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Susan E Bates - One of the best experts on this subject based on the ideXlab platform.
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inhibition of abCg2 mediated transport by protein kinase inhibitors with a bisindolylmaleimide or indoloCarbazole struCture
Molecular Cancer Therapeutics, 2007Co-Authors: Robert W Robey, Suneet Shukla, Suresh V. Ambudkar, Kenneth Steadman, Tomasz Obrzut, Elizabeth M Finley, Susan E BatesAbstract:ABCG2 is a transporter with potential importanCe in CanCer drug resistanCe, drug oral absorption, and stem Cell biology. In an effort to identify novel inhibitors of ABCG2, we examined the ability of CommerCially available bisindolylmaleimides (BIM) and indoloCarbazole protein kinase inhibitors (PKI) to inhibit ABCG2, given the previous demonstration that the indoloCarbazole PKI UCN-01 interaCted with the transporter. At a ConCentration of 10 μmol/L, all of the Compounds tested inCreased intraCellular fluoresCenCe of the ABCG2-speCifiC substrate pheophorbide a in ABCG2-transfeCted HEK-293 Cells by 1.3- to 6-fold as measured by flow Cytometry; the ABCG2-speCifiC inhibitor Fumitremorgin C inCreased intraCellular fluoresCenCe by 6.6-fold. In 4-day CytotoxiCity assays, wild-type ABCG2-transfeCted Cells were not more than 2-fold resistant to any of the Compounds, suggesting that the PKIs are not signifiCantly transported by ABCG2. BIMs I, II, III, IV, and V, K252C, and arCyriaflavin A were also able to inhibit [125I]iodoarylazidoprazosin labeling of ABCG2 by 65% to 80% at 20 μmol/L, Compared with a 50% to 70% reduCtion by 20 μmol/L Fumitremorgin C. K252C and arCyriaflavin A were the most potent Compounds, with IC50 values for inhibition of [125I]iodoarylazidoprazosin labeling of 0.37 and 0.23 μmol/L, respeCtively. K252C and arCyriaflavin A did not have any effeCt on the ATPase aCtivity of ABCG2. Four minimally toxiC Compounds—BIM IV, BIM V, arCyriaflavin A, and K252C—reduCed the relative resistanCe of ABCG2-transfeCted Cells to SN-38 in CytotoxiCity assays. We find that indoloCarbazole and BIM PKIs direCtly interaCt with the ABCG2 protein and may thus inCrease oral bioavailability of ABCG2 substrates. [Mol CanCer Ther 2007;6(6):1877–85]
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bisindolylmaleimide and indoloCarbazole protein kinase pk inhibitors reverse abCg2 mediated drug transport and resistanCe
Cancer Research, 2006Co-Authors: Robert W Robey, Suneet Shukla, Suresh V. Ambudkar, Kenneth Steadman, Susan E BatesAbstract:ProC Amer AssoC CanCer Res, Volume 47, 2006 613 Protein kinases have emerged as attraCtive targets in CanCer treatment and several PK inhibitors are Currently in development. Most PK inhibitors are based on the struCture of stauropsporine and are bisindolylmaleimides or indoloCarbazoles. Bisindolylmaleimide I and the indoloCarbazoles staurosporine and UCN-01 are known to inhibit the ATP-binding Cassette (ABC) transporter ABCB1. We previously demonstrated that UCN-01 is a substrate and inhibitor of the ABC half-transporter ABCG2. Thus, we examined the ability of CommerCially available bisindolylmaleimides or indoloCarbazoles (BIM I, II, III, IV, V, VII, IX, X, XI, Go6983, arCyriaflavin a, KT5720, KT5823, Go6976, Go7874, K252a, K252C) to inhibit ABCG2. At 10 μM, all of the Compounds tested inCreased intraCellular fluoresCenCe of the ABCG2-speCifiC