Estudio de oligomerización y mecanismos de regulación génica de la enzima nicotinamida/nicotinato mononucleótido adenililtransferasa de Leishmania braziliensis

ilustraciones

Autores:
Rojas Ramos, Bryan Steven
Tipo de recurso:
Fecha de publicación:
2023
Institución:
Universidad Nacional de Colombia
Repositorio:
Universidad Nacional de Colombia
Idioma:
spa
OAI Identifier:
oai:repositorio.unal.edu.co:unal/84167
Acceso en línea:
https://repositorio.unal.edu.co/handle/unal/84167
https://repositorio.unal.edu.co/
Palabra clave:
570 - Biología::572 - Bioquímica
Parasitos
Parasites
Leishmaniasis
Leishmania braziliensis
NAD
LbNMNAT
Oligomerización
Regulación post-transcripcional
UTR
RBP
Oligomerization
Post-transcriptional regulation
Rights
openAccess
License
Atribución-NoComercial-SinDerivadas 4.0 Internacional
id UNACIONAL2_3089119a8434fe90e8e0307b2a7c3e66
oai_identifier_str oai:repositorio.unal.edu.co:unal/84167
network_acronym_str UNACIONAL2
network_name_str Universidad Nacional de Colombia
repository_id_str
dc.title.spa.fl_str_mv Estudio de oligomerización y mecanismos de regulación génica de la enzima nicotinamida/nicotinato mononucleótido adenililtransferasa de Leishmania braziliensis
dc.title.translated.eng.fl_str_mv Study of oligomerization and gene regulation mechanisms of the enzyme nicotinamide/nicotinate mononucleotide adenylyltransferase from Leishmania braziliensis
dc.title.translated.deu.fl_str_mv Untersuchung der Oligomerisierungs- und Genregulationsmechanismen des Enzyms Nicotinamid/Nicotinat-Mononukleotid-Adenylyltransferase aus Leishmania braziliensis
title Estudio de oligomerización y mecanismos de regulación génica de la enzima nicotinamida/nicotinato mononucleótido adenililtransferasa de Leishmania braziliensis
spellingShingle Estudio de oligomerización y mecanismos de regulación génica de la enzima nicotinamida/nicotinato mononucleótido adenililtransferasa de Leishmania braziliensis
570 - Biología::572 - Bioquímica
Parasitos
Parasites
Leishmaniasis
Leishmania braziliensis
NAD
LbNMNAT
Oligomerización
Regulación post-transcripcional
UTR
RBP
Oligomerization
Post-transcriptional regulation
title_short Estudio de oligomerización y mecanismos de regulación génica de la enzima nicotinamida/nicotinato mononucleótido adenililtransferasa de Leishmania braziliensis
title_full Estudio de oligomerización y mecanismos de regulación génica de la enzima nicotinamida/nicotinato mononucleótido adenililtransferasa de Leishmania braziliensis
title_fullStr Estudio de oligomerización y mecanismos de regulación génica de la enzima nicotinamida/nicotinato mononucleótido adenililtransferasa de Leishmania braziliensis
title_full_unstemmed Estudio de oligomerización y mecanismos de regulación génica de la enzima nicotinamida/nicotinato mononucleótido adenililtransferasa de Leishmania braziliensis
title_sort Estudio de oligomerización y mecanismos de regulación génica de la enzima nicotinamida/nicotinato mononucleótido adenililtransferasa de Leishmania braziliensis
dc.creator.fl_str_mv Rojas Ramos, Bryan Steven
dc.contributor.advisor.none.fl_str_mv contreras, luis
dc.contributor.author.none.fl_str_mv Rojas Ramos, Bryan Steven
dc.contributor.researchgroup.spa.fl_str_mv Libbiq Un
dc.contributor.orcid.spa.fl_str_mv https://orcid.org/0000-0002-7196-2288
dc.contributor.cvlac.spa.fl_str_mv Rojas Ramos, Bryan Steven
dc.contributor.researchgate.spa.fl_str_mv Rojas Ramos, Bryan Steven
dc.subject.ddc.spa.fl_str_mv 570 - Biología::572 - Bioquímica
topic 570 - Biología::572 - Bioquímica
Parasitos
Parasites
Leishmaniasis
Leishmania braziliensis
NAD
LbNMNAT
Oligomerización
Regulación post-transcripcional
UTR
RBP
Oligomerization
Post-transcriptional regulation
dc.subject.lemb.spa.fl_str_mv Parasitos
dc.subject.lemb.eng.fl_str_mv Parasites
dc.subject.proposal.spa.fl_str_mv Leishmaniasis
Leishmania braziliensis
NAD
LbNMNAT
Oligomerización
Regulación post-transcripcional
