Browse
Submit Data
Databases
API
Help

Dataset Information

25 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Edaxadiene: a new bioactive diterpene from Mycobacterium tuberculosis.

ABSTRACT: Mycobacterium tuberculosis remains a widespread and devastating human pathogen. Presented here is the characterization of an atypical class I diterpene cyclase from M. tuberculosis that catalyzes an unusual cyclization reaction in converting the known M. tuberculosis metabolite halimadienyl diphosphate to a further cyclized novel diterpene, which we have termed edaxadiene, as it directly inhibits maturation of the phagosomal compartment in which the bacterium is taken up during infection.

SUBMITTER: Mann FM

PROVIDER: S-EPMC2787244 | biostudies-literature | 2009 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Edaxadiene: a new bioactive diterpene from Mycobacterium tuberculosis.

Mann Francis M FM Xu Meimei M Chen Xiaoming X Fulton D Bruce DB Russell David G DG Peters Reuben J RJ

Journal of the American Chemical Society 20091201 48

Mycobacterium tuberculosis remains a widespread and devastating human pathogen. Presented here is the characterization of an atypical class I diterpene cyclase from M. tuberculosis that catalyzes an unusual cyclization reaction in converting the known M. tuberculosis metabolite halimadienyl diphosphate to a further cyclized novel diterpene, which we have termed edaxadiene, as it directly inhibits maturation of the phagosomal compartment in which the bacterium is taken up during infection. ...[more]

PMID: 19583202

Similar Datasets

Diterpene production in Mycobacterium tuberculosis.

Project description:Diterpenes are a structurally diverse class of molecules common in plants, although they are very rarely found in bacteria. We report the identification in Mycobacterium tuberculosis (Mtb) of three diterpenes proposed to promote phagolysosome maturation arrest. MS analysis reveals that these diterpenes are novel compounds not previously identified in other organisms. The diterpene with highest abundance in Mtb has a mass fragmentation pattern identical to edaxadiene, which is produced in vitro from geranylgeranyl diphosphate by the enzymes Rv3377c and Rv3378c. A second diterpene found in Mtb has a similar mass spectrum, and is always observed in the same proportion relative to edaxadiene, indicating that it is a side product of the Rv3378c reaction in vivo. We name this second diterpene olefin edaxadiene B. The least abundant of the three diterpenes in Mtb extracts is tuberculosinol, a dephosphorylated side-product of the edaxadiene pathway intermediate produced by Rv3377c. A frameshift in Rv3377c in Mtb completely eliminates diterpene production, whereas expression of Rv3377c and Rv3378c in the nonpathogenic M. smegmatis is sufficient to produce edaxadiene and edaxadiene B. These studies define the pathway of edaxadiene and edaxadiene B biosynthesis in vivo. Rv3377c and Rv3378c are unique to Mtb and M. bovis, making them candidates for selective therapeutics and diagnostics.

| S-EPMC3181137 | biostudies-literature

Characterization and inhibition of a class II diterpene cyclase from Mycobacterium tuberculosis: implications for tuberculosis.

Project description:Mycobacterium tuberculosis remains a widespread and devastating human pathogen, whose ability to infiltrate macrophage host cells from the human immune system is an active area of investigation. We have recently reported the discovery of a novel diterpene from M. tuberculosis, edaxadiene, whose ability to arrest phagosomal maturation in isolation presumably contributes to this critical process in M. tuberculosis infections. (Mann, F. M., Xu, M., Chen, X., Fulton, D. B., Russell, D. G., and Peters, R. J. (2009) J. Am. Chem. Soc., in press). Here, we present characterization of the class II diterpene cyclase that catalyzes the committed step in edaxadiene biosynthesis, i.e. the previously identified halimadienyl-diphosphate synthase (HPS; EC 5.5.1.16). Intriguingly, our kinetic analysis suggests a potential biochemical regulatory mechanism that triggers edaxadiene production upon phagosomal engulfment. Furthermore, we report characterization of potential HPS inhibitors: specifically, two related transition state analogs (15-aza-14,15-dihydrogeranylgeranyl diphosphate (7a) and 15-aza-14,15-dihydrogeranylgeranyl thiolodiphosphate (7b)) that exhibit very tight binding. Although arguably not suitable for clinical use, these nevertheless provide a basis for pharmaceutical design against this intriguing biosynthetic pathway. Finally, we provide evidence indicating that this pathway exists only in M. tuberculosis and is not functional in the closely related Mycobacterium bovis because of an inactivating frameshift in the HPS-encoding gene. Thus, we hypothesize that the inability to produce edaxadiene may be a contributing factor in the decreased infectivity and/or virulence of M. bovis relative to M. tuberculosis in humans.

| S-EPMC2749132 | biostudies-literature

Synthesis enables a structural revision of the Mycobacterium tuberculosis-produced diterpene, edaxadiene.

