Biotransformação fúngica da hesperetina e sua aplicação na produção de metabólitos ativos
Autor(a) principal: | |
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Data de Publicação: | 2019 |
Tipo de documento: | Tese |
Idioma: | por |
Título da fonte: | Repositório Institucional da UFG |
Texto Completo: | http://repositorio.bc.ufg.br/tede/handle/tede/10018 |
Resumo: | Hesperetin belongs to the flavanone class of flavonoids, its human metabolites (i.e. hesperetin-3’-sulfate, hesperetin-7-sulfate, hesperetin-3’-glucoronide and hesperetin -7-glucoronide), and its glycosylated derivative has potential pharmacological properties. The use of microorganisms, such as filamentous fungi, is an alternative in derivatives production and a useful tool in scale up process. Therefore, the goal of the work was to apply and evaluate different bioprocesses for the production of active metabolites of hesperetin by fungal biotransformation. Application of microbioreactors, use of different carbon sources, substrate concentration, fungal immobilization and monitored reactions by liquid chromatography coupled to high resolution mass spectrometry were some of evaluated bioprocesses. From 15 tested fungi, 12 strains were able to biotransform hesperetin. In silico metabolite prediction modeling with MetaPrint 2D software, indicated positions 7 e 3’ as energetically favored for glycosylation, glucuronidation and sulfation reactions. Mortierella isabellina NRRL 1757 and Beauveria bassiana ATCC 7159 produced only sulfate and glucuronide hesperitins, respectively. Cunninghamella echinulata ATCC 9244 strain produced the glycosylated metabolite. A morphological difference was observed in C. echinulata ATCC 9245 growth using different microbioreactors. Square microwell plates resulted in an amorphous growth whereas round bottom microwell plates favored pellets growth. The latest, with volume well of 2.2 ml led to a higher content of fungi and 48 hours was found to be the ideal time to substract addition. All four strands of Cunninghamella tested for biotransformation in a microscale were able to produce the glycosylated metabolite. Analyzes of the biotransformation kinetics by HPLC-HRMS showed that Cunninghamella echinulata ATCC 9244 produced four microplate derivatives: eriodictiol, sulfated hesperetin, glycosylated hesperetin and glucuronidated hesperetin. Such analyzes have also shown that high concentrations of hesperetin inhibit these derivatives formation. Stainless steel sponge proved to be efficient for Cunninghamella echinulata and Cunninghamella elegans strains immobilization. The immobilization process achieved biofilm in 48 hours. ESI-IT-MS and ESI-IT-MS/MS analysis indicated production of a glycosylated and a hydroxylated-sulfonated derivative. Thus, studies demonstrated that different bioprocesses can be applied to optimize scale up reactions and produce hesperetin derivatives using filamentous fungi |
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Oliveira, Valéria dehttp://lattes.cnpq.br/6300240031300604Oliveira, Valéria deSilva, Lorena MaioneSilva, Maria do Rosário RodriguesCunha, Carla Rosane Mendanha daTerezan, Ana Paulahttp://lattes.cnpq.br/4275744776508451Cordeiro, Kelly Carolina Frauzino Araújo2019-09-13T14:25:04Z2019-01-11CORDEIRO, Kelly Carolina Frauzino Araújo. Biotransformação fúngica da hesperetina e sua aplicação na produção de metabólitos ativos. 2018. 135 f. Tese (Doutorado em Inovação Farmacêutica em Rede) - Universidade Federal de Goiás, Goiânia, 2019.http://repositorio.bc.ufg.br/tede/handle/tede/10018Hesperetin belongs to the flavanone class of flavonoids, its human metabolites (i.e. hesperetin-3’-sulfate, hesperetin-7-sulfate, hesperetin-3’-glucoronide and hesperetin -7-glucoronide), and its glycosylated derivative has potential pharmacological properties. The use of microorganisms, such as filamentous fungi, is an alternative in derivatives production and a useful tool in scale up process. Therefore, the goal of the work was to apply and evaluate different bioprocesses for the production of active metabolites of hesperetin by fungal biotransformation. Application of microbioreactors, use of different carbon sources, substrate concentration, fungal immobilization and monitored reactions by liquid chromatography coupled to high resolution mass spectrometry were some of evaluated bioprocesses. From 15 tested fungi, 12 strains were able to biotransform hesperetin. In silico metabolite prediction modeling with MetaPrint 2D software, indicated positions 