, 11(9), Article ID e0163115.
Öppna denna publikation i ny flik eller fönster >>Linkage between Fitness of Yeast Cells and Adenylate Kinase Catalysis
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2016 (Engelska)Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, nr 9, artikel-id e0163115Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Enzymes have evolved with highly specific values of their catalytic parameters kcat and KM. This poses fundamental biological questions about the selection pressures responsible for evolutionary tuning of these parameters. Here we are address these questions for the enzyme adenylate kinase (Adk) in eukaryotic yeast cells. A plasmid shuffling system was developed to allow quantification of relative fitness (calculated from growth rates) of yeast in response to perturbations of Adk activity introduced through mutations. Biophysical characterization verified that all variants studied were properly folded and that the mutations did not cause any substantial differences to thermal stability. We found that cytosolic Adk is essential for yeast viability in our strain background and that viability could not be restored with a catalytically dead, although properly folded Adk variant. There exist a massive overcapacity of Adk catalytic activity and only 12% of the wild type kcat is required for optimal growth at the stress condition 20°C. In summary, the approach developed here has provided new insights into the evolutionary tuning of kcat for Adk in a eukaryotic organism. The developed methodology may also become useful for uncovering new aspects of active site dynamics and also in enzyme design since a large library of enzyme variants can be screened rapidly by identifying viable colonies.

Nationell ämneskategori
Biokemi och molekylärbiologi
Identifikatorer
urn:nbn:se:umu:diva-125853 (URN)10.1371/journal.pone.0163115 (DOI)000383891900032 ()27642758 (PubMedID)
Forskningsfinansiär
Vetenskapsrådet, 621-2013-5954Vetenskapsrådet, 621-2012-3576
Tillgänglig från: 2016-09-20 Skapad: 2016-09-20 Senast uppdaterad: 2018-06-07Bibliografiskt granskad
Karlsborn, T., Mahmud, A. K., Tükenmez, H. & Byström, A. S. (2016). Loss of ncm5 and mcm5 wobble uridine side chains results in an altered metabolic profile. Metabolomics, 12(12), Article ID 177.
Öppna denna publikation i ny flik eller fönster >>Loss of ncm5 and mcm5 wobble uridine side chains results in an altered metabolic profile
2016 (Engelska)Ingår i: Metabolomics, ISSN 1573-3882, E-ISSN 1573-3890, Vol. 12, nr 12, artikel-id 177Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Introduction: The Elongator complex, comprising six subunits (Elp1p-Elp6p), is required for formation of 5-carbamoylmethyl (ncm(5)) and 5-methoxycarbonylmethyl (mcm(5)) side chains on wobble uridines in 11 out of 42 tRNA species in Saccharomyces cerevisiae. Loss of these side chains reduces the efficiency of tRNA decoding during translation, resulting in pleiotropic phenotypes. Overexpression of hypomodified tRNA(s2UUU)(Lys); tRNA(s2UUG)(Gln) and tRNA(s2UUC)(Glu), which in wild-type strains are modified with mcm(5)s(2)U, partially suppress phenotypes of an elp3 Delta strain. Objectives: To identify metabolic alterations in an elp3 Delta strain and elucidate whether these metabolic alterations are suppressed by overexpression of hypomodified tRNA(s2UUU)(Lys); tRNA(s2UUG)(Gln) and tRNA(s2UUC)(Glu). Method: Metabolic profiles were obtained using untargeted GC-TOF-MS of a temperature-sensitive elp3 Delta strain carrying either an empty low-copy vector, an empty high-copy vector, a low-copy vector harboring the wild-type ELP3 gene, or a high-copy vector overexpressing tRNA(s2UUU)(Lys); tRNA(s2UUG)(Gln) and tRNA(s2UUC)(Glu). The temperature sensitive elp3 Delta strain derivatives were cultivated at permissive (30 degrees C) or semi-permissive (34 degrees C) growth conditions. Results: Culturing an elp3 Delta strain at 30 or 34 degrees C resulted in altered metabolism of 36 and 46 %, respectively, of all metabolites detected when compared to an elp3D strain carrying the wild-type ELP3 gene. Overexpression of hypomodified tRNA(s2UUU)(Lys); tRNA(s2UUG)(Gln) and tRNA(s2UUC)(Glu) suppressed a subset of the metabolic alterations observed in the elp3 Delta strain. Conclusion: Our results suggest that the presence of ncm(5)- and mcm(5)-side chains on wobble uridines in tRNA are important for metabolic homeostasis.