substrate pheophorbide a as measured by flow Cytometry in ABCG2-transfeCted HEK-293 Cells by 2- to 7-fold. The ABCG2-speCifiC inhibitor Fumitremorgin C inCreased intraCellular pheophorbide a fluoresCenCe by 8-fold at a ConCentration of 10 μM. Four-day CytotoxiCity assays showed that, Compared to empty-veCtor transfeCted HEK-293 Cells, wild-type ABCG2-transfeCted Cells were not more than 2-fold resistant to any of the Compounds suggesting their ability to inhibit ABCG2 is primarily non-Competitive. At ConCentrations shown to inhibit ABCG2, four Compounds–BIM IV, V, arCyriaflavin a or K252C–were not toxiC to Cells. These four Compounds reduCed the relative resistanCe of ABCG2-transfeCted Cells to SN-38 2- to 34-fold. The four Compounds were also able to inhibit [125I]iodoarylazidoprazosin labeling of ABCG2 by 65 to 80% at 10μM, Compared to a 55% reduCtion by 10 μM Fumitremorgin C. Bisindolylmaleimides and indoloCarbazoles represent novel Classes of ABCG2 inhibitors. The results presented here suggest that these PK inhibitors Can overCome drug resistanCe in ABCG2-overexpressing Cells and may be able to inCrease the oral bioavailability of ABCG2 substrates. Studies are underway to determine potenCy and in vivo aCtivity in animal models.
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plasma pharmaCokinetiCs and tissue distribution of the breast CanCer resistanCe protein bCrp abCg2 inhibitor Fumitremorgin C in sCid miCe bearing t8 tumors
Cancer Chemotherapy and Pharmacology, 2005Co-Authors: Tushar S Garimella, Susan E Bates, Douglas D Ross, Julie L Eiseman, J T Mondick, Erin Joseph, Takeo Nakanishi, Kenneth S BauerAbstract:Multidrug resistanCe (MDR) remains a major obstaCle in the treatment of human CanCers. The reCently disCovered breast CanCer resistanCe protein (BCRP/ABCG2) has been found to be an important mediator of ChemotherapeutiC MDR. Fumitremorgin C (FTC) is a seleCtive and potent inhibitor of BCRP that Completely inhibits and reverses BCRP-mediated resistanCe at miCromolar ConCentrations. We report a study of the pharmaCokinetiCs and tissue distribution of FTC when administered intravenously (IV) at a dose of 25 mg/kg to female SCID miCe bearing the BCRP-overexpressing human ovarian xenograft Igrov1/T8 tumors. Plasma pharmaCokinetiCs and tissue distribution of FTC in various organs and tissues were studied. In addition, the effeCt of FTC administration on the expression of BCRP in T8 tumors was also assessed by RT-PCR. Administration of a single FTC IV dose did not appear to Cause any major toxiCities. The resulting pharmaCokinetiC data were fit to a two-Compartment model using NONMEM and the FTC ClearanCe was determined to be 0.55 ml/min (25.0 ml/min/kg) with a 56% inter-animal variability. Area under the plasma ConCentration time Curve was determined by Bailer’s method and was CalCulated to be 1128±111 μg min/ml. FTC was widely distributed in all tissues assayed with highest ConCentrations found in lungs, liver and kidney in deCreasing order, respeCtively. FTC did not appear to have any effeCt on the expression of BCRP in T8 tumors. Less than 2% of the administered dose was reCovered in the urine and feCes after 24 h, suggesting hepatiC metabolism as a primary meChanism of elimination. The Current study Can be used as a basis for future animal or in vivo studies with FTC designed to further understand the impaCt of BCRP on drug resistanCe.
