Jackson M

References (18)

Title : beta-Caryophyllene inhibits monoacylglycerol lipase activity and increases 2-arachidonoyl glycerol levels in vivo: a new mechanism of endocannabinoid-mediated analgesia? - Klawitter_2024_Mol.Pharmacol__
Author(s) : Klawitter J , Weissenborn W , Gvon I , Walz M , Jackson M , Sempio C , Joksimovic SL , Shokati T , Just I , Christians U , Todorovic SM
Ref : Molecular Pharmacology , : , 2024
Abstract : Introduction. The mechanisms of BCP-induced analgesia are not well studied. Here, we tested the efficacy of BCP in an acute post-surgical pain model and evaluated its effect on the endocannabinoid system. Methods. Efficacy of BCP was tested in an acute postsurgical pain model. Rats were treated with vehicle, 10, 25, 50, and 75 mg/kg BCP. Paw withdrawal responses (PWR) to mechanical stimuli were evaluated using von Frey filaments. Results. Endocannabinoids including 2-arachidonoylglycerol (2-AG) were also evaluated in plasma and tissues using an HPLC-MS-based approach. Monoacylglycerol lipase (MAGL) activity was evaluated in vitro as well as ex vivo. We observed a dose-dependent and time-dependent alleviation of hyperalgesia in incised paws up to 85% of the baseline value at 30 minutes after administration of BCP. We also observed dose-dependent increase in the 2-AG levels of about 3-fold after administration of BCP as compared to vehicle controls. Incubations of spinal cord tissue homogenates from BCP-treated rats with isotope-labeled 2-arachidonoylglycerol-d8 revealed a significantly reduced formation of the isotope-labeled MAGL product 2-AG-d8 as compared to vehicle controls indicating MAGL enzyme inhibition. In vitro MAGL enzyme activity assessment using 2-AG as the substrate revealed an IC of 15.8 microM for MAGL inhibition using BCP. Conclusion. These data showed that BCP inhibits MAGL activity in vitro and in vivo causing 2-AG levels to rise. Since the endocannabinoid 2-AG is a CB1 and CB2 receptor agonist, we propose the 2-AG-mediated cannabinoid receptor activation may contribute to BCP's mechanism of analgesia. Significance Statement In contrast to opioids or cannabinoids, BCP consumption is relatively safe and is approved the FDA as a flavoring agent, which can be used in cosmetic and food additives. BCP is a potent anti-inflammatory agent which showed excellent anti-hyperalgesic properties in this study of acute pain. Based on this BCP might be a valuable alternative to opioids. We show an additive mechanism (monoacylglycerol lipase inhibition) by which BCP might indirectly alter CB2 receptor activity and exhibit its pharmacological properties.
ESTHER : Klawitter_2024_Mol.Pharmacol__
PubMedSearch : Klawitter_2024_Mol.Pharmacol__
PubMedID: 38195158

Title : Mycobacterial Epoxide Hydrolase EphD Is Inhibited by Urea and Thiourea Derivatives - Madacki_2021_Int.J.Mol.Sci_22_
Author(s) : Madacki J , Kopal M , Jackson M , Kordulakova J
Ref : Int J Mol Sci , 22 : , 2021
Abstract : The genome of the human intracellular pathogen Mycobacterium tuberculosis encodes an unusually large number of epoxide hydrolases, which are thought to be involved in lipid metabolism and detoxification reactions needed to endure the hostile environment of host macrophages. These enzymes therefore represent suitable targets for compounds such as urea derivatives, which are known inhibitors of soluble epoxide hydrolases. In this work, we studied in vitro the effect of the thiourea drug isoxyl on six epoxide hydrolases of M. tuberculosis using a fatty acid substrate. We show that one of the proteins inhibited by isoxyl is EphD, an enzyme involved in the metabolism of mycolic acids, key components of the mycobacterial cell wall. By analyzing mycolic acid profiles, we demonstrate the inhibition of EphD epoxide hydrolase activity by isoxyl and two other urea-based inhibitors, thiacetazone and AU1235, inside the mycobacterial cell.
ESTHER : Madacki_2021_Int.J.Mol.Sci_22_
PubMedSearch : Madacki_2021_Int.J.Mol.Sci_22_
PubMedID: 33809178