Project description:A stereodivergent synthesis of the [3.3.1] bicyclic core of edaxadiene was completed utilizing a key intramolecular oxidative ketone allylation. Significant discrepancies between the spectroscopic data obtained for the synthetic construct and the natural isolate raised questions about the structural assignment of edaxadiene. A subsequent structural reassignment was validated by completion of a total synthesis of the correct structure of the natural product.

| S-EPMC3221386 | biostudies-literature

A new bioactive diterpene glycoside from Molinaea retusa from the Madagascar dry forest.

Project description:In a continuing collaboration in a search for new antiproliferative compounds in Madagascar as part of an International Cooperative Biodiversity Group (ICBG), an ethanol extract of Molinaea retusa Radlk. (Sapindaceae) was investigated on the basis of its moderate antiproliferative activity against the A2780 human ovarian cancer cell line (IC50 16 microg/mL). One new compound, 2", 3", 4", 6'-de-O-acetylcupacinoside (1, IC50 15.4 microM) and two known compounds, cupacinoside (2, IC50 9.5 microM) and 6-de-O-acetylcupacinoside (3, IC50 10.9 microM), were isolated by bioassay-directed fractionation using liquid-liquid partitioning, column chromatography, and HPLC. Compounds 2 and 3 also had moderate antiplasmodial activities, with IC50 values of 4.0 and 6.4 microM, respectively, against Plasmodium falciparum, Dd2 strain. The structures were determined using spectroscopic methods.

| S-EPMC3904959 | biostudies-literature

Crystal Structure and Mechanistic Molecular Modeling Studies of <i>Mycobacterium tuberculosis</i> Diterpene Cyclase Rv3377c.

Project description:Terpenes make up the largest class of natural products, with extensive chemical and structural diversity. Diterpenes, mostly isolated from plants and rarely prokaryotes, exhibit a variety of important biological activities and valuable applications, including providing antitumor and antibiotic pharmaceuticals. These natural products are constructed by terpene synthases, a class of enzymes that catalyze one of the most complex chemical reactions in biology: converting simple acyclic oligo-isoprenyl diphosphate substrates to complex polycyclic products via carbocation intermediates. Here we obtained the second ever crystal structure of a class II diterpene synthase from bacteria, tuberculosinol pyrophosphate synthase (i.e., Halimadienyl diphosphate synthase, MtHPS, or Rv3377c) from Mycobacterium tuberculosis (Mtb). This enzyme transforms (E,E,E)-geranylgeranyl diphosphate into tuberculosinol pyrophosphate (Halimadienyl diphosphate). Rv3377c is part of the Mtb diterpene pathway along with Rv3378c, which converts tuberculosinol pyrophosphate to 1-tuberculosinyl adenosine (1-TbAd). This pathway was shown to exist only in virulent Mycobacterium species, but not in closely related avirulent species, and was proposed to be involved in phagolysosome maturation arrest. To gain further insight into the reaction pathway and the mechanistically relevant enzyme substrate binding orientation, electronic structure calculation and docking studies of reaction intermediates were carried out. Results reveal a plausible binding mode of the substrate that can provide the information to guide future drug design and anti-infective therapies of this biosynthetic pathway.

| S-EPMC8120997 | biostudies-literature

Rational Design of Selective and Bioactive Inhibitors of the Mycobacterium tuberculosis Proteasome.

Project description:The 20S core particle of the proteasome in Mycobacterium tuberculosis (Mtb) is a promising, yet unconventional, drug target. This multimeric peptidase is not essential, yet degrades proteins that have become damaged and toxic via reactions with nitric oxide (and/or the associated reactive nitrogen intermediates) produced during the host immune response. Proteasome inhibitors could render Mtb susceptible to the immune system, but they would only be therapeutically viable if they do not inhibit the essential 20S counterpart in humans. Selective inhibitors of the Mtb 20S were designed and synthesized on the bases of both its unique substrate preferences and the structures of substrate-mimicking covalent inhibitors of eukaryotic proteasomes called syringolins. Unlike the parent syringolins, the designed analogues weakly inhibit the human 20S (Hs 20S) proteasome and preferentially inhibit Mtb 20S over the human counterpart by as much as 74-fold. Moreover, they can penetrate the mycobacterial cell envelope and render Mtb susceptible to nitric oxide-mediated stress. Importantly, they do not inhibit the growth of human cell lines in vitro and thus may be starting points for tuberculosis drug development.

| S-EPMC5410965 | biostudies-literature

New Mycobacterium tuberculosis Complex Sublineage, Brazzaville, Congo.