dc.subject.proposal.eng.fl_str_mv UTR
RBP
Oligomerization
Post-transcriptional regulation
description ilustraciones
publishDate 2023
dc.date.accessioned.none.fl_str_mv 2023-07-07T19:57:09Z
dc.date.available.none.fl_str_mv 2023-07-07T19:57:09Z
dc.date.issued.none.fl_str_mv 2023
dc.type.spa.fl_str_mv Trabajo de grado - Maestría
dc.type.driver.spa.fl_str_mv info:eu-repo/semantics/masterThesis
dc.type.version.spa.fl_str_mv info:eu-repo/semantics/acceptedVersion
dc.type.content.spa.fl_str_mv Text
dc.type.redcol.spa.fl_str_mv http://purl.org/redcol/resource_type/TM
status_str acceptedVersion
dc.identifier.uri.none.fl_str_mv https://repositorio.unal.edu.co/handle/unal/84167
dc.identifier.instname.spa.fl_str_mv Universidad Nacional de Colombia
dc.identifier.reponame.spa.fl_str_mv Repositorio Institucional Universidad Nacional de Colombia
dc.identifier.repourl.spa.fl_str_mv https://repositorio.unal.edu.co/
url https://repositorio.unal.edu.co/handle/unal/84167
https://repositorio.unal.edu.co/
identifier_str_mv Universidad Nacional de Colombia
Repositorio Institucional Universidad Nacional de Colombia
dc.language.iso.spa.fl_str_mv spa
language spa
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dc.publisher.spa.fl_str_mv Universidad Nacional de Colombia
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institution Universidad Nacional de Colombia
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spelling Atribución-NoComercial-SinDerivadas 4.0 Internacionalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccesshttp://purl.org/coar/access_right/c_abf2contreras, luis62876ec184e5db1ab336ead057619899600Rojas Ramos, Bryan Steven17d357341df3152ab7e826c8804df268600Libbiq Unhttps://orcid.org/0000-0002-7196-2288Rojas Ramos, Bryan StevenRojas Ramos, Bryan Steven2023-07-07T19:57:09Z2023-07-07T19:57:09Z2023https://repositorio.unal.edu.co/handle/unal/84167Universidad Nacional de ColombiaRepositorio Institucional Universidad Nacional de Colombiahttps://repositorio.unal.edu.co/ilustracionesLa Leishmaniasis es una enfermedad que puede manifestarse en tres formas clínicas: cutánea, mucocutánea y visceral, siendo causada por parásitos protozoarios del género Leishmania, del cual se conocen 22 especies patogénicas para el hombre. Según la Organización Mundial de la Salud, anualmente se registran 1,3 millones de casos, siendo Colombia uno de los países afectados, donde circulan varias especies, incluyendo Leishmania braziliensis. Actualmente, no se dispone de vacunas aprobadas para la prevención de la Leishmaniasis y el tratamiento de primera línea, como son los antimoniatos pentavalentes, generan diversos y graves efectos adversos destacándose nefrotoxicidad, hepatotoxicidad y mialgias. Adicionalmente, se ha reportado la aparición de cepas farmacorresistentes. Por lo tanto, se requiere la exploración de nuevas dianas terapéuticas, como, por ejemplo, la síntesis del dinucleótido de nicotinamida y adenina (NAD), que se destaca como una ruta metabólica promisoria, dada la importancia de este transportador electrónico. En los últimos años, nuestro grupo de investigación se ha enfocado en la obtención y caracterización de las proteínas del metabolismo del NAD de protozoarios como Giardia lamblia, Plasmodium falciparum, Trypanosoma cruzi y L. braziliensis. Específicamente en Leishmania, se han realizado trabajos para la caracterización de proteínas como la NAD quinasa y la nicotinamida/nicotinato mononucleótido adenilil transferasa (LbNMNAT); sin embargo, estos estudios se han enfocado principalmente en su actividad enzimática y estructura cuaternaria en ausencia de sustratos. En este trabajo se analizó el efecto que ejercen los sustratos de la enzima LbNMNAT sobre su oligomerización, encontrándose que sus organizaciones en forma de dímeros, trímeros y tetrámeros, no es modificada por la presencia de los sustratos analizados. Esta evidencia estructural es concordante con la cinética de tipo