Title : Stepwise pathogenic evolution of Mycobacterium abscessus - Bryant_2021_Science_372_
Author(s) : Bryant JM , Brown KP , Burbaud S , Everall I , Belardinelli JM , Rodriguez-Rincon D , Grogono DM , Peterson CM , Verma D , Evans IE , Ruis C , Weimann A , Arora D , Malhotra S , Bannerman B , Passemar C , Templeton K , MacGregor G , Jiwa K , Fisher AJ , Blundell TL , Ordway DJ , Jackson M , Parkhill J , Floto RA
Ref : Science , 372 : , 2021
Abstract : Although almost all mycobacterial species are saprophytic environmental organisms, a few, such as Mycobacterium tuberculosis, have evolved to cause transmissible human infection. By analyzing the recent emergence and spread of the environmental organism M. abscessus through the global cystic fibrosis population, we have defined key, generalizable steps involved in the pathogenic evolution of mycobacteria. We show that epigenetic modifiers, acquired through horizontal gene transfer, cause saltational increases in the pathogenic potential of specific environmental clones. Allopatric parallel evolution during chronic lung infection then promotes rapid increases in virulence through mutations in a discrete gene network; these mutations enhance growth within macrophages but impair fomite survival. As a consequence, we observe constrained pathogenic evolution while person-to-person transmission remains indirect, but postulate accelerated pathogenic adaptation once direct transmission is possible, as observed for M. tuberculosis Our findings indicate how key interventions, such as early treatment and cross-infection control, might restrict the spread of existing mycobacterial pathogens and prevent new, emergent ones.
ESTHER : Bryant_2021_Science_372_
PubMedSearch : Bryant_2021_Science_372_
PubMedID: 33926925

Title : Impact of the epoxide hydrolase EphD on the metabolism of mycolic acids in mycobacteria - Madacki_2018_J.Biol.Chem_293_5172
Author(s) : Madacki J , Laval F , Grzegorzewicz A , Lemassu A , Zahorszka M , Arand M , McNeil M , Daffe M , Jackson M , Laneelle MA , Kordulakova J
Ref : Journal of Biological Chemistry , 293 :5172 , 2018
Abstract : Mycolic acids are the hallmark of the cell envelope in mycobacteria, which include the important human pathogens Mycobacterium tuberculosis and Mycobacterium leprae Mycolic acids are very long C60-C90 alpha-alkyl beta-hydroxy fatty acids having a variety of functional groups on their hydrocarbon chain that define several mycolate types. Mycobacteria also produce an unusually large number of putative epoxide hydrolases, but the physiological functions of these enzymes are still unclear. Here, we report that the mycobacterial epoxide hydrolase EphD is involved in mycolic acid metabolism. We found that orthologs of EphD from M. tuberculosis and M. smegmatis are functional epoxide hydrolases, cleaving a lipophilic substrate, 9,10-cis-epoxystearic acid, in vitro and forming a vicinal diol. The results of EphD overproduction in M. smegmatis and M. bovis BCG Deltahma strains producing epoxymycolic acids indicated that EphD is involved in the metabolism of these forms of mycolates in both fast- and slow-growing mycobacteria. Moreover, using MALDI-TOF-MS and (1)H NMR spectroscopy of mycolic acids and lipids isolated from EphD-overproducing M. smegmatis, we identified new oxygenated mycolic acid species that accumulated during epoxymycolate depletion. Disruption of the ephD gene in M. tuberculosis specifically impaired the synthesis of ketomycolates and caused accumulation of their precursor, hydroxymycolate, indicating either direct or indirect involvement of EphD in ketomycolate biosynthesis. Our results clearly indicate that EphD plays a role in metabolism of oxygenated mycolic acids in mycobacteria.
ESTHER : Madacki_2018_J.Biol.Chem_293_5172
PubMedSearch : Madacki_2018_J.Biol.Chem_293_5172
PubMedID: 29472294

