Cargando…

The superfamily keeps growing: Identification in trypanosomatids of RibJ, the first riboflavin transporter family in protists

BACKGROUND: Trypanosomatid parasites represent a major health issue affecting hundreds of million people worldwide, with clinical treatments that are partially effective and/or very toxic. They are responsible for serious human and plant diseases including Trypanosoma cruzi (Chagas disease), Trypano...

Descripción completa

Detalles Bibliográficos
Autores principales: Balcazar, Darío E., Vanrell, María Cristina, Romano, Patricia S., Pereira, Claudio A., Goldbaum, Fernando A., Bonomi, Hernán R., Carrillo, Carolina
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5404878/
https://www.ncbi.nlm.nih.gov/pubmed/28406895
http://dx.doi.org/10.1371/journal.pntd.0005513
_version_ 1783231667476889600
author Balcazar, Darío E.
Vanrell, María Cristina
Romano, Patricia S.
Pereira, Claudio A.
Goldbaum, Fernando A.
Bonomi, Hernán R.
Carrillo, Carolina
author_facet Balcazar, Darío E.
Vanrell, María Cristina
Romano, Patricia S.
Pereira, Claudio A.
Goldbaum, Fernando A.
Bonomi, Hernán R.
Carrillo, Carolina
author_sort Balcazar, Darío E.
collection PubMed
description BACKGROUND: Trypanosomatid parasites represent a major health issue affecting hundreds of million people worldwide, with clinical treatments that are partially effective and/or very toxic. They are responsible for serious human and plant diseases including Trypanosoma cruzi (Chagas disease), Trypanosoma brucei (Sleeping sickness), Leishmania spp. (Leishmaniasis), and Phytomonas spp. (phytoparasites). Both, animals and trypanosomatids lack the biosynthetic riboflavin (vitamin B2) pathway, the vital precursor of flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD) cofactors. While metazoans obtain riboflavin from the diet through RFVT/SLC52 transporters, the riboflavin transport mechanisms in trypanosomatids still remain unknown. METHODOLOGY/PRINCIPAL FINDINGS: Here, we show that riboflavin is imported with high affinity in Trypanosoma cruzi, Trypanosoma brucei, Leishmania (Leishmania) mexicana, Crithidia fasciculata and Phytomonas Jma using radiolabeled riboflavin transport assays. The vitamin is incorporated through a saturable carrier-mediated process. Effective competitive uptake occurs with riboflavin analogs roseoflavin, lumiflavin and lumichrome, and co-factor derivatives FMN and FAD. Moreover, important biological processes evaluated in T. cruzi (i.e. proliferation, metacyclogenesis and amastigote replication) are dependent on riboflavin availability. In addition, the riboflavin competitive analogs were found to interfere with parasite physiology on riboflavin-dependent processes. By means of bioinformatics analyses we identified a novel family of riboflavin transporters (RibJ) in trypanosomatids. Two RibJ members, TcRibJ and TbRibJ from T. cruzi and T. brucei respectively, were functionally characterized using homologous and/or heterologous expression systems. CONCLUSIONS/SIGNIFICANCE: The RibJ family represents the first riboflavin transporters found in protists and the third eukaryotic family known to date. The essentiality of riboflavin for trypanosomatids, and the structural/biochemical differences that RFVT/SLC52 and RibJ present, make the riboflavin transporter -and its downstream metabolism- a potential trypanocidal drug target.
format Online
Article
Text
id pubmed-5404878
institution National Center for Biotechnology Information
language English
publishDate 2017
publisher Public Library of Science
record_format MEDLINE/PubMed
spelling pubmed-54048782017-05-14 The superfamily keeps growing: Identification in trypanosomatids of RibJ, the first riboflavin transporter family in protists Balcazar, Darío E. Vanrell, María Cristina Romano, Patricia S. Pereira, Claudio A. Goldbaum, Fernando A. Bonomi, Hernán R. Carrillo, Carolina PLoS Negl Trop Dis Research Article BACKGROUND: Trypanosomatid parasites represent a major health issue affecting hundreds of million people worldwide, with clinical treatments that are partially effective and/or very toxic. They are responsible for serious human and plant diseases including Trypanosoma cruzi (Chagas disease), Trypanosoma brucei (Sleeping sickness), Leishmania spp. (Leishmaniasis), and Phytomonas spp. (phytoparasites). Both, animals and trypanosomatids lack the biosynthetic riboflavin (vitamin B2) pathway, the vital precursor of flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD) cofactors. While metazoans obtain riboflavin from the diet through RFVT/SLC52 transporters, the riboflavin transport mechanisms in trypanosomatids still remain unknown. METHODOLOGY/PRINCIPAL