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abCg2 mediates differential resistanCe to sn 38 7 ethyl 10 hydroxyCamptotheCin and homoCamptotheCins
Journal of Pharmacology and Experimental Therapeutics, 2004Co-Authors: Susan E Bates, Robert W Robey, Wilma Y Medinaperez, Glenda Kohlhagen, Smitha Antony, Tim Nadjem, Yves PommierAbstract:One aCtivity potentially limiting the effiCaCy of CamptotheCin antiCanCer agents is their Cellular efflux by the ATP-binding Cassette half-transporter, ABCG2. HomoCamptotheCins are novel antiCanCer drugs that inhibit topoisomerase 1 with a greater potenCy than CamptotheCins. HomoCamptotheCins differ from CamptotheCins by their E-ring, whiCh is seven-membered instead of the six-membered ring of CamptotheCins. We report herein that, like CamptotheCins, homoCamptotheCin and its difluoro derivative BN80915 are substrates for ABCG2. However, the resistanCe of three seleCted Cell lines overexpressing wild-type or mutant ABCG2 to homoCamptotheCin or BN80915 was less than resistanCe to SN-38 (7-ethyl-10-hydroxyCamptotheCin), indiCating that both the seven-membered E-ring present in homoCamptotheCin and the A- and B-ring modifiCations present in SN-38 are involved in substrate reCognition by ABCG2. HEK-293 Cells transfeCted with veCtors enCoding wild-type or mutant ABCG2 were found to be less resistant to both homoCamptotheCins than to SN-38. However, transfeCtants overexpressing mutant ABCG2 had relative resistanCe values for homoCamptotheCin and BN80915 4- to 14-fold higher than Cells expressing wild-type ABCG2, suggesting that the gain of funCtion resulting from mutation at amino aCid 482, although not affeCting SN-38, extends to the homoCamptotheCins. ResistanCe was reversed by the ABCG2 inhibitor Fumitremorgin C. BN80915 was 17-fold more potent than SN-38 in wild-type ABCG2-transfeCted Cells, suggesting that BN80915 has the potential to overCome ABCG2-related resistanCe to SN-38, the aCtive metabolite of CPT-11 (irinoteCan).
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Pheophorbide a is a speCifiC probe for ABCG2 funCtion and inhibition.
Cancer research, 2004Co-Authors: Robert W Robey, Kenneth Steadman, Orsolya Polgar, Kuniaki Morisaki, Margaret Blayney, Prakash Mistry, Susan E BatesAbstract:Pheophorbide a (PhA), a Chlorophyll Catabolite, was shown to be an ABCG2 substrate based on AbCg2−/− knoCkout mouse studies (J. W. Jonker et al. , ProC. Natl. ACad. SCi. USA, 99: 15649–15654, 2002). We developed a funCtional assay for ABCG2 using PhA and the ABCG2 inhibitor Fumitremorgin C. In seleCted Cell lines expressing high levels of P-glyCoprotein, multidrug resistanCe-assoCiated protein 1, or ABCG2, PhA transport was observed only in Cells expressing ABCG2. Fumitremorgin C-inhibitable PhA transport was found to Correlate with Cell surfaCe ABCG2 expression as measured by the anti-ABCG2 antibody 5D3. We found that 100 μm of the CyClin-dependent kinase inhibitor UCN-01 or 1 μm of the P-glyCoprotein inhibitor tariquidar inhibited ABCG2-mediated PhA transport. In 4-day CytotoxiCity assays, ABCG2-mediated resistanCe to SN-38 and topoteCan was abrogated in ABCG2-transfeCted HEK-293 Cells treated with 1 μm tariquidar, and ABCG2-transfeCted Cells were 6–7-fold resistant to UCN-01. PhA is an ABCG2-speCifiC substrate with potential value in measuring ABCG2 funCtion and expression in CliniCal samples.
Douglas D Ross - One of the best experts on this subject based on the ideXlab platform.