7 e 3’ as energetically favored for glycosylation, glucuronidation and sulfation reactions. Mortierella isabellina NRRL 1757 and Beauveria bassiana ATCC 7159 produced only sulfate and glucuronide hesperitins, respectively. Cunninghamella echinulata ATCC 9244 strain produced the glycosylated metabolite. A morphological difference was observed in C. echinulata ATCC 9245 growth using different microbioreactors. Square microwell plates resulted in an amorphous growth whereas round bottom microwell plates favored pellets growth. The latest, with volume well of 2.2 ml led to a higher content of fungi and 48 hours was found to be the ideal time to substract addition. All four strands of Cunninghamella tested for biotransformation in a microscale were able to produce the glycosylated metabolite. Analyzes of the biotransformation kinetics by HPLC-HRMS showed that Cunninghamella echinulata ATCC 9244 produced four microplate derivatives: eriodictiol, sulfated hesperetin, glycosylated hesperetin and glucuronidated hesperetin. Such analyzes have also shown that high concentrations of hesperetin inhibit these derivatives formation. Stainless steel sponge proved to be efficient for Cunninghamella echinulata and Cunninghamella elegans strains immobilization. The immobilization process achieved biofilm in 48 hours. ESI-IT-MS and ESI-IT-MS/MS analysis indicated production of a glycosylated and a hydroxylated-sulfonated derivative. Thus, studies demonstrated that different bioprocesses can be applied to optimize scale up reactions and produce hesperetin derivatives using filamentous fungiA hesperetina é um flavonoide da classe das flavanonas. Seus metabólitos humanos, hesperetina-3’-sulfato, hesperetina-3’-glicuronideo, hesperetina-7-sulfato e hesperetina-7-glicuronideo, e o derivado glicosilado apresentam potenciais propriedades farmacológicas. A utilização de microrganismos, como fungos filamentosos, é uma alternativa na produção destes derivados e uma ferramenta útil no processo de escalonamento das reações. Desta forma, o objetivo deste trabalho foi aplicar e avaliar diferentes bioprocessos para produção de metabólitos ativos da hesperetina por biotransformação fúngica. Aplicação de microbiorreatores, uso de diferentes fontes de carbono, concentração do substrato e imobilização fúngica foram alguns dos bioprocessos avaliados além do monitoramento da reação por cromatografia líquida acoplada a espectrometria de massas de alta resolução. Dentre os 15 fungos testados 12 cepas foram capazes de biotransformar a hesperetina. A previsão do metabolismo in silico utilizando o programa Metaprint 2D, indicou a possibilidade de reações de glicosilação, glicuronidação, sulfatação, com maior propabilidade nas posições 7 e 3’. A Mortierella isabellina NRRL 1757 e Beauveria bassiana ATCC 7159 foram capazes de produzir os metabólitos da hesperetina sulfatado e glicuronidado, respectivamente. A cepa Cunninghamella echinulata ATCC 9244 produziu o metabólito glicosilado da hesperetina. Houve diferença na morfologia da C. echinulata ATCC 9245 no crescimento em diferentes microbiorreatores. A microplaca de orifício quadrado provocou um crescimento amorfo enquanto que as microplacas de fundo redondo favoreceram o crescimento de pellets. A placa redonda com capacidade de 2,2 mL demonstrou uma maior produção de massa fúngica e o tempo de 48 horas foi considerado ideal para adição do substrato. As quatro cepas de Cunninghamella testadas para biotransformação em microescala foram capazes de produzir o derivado glicosilado. Análises da cinética da biotransformação por CLAE-EMAR demonstraram que Cunninghamella echinulata ATCC 9244 produziu quatro derivados em microplacas, sendo eles: eriodictiol, hesperetina sulfatada, hesperetina glicosilada e hesperetina glicuronidada. Tais análises também demonstraram que altas concentrações de hesperetina inibem a formação destes derivados. Esponjas de aço inoxidável foram eficientes para a imobilização de cepas de Cunninghamella echinulata e Cunninghamella elegans, estando o biofilme já formado em 48 horas. Análises de ESI-IT-MS e ESI-IT-MS/MS indicaram a produção de um derivado da hesperetina glicosilado e outro hidroxilado e sulfatado. Assim, os estudos demonstraram que diferentes bioprocessos podem ser aplicados para otimizar o escalonamento da reação e produzir derivados da hesperetina utilizando fungos filamentosos.Submitted by Onia Arantes Albuquerque (onia.ufg@gmail.com) on 2019-09-12T16:20:53Z No. of bitstreams: 2 Tese - Kelly Carolina Frauzino Araújo Cordeiro - 2019.pdf: 4089806 bytes, checksum: 4814e00a54351666192f0e554dcda853 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5)Rejected by Luciana Ferreira (lucgeral@gmail.com), reason: Olhe a citação, ENTRE PARÊNTESES FICA (Doutorado em ....) CORDEIRO, Kelly Carolina Frauzino Araújo. Biotransformação fúngica da hesperetina e sua aplicação na produção de metabólitos ativos. 