FINDINGS: Here, we show that riboflavin is imported with high affinity in Trypanosoma cruzi, Trypanosoma brucei, Leishmania (Leishmania) mexicana, Crithidia fasciculata and Phytomonas Jma using radiolabeled riboflavin transport assays. The vitamin is incorporated through a saturable carrier-mediated process. Effective competitive uptake occurs with riboflavin analogs roseoflavin, lumiflavin and lumichrome, and co-factor derivatives FMN and FAD. Moreover, important biological processes evaluated in T. cruzi (i.e. proliferation, metacyclogenesis and amastigote replication) are dependent on riboflavin availability. In addition, the riboflavin competitive analogs were found to interfere with parasite physiology on riboflavin-dependent processes. By means of bioinformatics analyses we identified a novel family of riboflavin transporters (RibJ) in trypanosomatids. Two RibJ members, TcRibJ and TbRibJ from T. cruzi and T. brucei respectively, were functionally characterized using homologous and/or heterologous expression systems. CONCLUSIONS/SIGNIFICANCE: The RibJ family represents the first riboflavin transporters found in protists and the third eukaryotic family known to date. The essentiality of riboflavin for trypanosomatids, and the structural/biochemical differences that RFVT/SLC52 and RibJ present, make the riboflavin transporter -and its downstream metabolism- a potential trypanocidal drug target. Public Library of Science 2017-04-13 /pmc/articles/PMC5404878/ /pubmed/28406895 http://dx.doi.org/10.1371/journal.pntd.0005513 Text en © 2017 Balcazar et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Balcazar, Darío E.
Vanrell, María Cristina
Romano, Patricia S.
Pereira, Claudio A.
Goldbaum, Fernando A.
Bonomi, Hernán R.
Carrillo, Carolina
The superfamily keeps growing: Identification in trypanosomatids of RibJ, the first riboflavin transporter family in protists
title The superfamily keeps growing: Identification in trypanosomatids of RibJ, the first riboflavin transporter family in protists
title_full The superfamily keeps growing: Identification in trypanosomatids of RibJ, the first riboflavin transporter family in protists
title_fullStr The superfamily keeps growing: Identification in trypanosomatids of RibJ, the first riboflavin transporter family in protists
title_full_unstemmed The superfamily keeps growing: Identification in trypanosomatids of RibJ, the first riboflavin transporter family in protists
title_short The superfamily keeps growing: Identification in trypanosomatids of RibJ, the first riboflavin transporter family in protists
title_sort superfamily keeps growing: identification in trypanosomatids of ribj, the first riboflavin transporter family in protists
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5404878/
https://www.ncbi.nlm.nih.gov/pubmed/28406895
http://dx.doi.org/10.1371/journal.pntd.0005513
work_keys_str_mv AT balcazardarioe thesuperfamilykeepsgrowingidentificationintrypanosomatidsofribjthefirstriboflavintransporterfamilyinprotists
AT vanrellmariacristina thesuperfamilykeepsgrowingidentificationintrypanosomatidsofribjthefirstriboflavintransporterfamilyinprotists
AT romanopatricias thesuperfamilykeepsgrowingidentificationintrypanosomatidsofribjthefirstriboflavintransporterfamilyinprotists
AT pereiraclaudioa thesuperfamilykeepsgrowingidentificationintrypanosomatidsofribjthefirstriboflavintransporterfamilyinprotists
AT goldbaumfernandoa thesuperfamilykeepsgrowingidentificationintrypanosomatidsofribjthefirstriboflavintransporterfamilyinprotists
AT bonomihernanr thesuperfamilykeepsgrowingidentificationintrypanosomatidsofribjthefirstriboflavintransporterfamilyinprotists
AT carrillocarolina thesuperfamilykeepsgrowingidentificationintrypanosomatidsofribjthefirstriboflavintransporterfamilyinprotists
AT balcazardarioe superfamilykeepsgrowingidentificationintrypanosomatidsofribjthefirstriboflavintransporterfamilyinprotists
AT vanrellmariacristina superfamilykeepsgrowingidentificationintrypanosomatidsofribjthefirstriboflavintransporterfamilyinprotists
AT romanopatricias superfamilykeepsgrowingidentificationintrypanosomatidsofribjthefirstriboflavintransporterfamilyinprotists
AT pereiraclaudioa superfamilykeepsgrowingidentificationintrypanosomatidsofribjthefirstriboflavintransporterfamilyinprotists
AT goldbaumfernandoa superfamilykeepsgrowingidentificationintrypanosomatidsofribjthefirstriboflavintransporterfamilyinprotists
AT bonomihernanr superfamilykeepsgrowingidentificationintrypanosomatidsofribjthefirstriboflavintransporterfamilyinprotists
AT carrillocarolina superfamilykeepsgrowingidentificationintrypanosomatidsofribjthefirstriboflavintransporterfamilyinprotists