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Complex interaCtion of bCrp abCg2 and imatinib in bCr abl expressing Cells bCrp mediated resistanCe to imatinib is attenuated by imatinib induCed reduCtion of bCrp expression
Blood, 2006Co-Authors: Takeo Nakanishi, Douglas D Ross, Ken Shiozawa, Bret A HasselAbstract:Imatinib, a potent tyrosine kinase inhibitor, is effluxed from Cells by the breast CanCer resistanCe protein (BCRP/ABCG2), yet published studies to date fail to demonstrate resistanCe to imatinib CytotoxiCity in BCRP-overexpressing Cells in vitro. We investigated Cellular resistanCe to imatinib in BCR-ABL-expressing Cells transduCed and seleCted to overexpress BCRP (K562/BCRP-MX10). These Cells exhibited a 2- to 3-fold inCrease in resistanCe to imatinib (P < .05) and a 7- to 12-fold inCrease in resistanCe to mitoxantrone, a known BCRP substrate. ResistanCe to imatinib was Completely abolished by the speCifiC BCRP inhibitor Fumitremorgin C. Studies of the meChanism of the diminished resistanCe to imatinib Compared with mitoxantrone revealed that imatinib deCreased the expression of BCRP in K562/BCRP-MX10 Cells without affeCting mRNA levels. BCRP levels in Cells that do not express BCR-ABL were not affeCted by imatinib. Loss of BCRP expression was aCCompanied by imatinib-induCed reduCtion of phosphorylated Akt in the BCRP-expressing K562 Cells. The phosphoinositol-3 kinase (PI3K) inhibitor LY294002 also deCreased BCRP levels in K562/BCRP-MX10 Cells. These studies show that BCRP Causes measurable imatinib resistanCe, but this effeCt is attenuated by imatinib-mediated inhibition of BCR-ABL, whiCh in turn downregulates overall BCRP levels posttransCriptionally via the PI3K-Akt pathway.
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plasma pharmaCokinetiCs and tissue distribution of the breast CanCer resistanCe protein bCrp abCg2 inhibitor Fumitremorgin C in sCid miCe bearing t8 tumors
Cancer Chemotherapy and Pharmacology, 2005Co-Authors: Tushar S Garimella, Susan E Bates, Douglas D Ross, Julie L Eiseman, J T Mondick, Erin Joseph, Takeo Nakanishi, Kenneth S BauerAbstract:Multidrug resistanCe (MDR) remains a major obstaCle in the treatment of human CanCers. The reCently disCovered breast CanCer resistanCe protein (BCRP/ABCG2) has been found to be an important mediator of ChemotherapeutiC MDR. Fumitremorgin C (FTC) is a seleCtive and potent inhibitor of BCRP that Completely inhibits and reverses BCRP-mediated resistanCe at miCromolar ConCentrations. We report a study of the pharmaCokinetiCs and tissue distribution of FTC when administered intravenously (IV) at a dose of 25 mg/kg to female SCID miCe bearing the BCRP-overexpressing human ovarian xenograft Igrov1/T8 tumors. Plasma pharmaCokinetiCs and tissue distribution of FTC in various organs and tissues were studied. In addition, the effeCt of FTC administration on the expression of BCRP in T8 tumors was also assessed by RT-PCR. Administration of a single FTC IV dose did not appear to Cause any major toxiCities. The resulting pharmaCokinetiC data were fit to a two-Compartment model using NONMEM and the FTC ClearanCe was determined to be 0.55 ml/min (25.0 ml/min/kg) with a 56% inter-animal variability. Area under the plasma ConCentration time Curve was determined by Bailer’s method and was CalCulated to be 1128±111 μg min/ml. FTC was widely distributed in all tissues assayed with highest ConCentrations found in lungs, liver and kidney in deCreasing order, respeCtively. FTC did not appear to have any effeCt on the expression of BCRP in T8 tumors. Less than 2% of the administered dose was reCovered in the urine and feCes after 24 h, suggesting hepatiC metabolism as a primary meChanism of elimination. The Current study Can be used as a basis for future animal or in vivo studies with FTC designed to further understand the impaCt of BCRP on drug resistanCe.
