Intrinsic dynamic behavior of enzyme:substrate complexes govern the catalytic action of β-galactosidases across clan GH-A

Abstract The conformational itineraries taken by carbohydrate residues in the catalytic subsite of retaining glycoside hydrolases (GHs), harness the link between substrate conformation and reactivity. GHs’ active sites may be described as a combination of subsites dedicated to the binding of individ...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Rajender Kumar, Bernard Henrissat, Pedro M. Coutinho
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2019
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/90cf090af64a42b2af026657e6b93396
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:90cf090af64a42b2af026657e6b93396
record_format	dspace
spelling	oai:doaj.org-article:90cf090af64a42b2af026657e6b933962021-12-02T15:08:07ZIntrinsic dynamic behavior of enzyme:substrate complexes govern the catalytic action of β-galactosidases across clan GH-A10.1038/s41598-019-46589-82045-2322https://doaj.org/article/90cf090af64a42b2af026657e6b933962019-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-019-46589-8https://doaj.org/toc/2045-2322Abstract The conformational itineraries taken by carbohydrate residues in the catalytic subsite of retaining glycoside hydrolases (GHs), harness the link between substrate conformation and reactivity. GHs’ active sites may be described as a combination of subsites dedicated to the binding of individual sugar residues and to catalysis. The three-dimensional structure of GH:carbohydrate complexes has demonstrated that carbohydrate ring conformation changes in an ordered manner during catalysis. Here we demonstrate in silico that a link exists between subsite binding dynamics and substrate specificity for β-galactosidases from clan GH-A families GH1, GH2, GH35, GH42 and GH59. Different oligosaccharides were docked in the active site of reference β-galactosidase structures using Vina-Carb. Subsequent molecular dynamics (MD) simulations revealed that these enzymes favor a high degree of flexibility and ring distortion of the substrate the lytic subsite −1. Although the β-galactosidase families examined are structurally and mechanistically related, distinct patterns of ring distortion were unveiled for the different families. For β-galactosidases, three different family-dependent reaction itineraries (1 S 3 → 4 H 3 ‡ → 4 C 1, 1,4 B → 4 H 3 / 4 E ‡ → 4 C 1, and 1 S 5 → 4 E/ 4 H 5 ‡ → 4 C 1) were identified, all compatible with the antiperiplanar lone pair hypothesis (ALPH) for the hydrolysis of β-glycosides. This comparative study reveals the fuzzy character of the changes in carbohydrate ring geometry prior to carbohydrate hydrolysis.Rajender KumarBernard HenrissatPedro M. CoutinhoNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 9, Iss 1, Pp 1-14 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Rajender Kumar Bernard Henrissat Pedro M. Coutinho Intrinsic dynamic behavior of enzyme:substrate complexes govern the catalytic action of β-galactosidases across clan GH-A
description	Abstract The conformational itineraries taken by carbohydrate residues in the catalytic subsite of retaining glycoside hydrolases (GHs), harness the link between substrate conformation and reactivity. GHs’ active sites may be described as a combination of subsites dedicated to the binding of individual sugar residues and to catalysis. The three-dimensional structure of GH:carbohydrate complexes has demonstrated that carbohydrate ring conformation changes in an ordered manner during catalysis. Here we demonstrate in silico that a link exists between subsite binding dynamics and substrate specificity for β-galactosidases from clan GH-A families GH1, GH2, GH35, GH42 and GH59. Different oligosaccharides were docked in the active site of reference β-galactosidase structures using Vina-Carb. Subsequent molecular dynamics (MD) simulations revealed that these enzymes favor a high degree of flexibility and ring distortion of the substrate the lytic subsite −1. Although the β-galactosidase families examined are structurally and mechanistically related, distinct patterns of ring distortion were unveiled for the different families. For β-galactosidases, three different family-dependent reaction itineraries (1 S 3 → 4 H 3 ‡ → 4 C 1, 1,4 B → 4 H 3 / 4 E ‡ → 4 C 1, and 1 S 5 → 4 E/ 4 H 5 ‡ → 4 C 1) were identified, all compatible with the antiperiplanar lone pair hypothesis (ALPH) for the hydrolysis of β-glycosides. This comparative study reveals the fuzzy character of the changes in carbohydrate ring geometry prior to carbohydrate hydrolysis.
format	article
author	Rajender Kumar Bernard Henrissat Pedro M. Coutinho
author_facet	Rajender Kumar Bernard Henrissat Pedro M. Coutinho
author_sort	Rajender Kumar
title	Intrinsic dynamic behavior of enzyme:substrate complexes govern the catalytic action of β-galactosidases across clan GH-A
title_short	Intrinsic dynamic behavior of enzyme:substrate complexes govern the catalytic action of β-galactosidases across clan GH-A
title_full	Intrinsic dynamic behavior of enzyme:substrate complexes govern the catalytic action of β-galactosidases across clan GH-A
title_fullStr	Intrinsic dynamic behavior of enzyme:substrate complexes govern the catalytic action of β-galactosidases across clan GH-A
title_full_unstemmed	Intrinsic dynamic behavior of enzyme:substrate complexes govern the catalytic action of β-galactosidases across clan GH-A
title_sort	intrinsic dynamic behavior of enzyme:substrate complexes govern the catalytic action of β-galactosidases across clan gh-a
publisher	Nature Portfolio
publishDate	2019
url	https://doaj.org/article/90cf090af64a42b2af026657e6b93396
work_keys_str_mv	AT rajenderkumar intrinsicdynamicbehaviorofenzymesubstratecomplexesgovernthecatalyticactionofbgalactosidasesacrossclangha AT bernardhenrissat intrinsicdynamicbehaviorofenzymesubstratecomplexesgovernthecatalyticactionofbgalactosidasesacrossclangha AT pedromcoutinho intrinsicdynamicbehaviorofenzymesubstratecomplexesgovernthecatalyticactionofbgalactosidasesacrossclangha
_version_	1718388263460274176

Intrinsic dynamic behavior of enzyme:substrate complexes govern the catalytic action of β-galactosidases across clan GH-A

Ejemplares similares