Ort, förlag, år, upplaga, sidor
Springer, 2016
Nyckelord
Elongator complex, tRNA wobble uridine modifications, Translation, ELP3, Metabolomics, Metabolic profiling
Nationell ämneskategori
Biokemi och molekylärbiologi Endokrinologi och diabetes
Forskningsämne
molekylärbiologi
Identifikatorer
urn:nbn:se:umu:diva-125635 (URN)10.1007/s11306-016-1120-8 (DOI)000389604300002 ()27738410 (PubMedID)
Tillgänglig från: 2016-09-13 Skapad: 2016-09-13 Senast uppdaterad: 2018-06-07Bibliografiskt granskad
Nord, S., Bhatt, M. J., Tükenmez, H., Farabaugh, P. J. & Wikström, P. M. (2015). Mutations of ribosomal protein S5 suppress a defect in late-30S ribosomal subunit biogenesis caused by lack of the RbfA biogenesis factor. RNA: A publication of the RNA Society, 21(8), 1454-1468
Öppna denna publikation i ny flik eller fönster >>Mutations of ribosomal protein S5 suppress a defect in late-30S ribosomal subunit biogenesis caused by lack of the RbfA biogenesis factor
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2015 (Engelska)Ingår i: RNA: A publication of the RNA Society, ISSN 1355-8382, E-ISSN 1469-9001, Vol. 21, nr 8, s. 1454-1468Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

The in vivo assembly of ribosomal subunits requires assistance by maturation proteins that are not part of mature ribosomes. One such protein, RbfA, associates with the 30S ribosomal subunits. Loss of RbfA causes cold sensitivity and defects of the 30S subunit biogenesis and its overexpression partially suppresses the dominant cold sensitivity caused by a C23U mutation in the central pseudoknot of 16S rRNA, a structure essential for ribosome function. We have isolated suppressor mutations that restore partially the growth of an RbfA-lacking strain. Most of the strongest suppressor mutations alter one out of three distinct positions in the carboxy-terminal domain of ribosomal protein S5 (S5) in direct contact with helix 1 and helix 2 of the central pseudoknot. Their effect is to increase the translational capacity of the RbfA-lacking strain as evidenced by an increase in polysomes in the suppressed strains. Overexpression of RimP, a protein factor that along with RbfA regulates formation of the ribosome's central pseudoknot, was lethal to the RbfA-lacking strain but not to a wild-type strain and this lethality was suppressed by the alterations in S5. The S5 mutants alter translational fidelity but these changes do not explain consistently their effect on the RbfA-lacking strain. Our genetic results support a role for the region of S5 modified in the suppressors in the formation of the central pseudoknot in 16S rRNA.

Ort, förlag, år, upplaga, sidor
Cold Spring Harbor Laboratory Press (CSHL), 2015
Nyckelord
ribosome assembly, 16S rRNA central pseudoknot, RbfA, RimP, translational accuracy
Nationell ämneskategori
Cell- och molekylärbiologi
Identifikatorer
urn:nbn:se:umu:diva-106776 (URN)10.1261/rna.051383.115 (DOI)000358016000007 ()26089326 (PubMedID)
Tillgänglig från: 2015-08-21 Skapad: 2015-08-07 Senast uppdaterad: 2018-06-07Bibliografiskt granskad
Tükenmez, H., Xu, H., Esberg, A. & Byström, A. S. (2015). The role of wobble uridine modifications in +1 translational frameshifting in eukaryotes. Nucleic Acids Research, 43(19), 9489-9499
Öppna denna publikation i ny flik eller fönster >>The role of wobble uridine modifications in +1 translational frameshifting in eukaryotes
2015 (Engelska)Ingår i: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 43, nr 19, s. 9489-9499Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

In Saccharomyces cerevisiae, 11 out of 42 tRNA species contain 5-methoxycarbonylmethyl-2-thiouridine (mcm5s2U), 5-methoxycarbonylmethyluridine (mcm5U), 5-carbamoylmethyluridine (ncm5U) or 5-carbamoylmethyl-2′-O-methyluridine (ncm5Um) nucleosides in the anticodon at the wobble position (U34). Earlier we showed that mutants unable to form the side chain at position 5 (ncm5 or mcm5) or lacking sulphur at position 2 (s2) of U34 result in pleiotropic phenotypes, which are all suppressed by overexpression of hypomodified tRNAs. This observation suggests that the observed phenotypes are due to inefficient reading of cognate codons or an increased frameshifting. The latter may be caused by a ternary complex (aminoacyl-tRNA*eEF1A*GTP) with a modification deficient tRNA inefficiently being accepted to the ribosomal A-site and thereby allowing an increased peptidyl-tRNA slippage and thus a frameshift error. In this study, we have investigated the role of wobble uridine modifications in reading frame maintenance, using either the Renilla/Firefly luciferase bicistronic reporter system or a modified Ty1 frameshifting site in a HIS4A::lacZ reporter system. We here show that the presence of mcm5 and s2 side groups at wobble uridines are important for reading frame maintenance and thus the aforementioned mutant phenotypes might partly be due to frameshift errors.

