Structural basis for heterogeneous phenotype of ERG11 dependent Azole resistance in C.albicans clinical isolates

Correlating antifungal Azole drug resistance and mis-sense mutations of ERG11 has been paradoxical in pathogenic yeast Candida albicans. Amino acid substitutions (single or multiple) are frequent on ERG11, a membrane bound enzyme of Ergosterol biosynthesis pathway. Presence or absence of mutations c...

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Main Authors:	Debnath, Surajit, Addya, Soma
Format:	Online
Language:	English
Published:	Springer International Publishing 2014
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4237678/

id	pubmed-4237678
recordtype	oai_dc
spelling	pubmed-42376782014-12-15 Structural basis for heterogeneous phenotype of ERG11 dependent Azole resistance in C.albicans clinical isolates Debnath, Surajit Addya, Soma Research Correlating antifungal Azole drug resistance and mis-sense mutations of ERG11 has been paradoxical in pathogenic yeast Candida albicans. Amino acid substitutions (single or multiple) are frequent on ERG11, a membrane bound enzyme of Ergosterol biosynthesis pathway. Presence or absence of mutations can not sufficiently predict susceptibility. To analyze role of mis-sense mutations on Azole resistance energetically optimized, structurally validated homology model of wild C.albicans ERG11 using eukaryotic template was generated. A Composite Search Approach is proposed to identify vital residues for interaction at 3D active site. Structural analysis of catalytic groove, dynamics of substrate access channels and proximity of Heme prosthetic group characterized ERG11 active site. Several mis-sense mutations of ERG11 reported in C.albicans clinical isolates were selected through a stringent criterion and modeled. ERG11 mutants subsequently subjected to a four tier comparative biophysical analysis. This study indicates (i) critical interactions occur with residues at anterior part of 3D catalytic groove and substitution of these vital residues alters local geometry causing considerable change in catalytic pocket dimension. (ii) Substitutions of vital residues lead to confirmed resistance in clinical isolates that may be resultant to changed geometry of catalytic pocket. (iii)These substitutions also impart significant energetic changes on C.albicans ERG11 and (iv) include detectable dynamic fluctuations on the mutants. (v)Mis-sense mutations on the vital residues of the active site and at the vicinity of Heme prosthetic group are less frequent compared to rest of the enzyme. This large scale mutational study can aid to characterize the mutants in clinical isolates. Springer International Publishing 2014-11-06 /pmc/articles/PMC4237678/ /pubmed/25512882 http://dx.doi.org/10.1186/2193-1801-3-660 Text en © Debnath and Addya; licensee Springer. 2014 This article is published under license to BioMed Central Ltd. 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 work is properly credited.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Debnath, Surajit Addya, Soma
spellingShingle	Debnath, Surajit Addya, Soma Structural basis for heterogeneous phenotype of ERG11 dependent Azole resistance in C.albicans clinical isolates
author_facet	Debnath, Surajit Addya, Soma
author_sort	Debnath, Surajit
title	Structural basis for heterogeneous phenotype of ERG11 dependent Azole resistance in C.albicans clinical isolates
title_short	Structural basis for heterogeneous phenotype of ERG11 dependent Azole resistance in C.albicans clinical isolates
title_full	Structural basis for heterogeneous phenotype of ERG11 dependent Azole resistance in C.albicans clinical isolates
title_fullStr	Structural basis for heterogeneous phenotype of ERG11 dependent Azole resistance in C.albicans clinical isolates
title_full_unstemmed	Structural basis for heterogeneous phenotype of ERG11 dependent Azole resistance in C.albicans clinical isolates
title_sort	structural basis for heterogeneous phenotype of erg11 dependent azole resistance in c.albicans clinical isolates
description	Correlating antifungal Azole drug resistance and mis-sense mutations of ERG11 has been paradoxical in pathogenic yeast Candida albicans. Amino acid substitutions (single or multiple) are frequent on ERG11, a membrane bound enzyme of Ergosterol biosynthesis pathway. Presence or absence of mutations can not sufficiently predict susceptibility. To analyze role of mis-sense mutations on Azole resistance energetically optimized, structurally validated homology model of wild C.albicans ERG11 using eukaryotic template was generated. A Composite Search Approach is proposed to identify vital residues for interaction at 3D active site. Structural analysis of catalytic groove, dynamics of substrate access channels and proximity of Heme prosthetic group characterized ERG11 active site. Several mis-sense mutations of ERG11 reported in C.albicans clinical isolates were selected through a stringent criterion and modeled. ERG11 mutants subsequently subjected to a four tier comparative biophysical analysis. This study indicates (i) critical interactions occur with residues at anterior part of 3D catalytic groove and substitution of these vital residues alters local geometry causing considerable change in catalytic pocket dimension. (ii) Substitutions of vital residues lead to confirmed resistance in clinical isolates that may be resultant to changed geometry of catalytic pocket. (iii)These substitutions also impart significant energetic changes on C.albicans ERG11 and (iv) include detectable dynamic fluctuations on the mutants. (v)Mis-sense mutations on the vital residues of the active site and at the vicinity of Heme prosthetic group are less frequent compared to rest of the enzyme. This large scale mutational study can aid to characterize the mutants in clinical isolates.
publisher	Springer International Publishing
publishDate	2014
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4237678/
_version_	1613158778556907520

Structural basis for heterogeneous phenotype of ERG11 dependent Azole resistance in C.albicans clinical isolates

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