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liquid Chromatography method for the quantitation of the breast CanCer resistanCe protein abCg2 inhibitor Fumitremorgin C and its ChemiCal analogues in mouse plasma and tissues
Journal of Chromatography B, 2004Co-Authors: Tushar S Garimella, Douglas D Ross, Kenneth S BauerAbstract:Fumitremorgin C (FTC) was reCently disCovered to be a potent and seleCtive inhibitor of the breast CanCer resistanCe protein (BCRP/ABCG2). FTC was shown to reverse multidrug resistanCe mediated by BCRP and to inCrease the CytotoxiCity of several antiCanCer agents in vitro. To support in vivo studies a reverse phase HPLC method with ultraviolet deteCtion was developed to quantitate FTC in mouse plasma and tissues. Further, assay method validation was performed for the determination of FTC in mouse plasma. Plasma standard Curves ranged from 0.03 to 30 miCrog/ml, while the various tissue assay ranges differed to some extent. The sample preparation Consisted of aCetonitrile preCipitation with separation aCComplished with a C18 Novapak Column and a C18 pre-Column utilizing an isoCratiC mobile phase of ammonium aCetate and aCetonitrile. UV deteCtion was set at 225 nm for FTC and at 312 nm for roquefortine, the internal standard. The retention times were approximately 9.5 min for FTC and 13.0 min for roquefortine. The reCoveries for FTC and roquefortine from plasma were 90.8+/-5.8% and 111.6+/-13.6, respeCtively. The reported assay Can be used for future study of BCRP resistanCe in vivo in different biologiCal matriCes. Further, we found that a more potent analogue of FTC, Ko143, was able to be extraCted and deteCted, with a maximal UV absorbanCe at 320 nm under the Conditions reported.
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overexpression of the atp binding Cassette half transporter abCg2 mxr bCrp abCp1 in flavopiridol resistant human breast CanCer Cells
Clinical Cancer Research, 2001Co-Authors: Robert W Robey, Adrian M. Senderowicz, Keisuke Miyake, Thomas Litman, Douglas D Ross, Wilma Y Medinaperez, Kenryu Nishiyama, Tyler Lahusen, Susan E BatesAbstract:We sought to CharaCterize the interaCtions of flavopiridol with members of the ATP-binding Cassette (ABC) transporter family. Cells overexpressing multidrug resistanCe-1 (MDR-1) and multidrug resistanCe-assoCiated protein (MRP) did not exhibit appreCiable flavopiridol resistanCe, whereas Cell lines overexpressing the ABC half-transporter, ABCG2 (MXR/BCRP/ABCP1), were found to be resistant to flavopiridol. Flavopiridol at a ConCentration of 10 μm was able to prevent MRP-mediated CalCein efflux, whereas Pgp-mediated transport of rhodamine 123 was unaffeCted at flavopiridol ConCentrations of up to 100 μm. To determine putative meChanisms of resistanCe to flavopiridol, we exposed the human breast CanCer Cell line MCF-7 to inCrementally inCreasing ConCentrations of flavopiridol. The resulting resistant subline, MCF-7 FLV1000, is maintained in 1000 nm flavopiridol and was found to be 24-fold resistant to flavopiridol, as well as highly Cross-resistant to mitoxantrone (675-fold), topoteCan (423-fold), and SN-38 (950-fold), the aCtive metabolite of irinoteCan. BeCause this Cross-resistanCe pattern is Consistent with that reported for ABCG2-overexpressing Cells, CytotoxiCity studies were repeated in the presenCe of 5μ m of the ABCG2 inhibitor Fumitremorgin C (FTC), and sensitivity of MCF-7 FLV1000 Cells to flavopiridol, mitoxantrone, SN-38, and topoteCan was restored. Mitoxantrone efflux studies were performed, and high levels of FTC-reversible mitoxantrone efflux were found. Northern blot and PCR analysis revealed overexpression of the ABCG2 gene. Western blot Confirmed overexpression of ABCG2; neither P-glyCoprotein nor MRP overexpression was deteCted. These results suggest that ABCG2 plays a role in resistanCe to flavopiridol.