Project description:Tuberculosis is a leading cause of illness and death in Congo. No data are available about the population structure and transmission dynamics of the Mycobacterium tuberculosis complex strains prevalent in this central Africa country. On the basis of single-nucleotide polymorphisms detected by whole-genome sequencing, we phylogenetically characterized 74 MTBC isolates from Brazzaville, the capital of Congo. The diversity of the study population was high; most strains belonged to the Euro-American lineage, which split into Latin American Mediterranean, Uganda I, Uganda II, Haarlem, X type, and a new dominant sublineage named Congo type (n = 26). Thirty strains were grouped in 5 clusters (each within 12 single-nucleotide polymorphisms), from which 23 belonged to the Congo type. High cluster rates and low genomic diversity indicate recent emergence and transmission of the Congo type, a new Euro-American sublineage of MTBC.

| S-EPMC5382753 | biostudies-literature

Designing novel inhibitors against Mycobacterium tuberculosis FadA5 (acetyl-CoA acetyltransferase) by virtual screening of known anti-tuberculosis (bioactive) compounds.

Project description:By-products of fatty acid degradation are extensively utilized by Mycobacterium tuberculosis (Mtb) for lipid synthesis and energy production during the infection phase. Cholesterol from host is scavenged by Mtb to fulfill its metabolic requirements, evade host immunity and invade macrophages. Blocking cholesterol catabolic pathways leads to bacteriostasis. FadA5 (Acetyl-CoA acetyltransferase), a thiolase encoded by fadA5 (Rv3546) gene in Mtb, plays a crucial role in cholesterol aliphatic chain degradation. Hence, FadA5 is a potential target for designing antitubercular inhibitors. In this study, 60,284 anti-tuberculosis (bioactive) compounds from ChEMBL database and analogous library from ZINC database of commercially available compounds have been screened against FadA5 active site to identify compounds having inhibitory potential against both the apo (state I) and the intermediate (state II) states of FadA5. Altogether, this study reports 7 potential inhibitors against two functional states of FadA5, which can be further taken for invitro studies.

| S-EPMC6137569 | biostudies-literature

A new evolutionary scenario for the Mycobacterium tuberculosis complex.

Project description:The distribution of 20 variable regions resulting from insertion-deletion events in the genomes of the tubercle bacilli has been evaluated in a total of 100 strains of Mycobacterium tuberculosis, Mycobacterium africanum, Mycobacterium canettii, Mycobacterium microti, and Mycobacterium bovis. This approach showed that the majority of these polymorphisms did not occur independently in the different strains of the M. tuberculosis complex but, rather, resulted from ancient, irreversible genetic events in common progenitor strains. Based on the presence or absence of an M. tuberculosis specific deletion (TbD1), M. tuberculosis strains can be divided into ancestral and "modern" strains, the latter comprising representatives of major epidemics like the Beijing, Haarlem, and African M. tuberculosis clusters. Furthermore, successive loss of DNA, reflected by region of difference 9 and other subsequent deletions, was identified for an evolutionary lineage represented by M. africanum, M. microti, and M. bovis that diverged from the progenitor of the present M. tuberculosis strains before TbD1 occurred. These findings contradict the often-presented hypothesis that M. tuberculosis, the etiological agent of human tuberculosis evolved from M. bovis, the agent of bovine disease. M. canettii and ancestral M. tuberculosis strains lack none of these deleted regions, and, therefore, seem to be direct descendants of tubercle bacilli that existed before the M. africanum-->M. bovis lineage separated from the M. tuberculosis lineage. This observation suggests that the common ancestor of the tubercle bacilli resembled M. tuberculosis or M. canettii and could well have been a human pathogen already.

| S-EPMC122584 | biostudies-literature

Mycobacterium decipiens sp. nov., a new species closely related to the Mycobacterium tuberculosis complex.

Project description:Two mycobacterial strains with close similarity to the Mycobacterium tuberculosis complex (MTBC) were isolated from cutaneous lesions of patients in the USA and Italy. At the phenotypic level, similarities to the MTBC included slow growth rate, rough morphotype of the unpigmented colonies and nearly identical high-performance liquid chromatography profiles of mycolic acids. In contrast to the MTBC, the strains were niacin- and nitrate-negative, and catalase-positive both at 68 °C and in semi-quantitative tests. The clinical isolates were more closely related to M. tuberculosis than to any other known mycobacterium and scored positive with commercial DNA probes (Hologic AccuProbe M. tuberculosis). Both average nucleotide identity and genome-to-genome distance suggested the strains are different from the MTBC. Therefore, given the distinguishing phenotypic and genomic-scale differences, we submit that the strains belong to a new species we have named Mycobacteriumdecipiens with type strain TBL 1200985T (=ATCC TSD-117T=DSM 105360T).

| S-EPMC6607433 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data