Title : Synthesis and evaluation of new 2-aminothiophenes against Mycobacterium tuberculosis - Thanna_2016_Org.Biomol.Chem_14_6119
Author(s) : Thanna S , Knudson SE , Grzegorzewicz A , Kapil S , Goins CM , Ronning DR , Jackson M , Slayden RA , Sucheck SJ
Ref : Org Biomol Chem , 14 :6119 , 2016
Abstract : Tuberculosis (TB) and its drug resistant forms kills more people than any other infectious disease. This fact emphasizes the need to identify new drugs to treat TB. 2-Aminothiophenes (2AT) have been reported to inhibit Pks13, a validated anti-TB drug target. We synthesized a library of 42 2AT compounds. Among these, compound 33 showed remarkable potency against Mycobacterium tuberculosis (Mtb) H37RV (MIC = 0.23 muM) and showed an impressive potency (MIC = 0.20-0.44 muM) against Mtb strains resistant to isoniazid, rifampicin and fluoroquinolones. The site of action for the compound 33 is presumed to be Pks13 or an earlier enzyme in the mycolic acid biosynthetic pathway. This inference is based on structural similarity of the compound 33 with known Pks13 inhibitors, which is corroborated by mycolic acid biosynthesis studies showing that the compound strongly inhibits the biosynthesis of all forms of mycolic acid in Mtb. In summary, these studies suggest 33 represents a promising anti-TB lead that exhibits activity well below toxicity to human monocytic cells.
ESTHER : Thanna_2016_Org.Biomol.Chem_14_6119
PubMedSearch : Thanna_2016_Org.Biomol.Chem_14_6119
PubMedID: 27251120
Gene_locus related to this paper: myctu-PKS13

Title : Draft Genome Sequence of Mycobacterium chelonae Type Strain ATCC 35752 - Hasan_2015_Genome.Announc_3_e00536
Author(s) : Hasan NA , Davidson RM , de Moura VC , Garcia BJ , Reynolds PR , Epperson LE , Farias-Hesson E , DeGroote MA , Jackson M , Strong M
Ref : Genome Announc , 3 : , 2015
Abstract : Mycobacterium chelonae is a rapidly growing opportunistic nontuberculous mycobacterial (NTM) species that causes infections in humans and other hosts. Here, we report the draft genome sequence of Mycobacterium chelonae type strain ATCC 35752, consisting of 4.89 Mbp, 63.96% G+C content, 4,489 protein-coding genes, 48 tRNAs, and 3 rRNA genes.
ESTHER : Hasan_2015_Genome.Announc_3_e00536
PubMedSearch : Hasan_2015_Genome.Announc_3_e00536
PubMedID: 26021923
Gene_locus related to this paper: mycch-a0a0e3tpp7 , mycch-a0a0e3trt3 , mycch-a0a0e3tu73 , mycch-a0a0e3xmm1 , mycch-a0a0e3xpj7 , mycch-a0a0e3xt09 , mycch-a0a0e3xt43

Title : High-level relatedness among Mycobacterium abscessus subsp. massiliense strains from widely separated outbreaks - Tettelin_2014_Emerg.Infect.Dis_20_364
Author(s) : Tettelin H , Davidson RM , Agrawal S , Aitken ML , Shallom S , Hasan NA , Strong M , de Moura VC , De Groote MA , Duarte RS , Hine E , Parankush S , Su Q , Daugherty SC , Fraser CM , Brown-Elliott BA , Wallace RJ, Jr. , Holland SM , Sampaio EP , Olivier KN , Jackson M , Zelazny AM
Ref : Emerg Infect Dis , 20 :364 , 2014
Abstract : Three recently sequenced strains isolated from patients during an outbreak of Mycobacterium abscessus subsp. massiliense infections at a cystic fibrosis center in the United States were compared with 6 strains from an outbreak at a cystic fibrosis center in the United Kingdom and worldwide strains. Strains from the 2 cystic fibrosis outbreaks showed high-level relatedness with each other and major-level relatedness with strains that caused soft tissue infections during an epidemic in Brazil. We identified unique single-nucleotide polymorphisms in cystic fibrosis and soft tissue outbreak strains, separate single-nucleotide polymorphisms only in cystic fibrosis outbreak strains, and unique genomic traits for each subset of isolates. Our findings highlight the necessity of identifying M. abscessus to the subspecies level and screening all cystic fibrosis isolates for relatedness to these outbreak strains. We propose 2 diagnostic strategies that use partial sequencing of rpoB and secA1 genes and a multilocus sequence typing protocol.
ESTHER : Tettelin_2014_Emerg.Infect.Dis_20_364
PubMedSearch : Tettelin_2014_Emerg.Infect.Dis_20_364
PubMedID: 24565502
Gene_locus related to this paper: mycab-b1mch4 , mycab-b1mdu3 , mycab-b1mes2 , mycab-b1mes3 , mycab-b1mfj3 , mycab-b1mgd3 , mycab-b1mkl9 , mycab-r4v1a9

