Trichomonas vaginalis acid sphingomyelinases' theoretical structural analysis shows substrate binding diversity related to protein flexibility and mobility
Por:
Medina-Nieto A.L., Andrade-Guillen S.Y., Ramírez-Montiel F.B., Tornero-Gutiérrez F., Martínez-Álvarez J.A., Rangel-Serrano Á., Páramo-Pérez I., Vargas-Maya N.I., De La Mora J., Mendoza-Macías C.L., Cuéllar-Mata P., Alva-Murillo N., Franco B., Padilla-Vaca F.
Publicada:
1 ene 2026
Resumen:
© 2025 Elsevier LtdAcid sphingomyelinases (aSMases) are enzymes involved in the repair of the plasma membrane in eukaryotic cells. However, neutral sphingomyelinases (nSMases) have also been shown to possess other roles in bacteria and eukaryotic microorganisms, especially as virulence factors. These enzymes exhibit structural conservation but are characterized by elusive homology and the lack of sequence signatures or motifs. In a previous study, we reported the structural features of the complete set of sphingomyelinases (SMases) in Entamoeba histolytica and Trichomonas vaginalis, showing structural homology and functional differences in two aSMases from E. histolytica (EhSMase). However, the approach was limited due to the AlphaFold3 source code not being publicly available at the time. In this report, the structural transitions in the aSMases from T. vaginalis (TvSMase) were measured using open-source AlphaFold3 and collective motions of proteins via Normal Mode Analysis in internal coordinates. They compared them with the models from aSMase4 (EHI_100080) and aSMase6 (EHI_125660) from E. histolytica, containing different combinations of ligands. Using full-length sphingomyelin and the Mg2+ and Co2+ ions, where Co2+ was shown to inhibit the enzymes of both organisms, we demonstrate that the enzymes exhibit limited flexibility and deformability, except for the T. vaginalis TVAG_271580 enzyme, which displays high structural deformability. This contrasts with the inhibitory mechanism elicited by Co2+ as shown previously. TVSMase3 (TVAG_222460) could not be modelled with the sphingomyelin in the active site pocket, suggesting a regulatory role rather than a functional active enzyme. Additional physicochemical parameters calculated for T. vaginalis enzymes suggest unstable structures and high internal mobility (estimated using the Internal Coordinate method), which may be associated with the functional role of these enzymes. The results presented here open an avenue for searching for novel inhibitors of aSMases that target their physical properties, which could potentially complement treatment to control the parasite burden. These inhibitors could be valuable for further studying the role of these enzymes in parasite pathobiology and, potentially, as therapeutic targets.
Filiaciones:
Medina-Nieto A.L.:
Departamento de Biología, División de Ciencias Naturales y Exactas, Universidad de Guanajuato, Mexico 36050, Mexico
Andrade-Guillen S.Y.:
Departamento de Biología, División de Ciencias Naturales y Exactas, Universidad de Guanajuato, Mexico 36050, Mexico
Ramírez-Montiel F.B.:
Departamento de Farmacia, División de Ciencias Naturales y Exactas, Universidad de Guanajuato, Mexico 36050, Mexico
Tornero-Gutiérrez F.:
Departamento de Biología, División de Ciencias Naturales y Exactas, Universidad de Guanajuato, Mexico 36050, Mexico
Martínez-Álvarez J.A.:
Departamento de Biología, División de Ciencias Naturales y Exactas, Universidad de Guanajuato, Mexico 36050, Mexico
Rangel-Serrano Á.:
Departamento de Biología, División de Ciencias Naturales y Exactas, Universidad de Guanajuato, Mexico 36050, Mexico
Páramo-Pérez I.:
Departamento de Biología, División de Ciencias Naturales y Exactas, Universidad de Guanajuato, Mexico 36050, Mexico
Vargas-Maya N.I.:
Departamento de Biología, División de Ciencias Naturales y Exactas, Universidad de Guanajuato, Mexico 36050, Mexico
De La Mora J.:
Departamento de Bioquímica y Biología Estructural, Instituto de Fisiología Celular, Ciudad de México 04510, Mexico
Mendoza-Macías C.L.:
Departamento de Farmacia, División de Ciencias Naturales y Exactas, Universidad de Guanajuato, Mexico 36050, Mexico
Cuéllar-Mata P.:
Departamento de Biología, División de Ciencias Naturales y Exactas, Universidad de Guanajuato, Mexico 36050, Mexico
Alva-Murillo N.:
Departamento de Biología, División de Ciencias Naturales y Exactas, Universidad de Guanajuato, Mexico 36050, Mexico
Franco B.:
Departamento de Biología, División de Ciencias Naturales y Exactas, Universidad de Guanajuato, Mexico 36050, Mexico
Padilla-Vaca F.:
Departamento de Biología, División de Ciencias Naturales y Exactas, Universidad de Guanajuato, Mexico 36050, Mexico
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