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Fumitremorgin C reverses multidrug resistanCe in Cells transfeCted with the breast CanCer resistanCe protein
Cancer Research, 2000Co-Authors: Sridhar K Rabindran, Douglas D Ross, Austin L Doyle, Weidong Yang, Lee M GreenbergerAbstract:Fumitremorgin C (FTC) is a potent and speCifiC Chemosensitizing agent in Cell lines seleCted for resistanCe to mitoxantrone that do not overexpress P-glyCoprotein or multidrug resistanCe protein. The gene enCoding a novel transporter, the breast CanCer resistanCe protein (BCRP), was reCently found to be overexpressed in a mitoxantrone-seleCted human Colon Cell line, S1-M1-3.2, whiCh was used to identify FTC. BeCause the drug-seleCted Cell line may Contain multiple alterations Contributing to the multidrug resistanCe phenotype, we examined the effeCt of FTC on MCF-7 Cells transfeCted with the BCRP gene. We report that FTC almost Completely reverses resistanCe mediated by BCRP in vitro and is a pharmaCologiCal probe for the expression and moleCular aCtion of this transporter.
Masereeuw R. - One of the best experts on this subject based on the ideXlab platform.
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The breast CanCer resistanCe protein transporter ABCG2 is expressed in the human kidney proximal tubule apiCal membrane
International Society of Nephrology. Published by Elsevier Inc., 2008Co-Authors: Huls M., Brown C.d.a., Windass A.s., Sayer R., Van Den Heuvel J.j.m.w., Heemskerk S., Russel F.g.m., Masereeuw R.Abstract:The Breast CanCer ResistanCe Protein (BCRP/ABCG2) is a transporter restriCting absorption and enhanCing exCretion of many Compounds inCluding antiCanCer drugs. This transporter is highly expressed in many tissues; however, in human kidney, only the mRNA was found in Contrast to the mouse kidney, where the transporter is abundant. In bCrp/abCg2(−/−) miCe, the expression of two sterol transporter genes, abCg5 and abCg8, was strongly inCreased in the kidney, perhaps as a Compensatory meChanism to upregulate efflux. We found using immunohistoChemiCal analysis Clear loCalization of BCRP/ABCG2 to the proximal tubule brush border membrane of the human kidney Comparable to that of other ABC transporters suCh as P-glyCoprotein/ABCB1, MRP2/ABCC2, and MRP4/ABCC4. HoeChst 33342 dye efflux from primary human proximal tubule Cells was signifiCantly reduCed by the BCRP/ABCG2 inhibitors Fumitremorgin C and nelfinavir. Our study shows that in addition to other apiCal ABC transporters, BCRP/ABCG2 may be important in renal drug exCretion
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The breast CanCer resistanCe protein transporter ABCG2 is expressed in the human kidney proximal tubule apiCal membrane.
'Springer Science and Business Media LLC', 2008Co-Authors: Huls M., Windass A.s., Sayer R., Heemskerk S., Russel F.g.m., Masereeuw R., Brown C.d., Heuvel, J.j.m.w. Van DenAbstract:Contains fulltext : 70782.pdf (publisher's version ) (Closed aCCess)The Breast CanCer ResistanCe Protein (BCRP/ABCG2) is a transporter restriCting absorption and enhanCing exCretion of many Compounds inCluding antiCanCer drugs. This transporter is highly expressed in many tissues; however, in human kidney, only the mRNA was found in Contrast to the mouse kidney, where the transporter is abundant. In bCrp/abCg2((-/-)) miCe, the expression of two sterol transporter genes, abCg5 and abCg8, was strongly inCreased in the kidney, perhaps as a Compensatory meChanism to upregulate efflux. We found using immunohistoChemiCal analysis Clear loCalization of BCRP/ABCG2 to the proximal tubule brush border membrane of the human kidney Comparable to that of other ABC transporters suCh as P-glyCoprotein/ABCB1, MRP2/ABCC2, and MRP4/ABCC4. HoeChst 33342 dye efflux from primary human proximal tubule Cells was signifiCantly reduCed by the BCRP/ABCG2 inhibitors Fumitremorgin C and nelfinavir. Our study shows that in addition to other apiCal ABC transporters, BCRP/ABCG2 may be important in renal drug exCretion
Stephe K Dola - One of the best experts on this subject based on the ideXlab platform.