Title : Mechanism of inhibition of Mycobacterium tuberculosis antigen 85 by ebselen - Favrot_2013_Nat.Commun_4_2748
Author(s) : Favrot L , Grzegorzewicz AE , Lajiness DH , Marvin RK , Boucau J , Isailovic D , Jackson M , Ronning DR
Ref : Nat Commun , 4 :2748 , 2013
Abstract : The increasing prevalence of drug-resistant tuberculosis highlights the need for identifying new antitubercular drugs that can treat these infections. The antigen 85 (Ag85) complex has emerged as an intriguing mycobacterial drug target due to its central role in synthesizing major components of the inner and outer leaflets of the mycobacterial outer membrane. Here we identify ebselen (EBS) as a potent inhibitor of the Mycobacterium tuberculosis Ag85 complex. Mass spectrometry data show that EBS binds covalently to a cysteine residue (C209) located near the Ag85C active site. The crystal structure of Ag85C in the presence of EBS shows that C209 modification restructures the active site, thereby disrupting the hydrogen-bonded network within the active site that is essential for enzymatic activity. C209 mutations display marked decreases in enzymatic activity. These data suggest that compounds using this mechanism of action will strongly inhibit the Ag85 complex and minimize the selection of drug resistance.
ESTHER : Favrot_2013_Nat.Commun_4_2748
PubMedSearch : Favrot_2013_Nat.Commun_4_2748
PubMedID: 24193546
Gene_locus related to this paper: myctu-a85c

Title : Design, synthesis and anti-tuberculosis activity of 1-adamantyl-3-heteroaryl ureas with improved in vitro pharmacokinetic properties - North_2013_Bioorg.Med.Chem_21_2587
Author(s) : North EJ , Scherman MS , Bruhn DF , Scarborough JS , Maddox MM , Jones V , Grzegorzewicz A , Yang L , Hess T , Morisseau C , Jackson M , McNeil MR , Lee RE
Ref : Bioorganic & Medicinal Chemistry , 21 :2587 , 2013
Abstract : Out of the prominent global ailments, tuberculosis (TB) is still one of the leading causes of death worldwide due to infectious disease. Development of new drugs that shorten the current tuberculosis treatment time and have activity against drug resistant strains is of utmost importance. Towards these goals we have focused our efforts on developing novel anti-TB compounds with the general structure of 1-adamantyl-3-phenyl urea. This series is active against Mycobacteria and previous lead compounds were found to inhibit the membrane transporter MmpL3, the protein responsible for mycolic acid transport across the plasma membrane. However, these compounds suffered from poor in vitro pharmacokinetic (PK) profiles and they have a similar structure/SAR to inhibitors of human soluble epoxide hydrolase (sEH) enzymes. Therefore, in this study the further optimization of this compound class was driven by three factors: (1) to increase selectivity for anti-TB activity over human sEH activity, (2) to optimize PK profiles including solubility and (3) to maintain target inhibition. A new series of 1-adamantyl-3-heteroaryl ureas was designed and synthesized replacing the phenyl substituent of the original series with pyridines, pyrimidines, triazines, oxazoles, isoxazoles, oxadiazoles and pyrazoles. This study produced lead isoxazole, oxadiazole and pyrazole substituted adamantyl ureas with improved in vitro PK profiles, increased selectivity and good anti-TB potencies with sub mug/mL minimum inhibitory concentrations.
ESTHER : North_2013_Bioorg.Med.Chem_21_2587
PubMedSearch : North_2013_Bioorg.Med.Chem_21_2587
PubMedID: 23498915