2018. 135 f. Tese (Programa de Pós-graduação em Inovação Farmacêutica em Rede) - Universidade Federal de Goiás, Goiânia, 2019. on 2019-09-13T13:54:10Z (GMT)Submitted by Onia Arantes Albuquerque (onia.ufg@gmail.com) on 2019-09-13T14:11:05Z No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Tese - Kelly Carolina Frauzino Araújo Cordeiro - 2019.pdf: 4089806 bytes, checksum: 4814e00a54351666192f0e554dcda853 (MD5)Approved for entry into archive by Luciana Ferreira (lucgeral@gmail.com) on 2019-09-13T14:25:04Z (GMT) No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Tese - Kelly Carolina Frauzino Araújo Cordeiro - 2019.pdf: 4089806 bytes, checksum: 4814e00a54351666192f0e554dcda853 (MD5)Made available in DSpace on 2019-09-13T14:25:04Z (GMT). No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Tese - Kelly Carolina Frauzino Araújo Cordeiro - 2019.pdf: 4089806 bytes, checksum: 4814e00a54351666192f0e554dcda853 (MD5) Previous issue date: 2019-01-11Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPESapplication/pdfporUniversidade Federal de GoiásPrograma de Pós-graduação em Inovação Farmacêutica em Rede (FF)UFGBrasilFaculdade Farmácia - FF (RG)http://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessBiotransformaçãoHesperetinaMicrobiorreatorCunninghamellaBiotransformationHesperetinMicrobioreactorCunninghamellaCIENCIAS DA SAUDE::FARMACIABiotransformação fúngica da hesperetina e sua aplicação na produção de metabólitos ativosHesperetin fungal biotransformation and its application in the production of active metabolitesinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/doctoralThesis1510836041889931197600600600600601028116152420937569976364134497549962075167498588264571reponame:Repositório Institucional da UFGinstname:Universidade Federal de Goiás (UFG)instacron:UFGCC-LICENSElicense_urllicense_urltext/plain; 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dc.title.eng.fl_str_mv |
Biotransformação fúngica da hesperetina e sua aplicação na produção de metabólitos ativos |
dc.title.alternative.eng.fl_str_mv |
Hesperetin fungal biotransformation and its application in the production of active metabolites |
title |
Biotransformação fúngica da hesperetina e sua aplicação na produção de metabólitos ativos |
spellingShingle |
Biotransformação fúngica da hesperetina e sua aplicação na produção de metabólitos ativos Cordeiro, Kelly Carolina Frauzino Araújo Biotransformação Hesperetina Microbiorreator Cunninghamella Biotransformation Hesperetin Microbioreactor Cunninghamella CIENCIAS DA SAUDE::FARMACIA |
title_short |
Biotransformação fúngica da hesperetina e sua aplicação na produção de metabólitos ativos |
title_full |
Biotransformação fúngica da hesperetina e sua aplicação na produção de metabólitos ativos |
title_fullStr |
Biotransformação fúngica da hesperetina e sua aplicação na produção de metabólitos ativos |
title_full_unstemmed |
Biotransformação fúngica da hesperetina e sua aplicação na produção de metabólitos ativos |
title_sort |
Biotransformação fúngica da hesperetina e sua aplicação na produção de metabólitos ativos |
author |
Cordeiro, Kelly Carolina Frauzino Araújo |
author_facet |
Cordeiro, Kelly Carolina Frauzino Araújo |
author_role |
author |
dc.contributor.advisor1.fl_str_mv |
Oliveira, Valéria de |
dc.contributor.advisor1Lattes.fl_str_mv |
http://lattes.cnpq.br/6300240031300604 |
dc.contributor.referee1.fl_str_mv |
Oliveira, Valéria de |
dc.contributor.referee2.fl_str_mv |
Silva, Lorena Maione |
dc.contributor.referee3.fl_str_mv |
Silva, Maria do Rosário Rodrigues |
dc.contributor.referee4.fl_str_mv |
Cunha, Carla Rosane Mendanha da |
dc.contributor.referee5.fl_str_mv |
Terezan, Ana Paula |
dc.contributor.authorLattes.fl_str_mv |
http://lattes.cnpq.br/4275744776508451 |
dc.contributor.author.fl_str_mv |
Cordeiro, Kelly Carolina Frauzino Araújo |
contributor_str_mv |
Oliveira, Valéria de Oliveira, Valéria de Silva, Lorena Maione Silva, Maria do Rosário Rodrigues Cunha, Carla Rosane Mendanha da Terezan, Ana Paula |
dc.subject.por.fl_str_mv |
Biotransformação Hesperetina Microbiorreator Cunninghamella |
topic |