Michaelis-Menten reportada para la enzima, puesto que los sustratos no ejercen regulación homo-trópica sobre la LbNMNAT. Por otro lado, considerando que uno de los principales niveles de regulación de expresión génica en los tripanosomátidos es post-transcripcional, entonces se efectuó una aproximación bioinformática basada en la identificación de sitios aceptores de splicing, para delimitar las regiones no codificantes (UTRs) del gen lbnmnat. En este sentido, se encontraron numerosos sitios aceptores que podrían generar UTRs de diferentes longitudes, como se ha reportado para otras especies del parásito. Adicionalmente, se identificaron 29 proteínas de unión a ARN (RBPs) con probabilidad de reconocer dichas UTRs, las cuales participan en procesos diversos como splicing, poli-adenilación y represión post-transcripcional. De este modo, se indican proteínas que posiblemente explican las diferencias reportadas por otros autores para la abundancia del transcrito del gen lbnmnat a través del ciclo biológico de L. braziliensis. Con el propósito de comprobar experimentalmente algunos de los hallazgos bioinformáticos de este trabajo, se implementó la técnica de Retro-Transcripción acoplada a PCR (RT-PCR), partiendo del ARN obtenido de promastigotes de L. braziliensis, para identificar los UTRs asociados al gen lbnmnat en este estadio del parásito. Dicha técnica permitió la síntesis de ADN complementario apropiado para el estudio de UTRs y la amplificación de un producto de menor tamaño al esperado para el UTR 5’. Este resultado indica la necesidad de determinar la secuencia exacta del amplicón mediante eventuales técnicas de aislamiento y secuenciamiento de ADN. En conclusión, el presente trabajo aporta evidencia experimental y bioinformática acerca del efecto estructural que ejercen los sustratos de la enzima LbNMNAT sobre su oligomerización y acerca de sus UTRs y proteínas de unión, que podrían explicar mecanismos de regulación de la expresión del gen lbnmnat en el parásito L. braziliensis. (Texto tomado de la fuente)Leishmaniasis is a disease that can manifest in three clinical forms: cutaneous, mucocutaneous, and visceral. This illness is caused by protozoan parasites of the genus Leishmania. There are 22 human pathogenic species. According to the World Health Organization, 1.3 million cases are recorded annually. Colombia is one of the affected countries, where several species circulate, including Leishmania braziliensis. Currently, there are no approved vaccines available for the prevention of Leishmaniasis, and first-line treatment, such as pentavalent antimonates, generate various and serious adverse effects, including nephrotoxicity, hepatotoxicity, and myalgia. Additionally, drug-resistant strains have been reported. Therefore, the exploration of new therapeutic targets is required, such as the synthesis of nicotinamide adenine dinucleotide (NAD), which stands out as a promising metabolic pathway, since the importance of this electronic transporter. In recent years, our research group has focused on obtaining and characterizing NAD metabolism proteins from protozoa such as Giardia lamblia, Plasmodium falciparum, Trypanosoma cruzi and L. braziliensis. Specifically, in Leishmania research has been carried out to characterize these kinds of proteins: NAD kinase and nicotinamide/nicotinate mononucleotide adenylyl transferase (LbNMNAT); however, these studies have mainly focused on their enzymatic activity and quaternary structure in the absence of substrates. In this Thesis, the effect of the substrates of the LbNMNAT enzyme on its oligomerization was analyzed, finding that its organizations in the form of dimers, trimers, and tetramers, is not modified by the presence of the analyzed substrates. This structural evidence is consistent with the Michaelis-Menten kinetics reported for the enzyme since the substrates do not exert homotropic regulation on LbNMNAT. On the