Title : Genome Sequence of an Epidemic Isolate of Mycobacterium abscessus subsp. bolletii from Rio de Janeiro, Brazil - Davidson_2013_Genome.Announc_1_e00617
Author(s) : Davidson RM , Reynolds PR , Farias-Hesson E , Duarte RS , Jackson M , Strong M
Ref : Genome Announc , 1 : , 2013
Abstract : Multiple isolates of Mycobacterium abscessus subsp. bolletii, collectively called BRA100, were associated with outbreaks of postsurgical skin infections across various regions of Brazil from 2003 to 2009. We announce the draft genome sequence of a newly sequenced BRA100 strain, M. abscessus subsp. bolletii CRM-0020, isolated from a patient in Rio de Janeiro, Brazil.
ESTHER : Davidson_2013_Genome.Announc_1_e00617
PubMedSearch : Davidson_2013_Genome.Announc_1_e00617
PubMedID: 23950125
Gene_locus related to this paper: mycab-b1mch4 , mycab-b1mdu3 , mycab-b1mes2 , mycab-b1mes3 , mycab-b1mfj3 , mycab-b1mgd3 , mycab-b1mkl9 , myca9-b1miq0 , mycab-r4v1a9

Title : Screening a library of 1600 adamantyl ureas for anti-Mycobacterium tuberculosis activity in vitro and for better physical chemical properties for bioavailability - Scherman_2012_Bioorg.Med.Chem_20_3255
Author(s) : Scherman MS , North EJ , Jones V , Hess TN , Grzegorzewicz AE , Kasagami T , Kim IH , Merzlikin O , Lenaerts AJ , Lee RE , Jackson M , Morisseau C , McNeil MR
Ref : Bioorganic & Medicinal Chemistry , 20 :3255 , 2012
Abstract : Adamantyl ureas were previously identified as a group of compounds active against Mycobacterium tuberculosis in culture with minimum inhibitor concentrations (MICs) below 0.1 mug/ml. These compounds have been shown to target MmpL3, a protein involved in secretion of trehalose mono-mycolate. They also inhibit both human soluble epoxide hydrolase (hsEH) and M. tuberculosis epoxide hydrolases. However, active compounds to date have high cLogP's and are poorly soluble, leading to low bioavailability and thus limiting any therapeutic application. In this study, a library of 1600 ureas (mostly adamantyl ureas), which were synthesized for the purpose of increasing the bioavailability of inhibitors of hsEH, was screened for activity against M. tuberculosis. 1-Adamantyl-3-phenyl ureas with a polar para substituent were found to retain moderate activity against M. tuberculosis and one of these compounds was shown to be present in serum after oral administration to mice. However, neither it, nor a closely related analog, reduced M. tuberculosis infection in mice. No correlation between in vitro potency against M. tuberculosis and the hsEH inhibition were found supporting the concept that activity against hsEH and M. tuberculosis can be separated. Also there was a lack of correlation with cLogP and inhibition of the growth of M. tuberculosis. Finally, members of two classes of adamantyl ureas that contained polar components to increase their bioavailability, but lacked efficacy against growing M. tuberculosis, were found to taken up by the bacterium as effectively as a highly active apolar urea suggesting that these modifications to increase bioavailability affected the interaction of the urea against its target rather than making them unable to enter the bacterium.
ESTHER : Scherman_2012_Bioorg.Med.Chem_20_3255
PubMedSearch : Scherman_2012_Bioorg.Med.Chem_20_3255
PubMedID: 22522007