Biotransformação Hesperetina Microbiorreator Cunninghamella Biotransformation Hesperetin Microbioreactor Cunninghamella CIENCIAS DA SAUDE::FARMACIA |
dc.subject.eng.fl_str_mv |
Biotransformation Hesperetin Microbioreactor Cunninghamella |
dc.subject.cnpq.fl_str_mv |
CIENCIAS DA SAUDE::FARMACIA |
description |
Hesperetin belongs to the flavanone class of flavonoids, its human metabolites (i.e. hesperetin-3’-sulfate, hesperetin-7-sulfate, hesperetin-3’-glucoronide and hesperetin -7-glucoronide), and its glycosylated derivative has potential pharmacological properties. The use of microorganisms, such as filamentous fungi, is an alternative in derivatives production and a useful tool in scale up process. Therefore, the goal of the work was to apply and evaluate different bioprocesses for the production of active metabolites of hesperetin by fungal biotransformation. Application of microbioreactors, use of different carbon sources, substrate concentration, fungal immobilization and monitored reactions by liquid chromatography coupled to high resolution mass spectrometry were some of evaluated bioprocesses. From 15 tested fungi, 12 strains were able to biotransform hesperetin. In silico metabolite prediction modeling with MetaPrint 2D software, indicated positions 7 e 3’ as energetically favored for glycosylation, glucuronidation and sulfation reactions. Mortierella isabellina NRRL 1757 and Beauveria bassiana ATCC 7159 produced only sulfate and glucuronide hesperitins, respectively. Cunninghamella echinulata ATCC 9244 strain produced the glycosylated metabolite. A morphological difference was observed in C. echinulata ATCC 9245 growth using different microbioreactors. Square microwell plates resulted in an amorphous growth whereas round bottom microwell plates favored pellets growth. The latest, with volume well of 2.2 ml led to a higher content of fungi and 48 hours was found to be the ideal time to substract addition. All four strands of Cunninghamella tested for biotransformation in a microscale were able to produce the glycosylated metabolite. Analyzes of the biotransformation kinetics by HPLC-HRMS showed that Cunninghamella echinulata ATCC 9244 produced four microplate derivatives: eriodictiol, sulfated hesperetin, glycosylated hesperetin and glucuronidated hesperetin. Such analyzes have also shown that high concentrations of hesperetin inhibit these derivatives formation. Stainless steel sponge proved to be efficient for Cunninghamella echinulata and Cunninghamella elegans strains immobilization. The immobilization process achieved biofilm in 48 hours. ESI-IT-MS and ESI-IT-MS/MS analysis indicated production of a glycosylated and a hydroxylated-sulfonated derivative. Thus, studies demonstrated that different bioprocesses can be applied to optimize scale up reactions and produce hesperetin derivatives using filamentous fungi |
publishDate |
2019 |
dc.date.accessioned.fl_str_mv |
2019-09-13T14:25:04Z |
dc.date.issued.fl_str_mv |
2019-01-11 |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/doctoralThesis |
format |
doctoralThesis |
status_str |
publishedVersion |
dc.identifier.citation.fl_str_mv |
CORDEIRO, Kelly Carolina Frauzino Araújo. Biotransformação fúngica da hesperetina e sua aplicação na produção de metabólitos ativos. 2018. 135 f. Tese (Doutorado em Inovação Farmacêutica em Rede) - Universidade Federal de Goiás, Goiânia, 2019. |
dc.identifier.uri.fl_str_mv |
http://repositorio.bc.ufg.br/tede/handle/tede/10018 |
identifier_str_mv |
CORDEIRO, Kelly Carolina Frauzino Araújo. Biotransformação fúngica da hesperetina e sua aplicação na produção de metabólitos ativos. 2018. 135 f. Tese (Doutorado em Inovação Farmacêutica em Rede) - Universidade Federal de Goiás, Goiânia, 2019. |
url |
http://repositorio.bc.ufg.br/tede/handle/tede/10018 |
dc.language.iso.fl_str_mv |
por |
language |
por |
dc.relation.program.fl_str_mv |
1510836041889931197 |
dc.relation.confidence.fl_str_mv |
600 600 600 600 |
dc.relation.department.fl_str_mv |
6010281161524209375 |
dc.relation.cnpq.fl_str_mv |
6997636413449754996 |
dc.relation.sponsorship.fl_str_mv |
2075167498588264571 |
dc.rights.driver.fl_str_mv |
http://creativecommons.org/licenses/by-nc-nd/4.0/ info:eu-repo/semantics/openAccess |
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UFG |
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Brasil |
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Faculdade Farmácia - FF (RG) |
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Universidade Federal de Goiás |
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