other hand, considering that one of the main levels of regulation of gene expression in trypanosomatids is post-transcriptional, a bioinformatics approach based on the identification of splicing acceptor sites was carried out to delimit the non-coding regions (UTRs) of the lbnmnat gene. In this sense, numerous acceptor sites were found that could generate UTRs of different lengths, as has been reported for other species of the parasite. Additionally, 29 RNA-binding proteins (RBPs) were identified with a probability of recognizing these UTRs, which participate in various processes, for instance, splicing, polyadenylation, and post-transcriptional repression. In this way, this study indicates proteins that possibly explain the differences reported by other authors for the abundance of the lbnmnat gene transcript throughout the life cycle of L. braziliensis. In order to experimentally verify some of the bioinformatic findings of this work, the Retro-Transcription coupled to PCR (RT-PCR) technique was implemented, starting from the RNA obtained from L. braziliensis promastigotes, to identify the UTRs associated with the lbnmnat gene in this stage of the parasite. This technique allowed the synthesis of complementary DNA appropriate for studying UTRs and amplifying a product smaller than expected for the 5' UTR. This result indicates the need to determine the exact sequence of the amplicon by possible DNA isolation and sequencing techniques. In conclusion, the present work provides experimental and bioinformatic evidence about the structural effect of the LbNMNAT enzyme's substrates on its oligomerization and its UTRs and binding proteins, which could explain mechanisms of regulation of the expression of the lbnmnat gene in the parasite L. braziliensis.MaestríaMagíster en Ciencias - Bioquímicabioquímica básicaxix, 116 páginasapplication/pdfspaUniversidad Nacional de ColombiaBogotá - Ciencias - Maestría en Ciencias - BioquímicaFacultad de CienciasBogotá,ColombiaUniversidad Nacional de Colombia - Sede Bogotá570 - Biología::572 - BioquímicaParasitosParasitesLeishmaniasisLeishmania braziliensisNADLbNMNATOligomerizaciónRegulación post-transcripcionalUTRRBPOligomerizationPost-transcriptional regulationEstudio de oligomerización y mecanismos de regulación génica de la enzima nicotinamida/nicotinato mononucleótido adenililtransferasa de Leishmania braziliensisStudy of oligomerization and gene regulation mechanisms of the enzyme nicotinamide/nicotinate mononucleotide adenylyltransferase from Leishmania braziliensisUntersuchung der Oligomerisierungs- und Genregulationsmechanismen des Enzyms Nicotinamid/Nicotinat-Mononukleotid-Adenylyltransferase aus Leishmania braziliensisTrabajo de grado - Maestríainfo:eu-repo/semantics/masterThesisinfo:eu-repo/semantics/acceptedVersionTexthttp://purl.org/redcol/resource_type/TMWorld Health Organization, “leishmanisis,” Leishmanisis. https://www.who.int/news-room/fact-sheets/detail/leishmaniasis (accessed Oct. 10, 2022).Manual de procedimientos para la vigilancia y control de las leishmaniasis. 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Elsevier, 2019.INNOVANDO METODOLOGÍAS: DESARROLLO DE UN SISTEMA DE INFECCIÓN IN VITRO DE MACRÓFAGOS MURINOS CON PARÁSITOS FLUORESCENTES DE LEISHMANIA BRAZILIENSISUniversidad Nacional de Colombia - Sede de Bogotá - Facultad de cienciasEstudiantesInvestigadoresLICENSElicense.txtlicense.txttext/plain; charset=utf-85879https://repositorio.unal.edu.co/bitstream/unal/84167/1/license.txteb34b1cf90b7e1103fc9dfd26be24b4aMD51ORIGINAL1069752050_2023.pdf1069752050_2023.pdfTesis de Maestría en Ciencias - Químicaapplication/pdf4414114https://repositorio.unal.edu.co/bitstream/unal/84167/2/1069752050_2023.pdfbe2422892962829493234f992f814cc2MD52unal/84167oai:repositorio.unal.edu.co:unal/841672023-07-07 15:09:42.987Repositorio Institucional Universidad Nacional de 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