Title : Inhibition of mycolic acid transport across the Mycobacterium tuberculosis plasma membrane - Grzegorzewicz_2012_Nat.Chem.Biol_8_334
Author(s) : Grzegorzewicz AE , Pham H , Gundi VA , Scherman MS , North EJ , Hess T , Jones V , Gruppo V , Born SE , Kordulakova J , Chavadi SS , Morisseau C , Lenaerts AJ , Lee RE , McNeil MR , Jackson M
Ref : Nat Chemical Biology , 8 :334 , 2012
Abstract : New chemotherapeutics active against multidrug-resistant Mycobacterium tuberculosis are urgently needed. We report on the identification of an adamantyl urea compound that shows potent bactericidal activity against M. tuberculosis and a unique mode of action, namely the abolition of the translocation of mycolic acids from the cytoplasm, where they are synthesized to the periplasmic side of the plasma membrane and are in turn transferred onto cell wall arabinogalactan or used in the formation of virulence-associated, outer membrane, trehalose-containing glycolipids. Whole-genome sequencing of spontaneous-resistant mutants of M. tuberculosis selected in vitro followed by genetic validation experiments revealed that our prototype inhibitor targets the inner membrane transporter MmpL3. Conditional gene expression of mmpL3 in mycobacteria and analysis of inhibitor-treated cells validate MmpL3 as essential for mycobacterial growth and support the involvement of this transporter in the translocation of trehalose monomycolate across the plasma membrane.
ESTHER : Grzegorzewicz_2012_Nat.Chem.Biol_8_334
PubMedSearch : Grzegorzewicz_2012_Nat.Chem.Biol_8_334
PubMedID: 22344175

Title : The structure-activity relationship of urea derivatives as anti-tuberculosis agents - Brown_2011_Bioorg.Med.Chem_19_5585
Author(s) : Brown JR , North EJ , Hurdle JG , Morisseau C , Scarborough JS , Sun D , Kordulakova J , Scherman MS , Jones V , Grzegorzewicz A , Crew RM , Jackson M , McNeil MR , Lee RE
Ref : Bioorganic & Medicinal Chemistry , 19 :5585 , 2011
Abstract : The treatment of tuberculosis is becoming more difficult due to the ever increasing prevalence of drug resistance. Thus, it is imperative that novel anti-tuberculosis agents, with unique mechanisms of action, be discovered and developed. The direct anti-tubercular testing of a small compound library led to discovery of adamantyl urea hit compound 1. In this study, the hit was followed up through the synthesis of an optimization library. This library was generated by systematically replacing each section of the molecule with a similar moiety until a clear structure-activity relationship was obtained with respect to anti-tubercular activity. The best compounds in this series contained a 1-adamantyl-3-phenyl urea core and had potent activity against Mycobacterium tuberculosis plus an acceptable therapeutic index. It was noted that the compounds identified and the pharmacophore developed is consistent with inhibitors of epoxide hydrolase family of enzymes. Consequently, the compounds were tested for inhibition of representative epoxide hydrolases: M. tuberculosis EphB and EphE; and human soluble epoxide hydrolase. Many of the optimized inhibitors showed both potent EphB and EphE inhibition suggesting the antitubercular activity is through inhibition of multiple epoxide hydrolase enzymes. The inhibitors also showed potent inhibition of humans soluble epoxide hydrolase, but limited cytotoxicity suggesting that future studies must be towards increasing the selectivity of epoxide hydrolase inhibition towards the M. tuberculosis enzymes.
ESTHER : Brown_2011_Bioorg.Med.Chem_19_5585
PubMedSearch : Brown_2011_Bioorg.Med.Chem_19_5585
PubMedID: 21840723