Nationell ämneskategori
Biokemi och molekylärbiologi
Identifikatorer
urn:nbn:se:umu:diva-109852 (URN)10.1093/nar/gkv832 (DOI)000366405600036 ()
Tillgänglig från: 2015-10-07 Skapad: 2015-10-07 Senast uppdaterad: 2018-06-07Bibliografiskt granskad
Karlsborn, T., Tukenmez, H., Mahmud, A. K., Xu, F., Xu, H. & Byström, A. S. (2014). Elongator, a conserved complex required for wobble uridine modifications in Eukaryotes. RNA Biology, 11(12), 1519-1528
Öppna denna publikation i ny flik eller fönster >>Elongator, a conserved complex required for wobble uridine modifications in Eukaryotes
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2014 (Engelska)Ingår i: RNA Biology, ISSN 1547-6286, E-ISSN 1555-8584, Vol. 11, nr 12, s. 1519-1528Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Elongator is a 6 subunit protein complex highly conserved in eukaryotes. The role of this complex has been controversial as the pleiotropic phenotypes of Elongator mutants have implicated the complex in several cellular processes. However, in yeast there is convincing evidence that the primary and probably only role of this complex is in formation of the 5-methoxycarbonylmethyl (mcm(5)) and 5-carbamoylmethyl (ncm(5)) side chains on uridines at wobble position in tRNA. In this review we summarize the cellular processes that have been linked to the Elongator complex and discuss its role in tRNA modification and regulation of translation. We also describe additional gene products essential for formation of ncm(5) and mcm(5) side chains at U-34 and their influence on Elongator activity.

Ort, förlag, år, upplaga, sidor
Taylor & Francis, 2014
Nyckelord
elongator complex, KTI genes, SIT4, SAP genes, tRNA wobble uridine modifications, translation, uveromyces lactis gamma-toxin
Nationell ämneskategori
Biokemi och molekylärbiologi
Identifikatorer
urn:nbn:se:umu:diva-101625 (URN)10.4161/15476286.2014.992276 (DOI)000350568300005 ()25607684 (PubMedID)
Tillgänglig från: 2015-04-09 Skapad: 2015-04-07 Senast uppdaterad: 2018-06-07Bibliografiskt granskad
Karlsborn, T., Tukenmez, H., Chen, C. & Byström, A. (2014). Familial dysautonomia (FD) patients have reduced levels of the modified wobble nucleoside mcm(5)s(2)U in tRNA. Biochemical and Biophysical Research Communications - BBRC, 454(3), 441-445
Öppna denna publikation i ny flik eller fönster >>Familial dysautonomia (FD) patients have reduced levels of the modified wobble nucleoside mcm(5)s(2)U in tRNA
2014 (Engelska)Ingår i: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 454, nr 3, s. 441-445Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Familial dysautonomia (FD) is a recessive neurodegenerative genetic disease. FD is caused by a mutation in the IKBKAP gene resulting in a splicing defect and reduced levels of full length IKAP protein. IKAP homologues can be found in all eukaryotes and are part of a conserved six subunit protein complex, Elongator complex. Inactivation of any Elongator subunit gene in multicellular organisms cause a wide range of phenotypes, suggesting that Elongator has a pivotal role in several cellular processes. In yeast, there is convincing evidence that the main role of Elongator complex is in formation of modified wobble uridine nucleosides in tRNA and that their absence will influence translational efficiency. To date, no study has explored the possibility that FD patients display defects in formation of modified wobble uridine nucleosides as a consequence of reduced IKAP levels. In this study, we show that brain tissue and fibroblast cell lines from FD patients have reduced levels of the wobble uridine nucleoside 5-methoxycarbonylmethyl-2-thiouridine (mcm(5)s(2)U). Our findings indicate that FD could be caused by inefficient translation due to lower levels of wobble uridine nucleosides. 

Nyckelord
Familial dysautonomia (FD), Elongator complex, IKBKAP, ELP1, tRNA modification, 5- thoxycarbonylmethyl-2-thiouridine (mcm(5)s(2)U)
Nationell ämneskategori
Medicin och hälsovetenskap
Identifikatorer
urn:nbn:se:umu:diva-98910 (URN)10.1016/j.bbrc.2014.10.116 (DOI)000346690600015 ()25450681 (PubMedID)
Tillgänglig från: 2015-01-28 Skapad: 2015-01-28 Senast uppdaterad: 2018-06-07Bibliografiskt granskad
Tükenmez, H., Karlsborn, T., Mahmud, A. K., Chen, C., Xu, F. & Byström, A. S.Elongator complex enhances Rnr1p levels in response to DNA damage by influencing Ixr1p expression.
Öppna denna publikation i ny flik eller fönster >>Elongator complex enhances Rnr1p levels in response to DNA damage by influencing Ixr1p expression
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(Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
Nationell ämneskategori
Genetik
Forskningsämne
molekylärbiologi
Identifikatorer
urn:nbn:se:umu:diva-124966 (URN)
Tillgänglig från: 2016-08-31 Skapad: 2016-08-31 Senast uppdaterad: 2018-06-07
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