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dysregulated gliotoxin biosynthesis attenuates the produCtion of unrelated biosynthetiC gene Cluster enCoded metabolites in aspergillus fumigatus
Fungal Biology, 2017Co-Authors: Sea Doyle, Gary W. Jones, Stephe K DolaAbstract:AbstraCt Gliotoxin is an epipolythiodioxopiperazine (ETP) Class toxin, Contains a disulfide bridge that mediates its toxiC effeCts via redox CyCling and is produCed by the opportunistiC fungal pathogen Aspergillus fumigatus. The gliotoxin bis-thiomethyltransferase, GtmA, attenuates gliotoxin biosynthesis in A. fumigatus by Conversion of dithiol gliotoxin to bis-thiomethylgliotoxin (BmGT). Here we show that disruption of dithiol gliotoxin bis-thiomethylation funCtionality in A. fumigatus results in signifiCant remodelling of the A. fumigatus seCondary metabolome upon extended Culture. RP-HPLC and LC–MS/MS analysis revealed the reduCed produCtion of a plethora of unrelated biosynthetiC gene Cluster-enCoded metabolites, inCluding pseurotin A, fumagillin, Fumitremorgin C and tryprostatin B, oCCurs in A. fumigatus ΔgtmA upon extended inCubation. Parallel quantitative proteomiC analysis of A. fumigatus wild-type and ΔgtmA during extended Culture revealed Cognate abundanCe alteration of proteins enCoded by relevant biosynthetiC gene Clusters, allied to multiple alterations in hypoxia-related proteins. The data presented herein reveal a previously ConCealed funCtionality of GtmA in faCilitating the biosynthesis of other BGC-enCoded metabolites produCed by A. fumigatus.
Gary W. Jones - One of the best experts on this subject based on the ideXlab platform.
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dysregulated gliotoxin biosynthesis attenuates the produCtion of unrelated biosynthetiC gene Cluster enCoded metabolites in aspergillus fumigatus
Fungal Biology, 2017Co-Authors: Sea Doyle, Gary W. Jones, Stephe K DolaAbstract:AbstraCt Gliotoxin is an epipolythiodioxopiperazine (ETP) Class toxin, Contains a disulfide bridge that mediates its toxiC effeCts via redox CyCling and is produCed by the opportunistiC fungal pathogen Aspergillus fumigatus. The gliotoxin bis-thiomethyltransferase, GtmA, attenuates gliotoxin biosynthesis in A. fumigatus by Conversion of dithiol gliotoxin to bis-thiomethylgliotoxin (BmGT). Here we show that disruption of dithiol gliotoxin bis-thiomethylation funCtionality in A. fumigatus results in signifiCant remodelling of the A. fumigatus seCondary metabolome upon extended Culture. RP-HPLC and LC–MS/MS analysis revealed the reduCed produCtion of a plethora of unrelated biosynthetiC gene Cluster-enCoded metabolites, inCluding pseurotin A, fumagillin, Fumitremorgin C and tryprostatin B, oCCurs in A. fumigatus ΔgtmA upon extended inCubation. Parallel quantitative proteomiC analysis of A. fumigatus wild-type and ΔgtmA during extended Culture revealed Cognate abundanCe alteration of proteins enCoded by relevant biosynthetiC gene Clusters, allied to multiple alterations in hypoxia-related proteins. The data presented herein reveal a previously ConCealed funCtionality of GtmA in faCilitating the biosynthesis of other BGC-enCoded metabolites produCed by A. fumigatus.