Title : Discovery of a new biomarker for the mucopolysaccharidoses (MPS), dipeptidyl peptidase IV (DPP-IV\; CD26), by SELDI-TOF mass spectrometry - Beesley_2009_Mol.Genet.Metab_96_218
Author(s) : Beesley CE , Young EP , Finnegan N , Jackson M , Mills K , Vellodi A , Cleary M , Winchester BG
Ref : Mol Genet Metab , 96 :218 , 2009
Abstract : Surface enhanced laser desorption/ionisation time of flight (SELDI-TOF) mass spectrometry has been used to search for new protein biomarkers in the plasma of patients with mucopolysacharidoses (MPS). Differences in the levels of some plasma proteins, particularly the apolipoprotein ApoCI, were observed between MPS patients and normal controls, using the different chromatographic surfaces (ProteinChips). ApoCI was identified by both its mass and by immunological techniques. In plasma, it exists in two forms, ApoCI and a truncated form which lacks two N-terminal amino acids, ApoCI'. In controls, the ratio of ApoCI':ApoCI observed using the cation-exchange surface (CM10) was approximately 1:2 whereas in most MPS patients it varied from 1:1 to 1:0.8. The ratio of ApoCI':ApoCI in plasma is determined by the activity of dipeptidyl peptidase IV, DPP-IV (also known as the leucocyte antigen CD26), which was found to be elevated up to 3-fold in MPS patients. The DPP-IV activity decreased in MPS I patients undergoing enzyme replacement therapy, indicating that it could be a useful biomarker for monitoring the efficacy of treatment in MPS disease. As DPP-IV has an important regulatory role in metabolism, it is possible that its elevation could cause some of the secondary pathology in MPS, and inhibition of DPP-IV might have a role in MPS therapy.
ESTHER : Beesley_2009_Mol.Genet.Metab_96_218
PubMedSearch : Beesley_2009_Mol.Genet.Metab_96_218
PubMedID: 19153055

Title : Genome sequencing and analysis of the biomass-degrading fungus Trichoderma reesei (syn. Hypocrea jecorina) - Martinez_2008_Nat.Biotechnol_26_553
Author(s) : Martinez D , Berka RM , Henrissat B , Saloheimo M , Arvas M , Baker SE , Chapman J , Chertkov O , Coutinho PM , Cullen D , Danchin EG , Grigoriev IV , Harris P , Jackson M , Kubicek CP , Han CS , Ho I , Larrondo LF , de Leon AL , Magnuson JK , Merino S , Misra M , Nelson B , Putnam N , Robbertse B , Salamov AA , Schmoll M , Terry A , Thayer N , Westerholm-Parvinen A , Schoch CL , Yao J , Barabote R , Nelson MA , Detter C , Bruce D , Kuske CR , Xie G , Richardson P , Rokhsar DS , Lucas SM , Rubin EM , Dunn-Coleman N , Ward M , Brettin TS
Ref : Nat Biotechnol , 26 :553 , 2008
Abstract : Trichoderma reesei is the main industrial source of cellulases and hemicellulases used to depolymerize biomass to simple sugars that are converted to chemical intermediates and biofuels, such as ethanol. We assembled 89 scaffolds (sets of ordered and oriented contigs) to generate 34 Mbp of nearly contiguous T. reesei genome sequence comprising 9,129 predicted gene models. Unexpectedly, considering the industrial utility and effectiveness of the carbohydrate-active enzymes of T. reesei, its genome encodes fewer cellulases and hemicellulases than any other sequenced fungus able to hydrolyze plant cell wall polysaccharides. Many T. reesei genes encoding carbohydrate-active enzymes are distributed nonrandomly in clusters that lie between regions of synteny with other Sordariomycetes. Numerous genes encoding biosynthetic pathways for secondary metabolites may promote survival of T. reesei in its competitive soil habitat, but genome analysis provided little mechanistic insight into its extraordinary capacity for protein secretion. Our analysis, coupled with the genome sequence data, provides a roadmap for constructing enhanced T. reesei strains for industrial applications such as biofuel production.
ESTHER : Martinez_2008_Nat.Biotechnol_26_553
PubMedSearch : Martinez_2008_Nat.Biotechnol_26_553
PubMedID: 18454138
Gene_locus related to this paper: hypjq-g0rh85 , hypjq-cip2 , hypjq-g0r9d1 , hypjq-g0r810 , hypjq-g0rbm4 , hypjq-g0rez4 , hypjq-g0rfr3 , hypjq-g0rg60 , hypjq-g0rij9 , hypjq-g0riu1 , hypjq-g0rl87 , hypjq-g0rlh4 , hypjq-g0rme5 , hypjq-g0rwy5 , hypje-axylest , hypje-q7z9m3 , hypjq-g0r6x2 , hypje-a0a024s1b8 , hypjr-a0a024s1s9 , hypjq-g0rxi5

