Cargando…
Structure-Function Features of a Mycoplasma Glycolipid Synthase Derived from Structural Data Integration, Molecular Simulations, and Mutational Analysis
Glycoglycerolipids are structural components of mycoplasma membranes with a fundamental role in membrane properties and stability. Their biosynthesis is mediated by glycosyltransferases (GT) that catalyze the transfer of glycosyl units from a sugar nucleotide donor to diacylglycerol. The essential f...
Autores principales: | , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2013
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3849446/ https://www.ncbi.nlm.nih.gov/pubmed/24312618 http://dx.doi.org/10.1371/journal.pone.0081990 |
_version_ | 1782293926817824768 |
---|---|
author | Romero-García, Javier Francisco, Carles Biarnés, Xevi Planas, Antoni |
author_facet | Romero-García, Javier Francisco, Carles Biarnés, Xevi Planas, Antoni |
author_sort | Romero-García, Javier |
collection | PubMed |
description | Glycoglycerolipids are structural components of mycoplasma membranes with a fundamental role in membrane properties and stability. Their biosynthesis is mediated by glycosyltransferases (GT) that catalyze the transfer of glycosyl units from a sugar nucleotide donor to diacylglycerol. The essential function of glycolipid synthases in mycoplasma viability, and the absence of glycoglycerolipids in animal host cells make these GT enzymes a target for drug discovery by designing specific inhibitors. However, rational drug design has been hampered by the lack of structural information for any mycoplasma GT. Most of the annotated GTs in pathogenic mycoplasmas belong to family GT2. We had previously shown that MG517 in Mycoplasma genitalium is a GT-A family GT2 membrane-associated glycolipid synthase. We present here a series of structural models of MG517 obtained by homology modeling following a multiple-template approach. The models have been validated by mutational analysis and refined by long scale molecular dynamics simulations. Based on the models, key structure-function relationships have been identified: The N-terminal GT domain has a GT-A topology that includes a non-conserved variable region involved in acceptor substrate binding. Glu193 is proposed as the catalytic base in the GT mechanism, and Asp40, Tyr126, Tyr169, Ile170 and Tyr218 define the substrates binding site. Mutation Y169F increases the enzyme activity and significantly alters the processivity (or sequential transferase activity) of the enzyme. This is the first structural model of a GT-A glycoglycerolipid synthase and provides preliminary insights into structure and function relationships in this family of enzymes. |
format | Online Article Text |
id | pubmed-3849446 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-38494462013-12-05 Structure-Function Features of a Mycoplasma Glycolipid Synthase Derived from Structural Data Integration, Molecular Simulations, and Mutational Analysis Romero-García, Javier Francisco, Carles Biarnés, Xevi Planas, Antoni PLoS One Research Article Glycoglycerolipids are structural components of mycoplasma membranes with a fundamental role in membrane properties and stability. Their biosynthesis is mediated by glycosyltransferases (GT) that catalyze the transfer of glycosyl units from a sugar nucleotide donor to diacylglycerol. The essential function of glycolipid synthases in mycoplasma viability, and the absence of glycoglycerolipids in animal host cells make these GT enzymes a target for drug discovery by designing specific inhibitors. However, rational drug design has been hampered by the lack of structural information for any mycoplasma GT. Most of the annotated GTs in pathogenic mycoplasmas belong to family GT2. We had previously shown that MG517 in Mycoplasma genitalium is a GT-A family GT2 membrane-associated glycolipid synthase. We present here a series of structural models of MG517 obtained by homology modeling following a multiple-template approach. The models have been validated by mutational analysis and refined by long scale molecular dynamics simulations. Based on the models, key structure-function relationships have been identified: The N-terminal GT domain has a GT-A topology that includes a non-conserved variable region involved in acceptor substrate binding. Glu193 is proposed as the catalytic base in the GT mechanism, and Asp40, Tyr126, Tyr169, Ile170 and Tyr218 define the substrates binding site. Mutation Y169F increases the enzyme activity and significantly alters the processivity (or sequential transferase activity) of the enzyme. This is the first structural model of a GT-A glycoglycerolipid synthase and provides preliminary insights into structure and function relationships in this family of enzymes. Public Library of Science 2013-12-03 /pmc/articles/PMC3849446/ /pubmed/24312618 http://dx.doi.org/10.1371/journal.pone.0081990 Text en © 2013 Romero-García 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, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Romero-García, Javier Francisco, Carles Biarnés, Xevi Planas, Antoni Structure-Function Features of a Mycoplasma Glycolipid Synthase Derived from Structural Data Integration, Molecular Simulations, and Mutational Analysis |
title | Structure-Function Features of a Mycoplasma Glycolipid Synthase Derived from Structural Data Integration, Molecular Simulations, and Mutational Analysis |
title_full | Structure-Function Features of a Mycoplasma Glycolipid Synthase Derived from Structural Data Integration, Molecular Simulations, and Mutational Analysis |
title_fullStr | Structure-Function Features of a Mycoplasma Glycolipid Synthase Derived from Structural Data Integration, Molecular Simulations, and Mutational Analysis |
title_full_unstemmed | Structure-Function Features of a Mycoplasma Glycolipid Synthase Derived from Structural Data Integration, Molecular Simulations, and Mutational Analysis |
title_short | Structure-Function Features of a Mycoplasma Glycolipid Synthase Derived from Structural Data Integration, Molecular Simulations, and Mutational Analysis |
title_sort | structure-function features of a mycoplasma glycolipid synthase derived from structural data integration, molecular simulations, and mutational analysis |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3849446/ https://www.ncbi.nlm.nih.gov/pubmed/24312618 http://dx.doi.org/10.1371/journal.pone.0081990 |
work_keys_str_mv | AT romerogarciajavier structurefunctionfeaturesofamycoplasmaglycolipidsynthasederivedfromstructuraldataintegrationmolecularsimulationsandmutationalanalysis AT franciscocarles structurefunctionfeaturesofamycoplasmaglycolipidsynthasederivedfromstructuraldataintegrationmolecularsimulationsandmutationalanalysis AT biarnesxevi structurefunctionfeaturesofamycoplasmaglycolipidsynthasederivedfromstructuraldataintegrationmolecularsimulationsandmutationalanalysis AT planasantoni structurefunctionfeaturesofamycoplasmaglycolipidsynthasederivedfromstructuraldataintegrationmolecularsimulationsandmutationalanalysis |