Title : Adult neuronal ceroid lipofuscinosis caused by deficiency in palmitoyl protein thioesterase 1 -
Author(s) : Ramadan H , Al-Din AS , Ismail A , Balen F , Varma A , Twomey A , Watts R , Jackson M , Anderson G , Green E , Mole SE
Ref : Neurology , 68 :387 , 2007
PubMedID: 17261688
Gene_locus related to this paper: human-PPT1

Title : LppX is a lipoprotein required for the translocation of phthiocerol dimycocerosates to the surface of Mycobacterium tuberculosis - Sulzenbacher_2006_EMBO.J_25_1436
Author(s) : Sulzenbacher G , Canaan S , Bordat Y , Neyrolles O , Stadthagen G , Roig-Zamboni V , Rauzier J , Maurin D , Laval F , Daffe M , Cambillau C , Gicquel B , Bourne Y , Jackson M
Ref : EMBO Journal , 25 :1436 , 2006
Abstract : Cell envelope lipids play an important role in the pathogenicity of mycobacteria, but the mechanisms by which they are transported to the outer membrane of these prokaryotes are largely unknown. Here, we provide evidence that LppX is a lipoprotein required for the translocation of complex lipids, the phthiocerol dimycocerosates (DIM), to the outer membrane of Mycobacterium tuberculosis. Abolition of DIM transport following disruption of the lppX gene is accompanied by an important attenuation of the virulence of the tubercle bacillus. The crystal structure of LppX unveils an U-shaped beta-half-barrel dominated by a large hydrophobic cavity suitable to accommodate a single DIM molecule. LppX shares a similar fold with the periplasmic molecular chaperone LolA and the outer membrane lipoprotein LolB, which are involved in the localization of lipoproteins to the outer membrane of Gram-negative bacteria. Based on the structure and although an indirect participation of LppX in DIM transport cannot yet be ruled out, we propose LppX to be the first characterized member of a family of structurally related lipoproteins that carry lipophilic molecules across the mycobacterial cell envelope.
ESTHER : Sulzenbacher_2006_EMBO.J_25_1436
PubMedSearch : Sulzenbacher_2006_EMBO.J_25_1436
PubMedID: 16541102

Title : Inactivation of the antigen 85C gene profoundly affects the mycolate content and alters the permeability of the Mycobacterium tuberculosis cell envelope - Jackson_1999_Mol.Microbiol_31_1573
Author(s) : Jackson M , Raynaud C , Laneelle MA , Guilhot C , Laurent-Winter C , Ensergueix D , Gicquel B , Daffe M
Ref : Molecular Microbiology , 31 :1573 , 1999
Abstract : The antigen 85 complex of Mycobacterium tuberculosis consists of three abundantly secreted proteins. The recent characterization of a mycoloyltransferase activity associated in vitro with each of these antigens suggested that they are potentially important for the building of the unusual cell envelope of mycobacteria. To define the physiological role of these proteins, the gene coding for antigen 85C was inactivated by transposon mutagenesis. The resulting mutant was shown to transfer 40% fewer mycolates to the cell wall with no change in the types of mycolates esterifying arabinogalactan or in the composition of non-covalently linked mycolates. As a consequence, the diffusion of the hydrophobic chenodeoxycholate and the hydrophilic glycerol, but not that of isoniazid, was found to be much faster through the cell envelope of the mutant than that of the parent strain. Taken together, these data demonstrate that: (i) antigen 85C is involved directly or indirectly in the transfer of mycolates onto the cell wall of the whole bacterium; (ii) the enzyme is not specific for a given type of mycolate; and (iii) the cell wall-linked mycolate layer may represent a barrier for the diffusion of small hydrophobic and hydrophilic molecules.
ESTHER : Jackson_1999_Mol.Microbiol_31_1573
PubMedSearch : Jackson_1999_Mol.Microbiol_31_1573
PubMedID: 10200974
Gene_locus related to this paper: myctu-a85c