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Heterogeneous multimeric structure of isocitrate lyase in complex with succinate and itaconate provides novel insights into its inhibitory mechanism

During the glyoxylate cycle, isocitrate lyases (ICLs) catalyze the lysis of isocitrate to glyoxylate and succinate. Itaconate has been reported to inhibit an ICL from Mycobacterium tuberculosis (tbICL). To elucidate the molecular mechanism of ICL inhibition, we determined the crystal structure of tb...

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Autores principales: Kwon, Sunghark, Chun, Hye Lin, Ha, Hyun Ji, Lee, So Yeon, Park, Hyun Ho
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099091/
https://www.ncbi.nlm.nih.gov/pubmed/33951112
http://dx.doi.org/10.1371/journal.pone.0251067
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author Kwon, Sunghark
Chun, Hye Lin
Ha, Hyun Ji
Lee, So Yeon
Park, Hyun Ho
author_facet Kwon, Sunghark
Chun, Hye Lin
Ha, Hyun Ji
Lee, So Yeon
Park, Hyun Ho
author_sort Kwon, Sunghark
collection PubMed
description During the glyoxylate cycle, isocitrate lyases (ICLs) catalyze the lysis of isocitrate to glyoxylate and succinate. Itaconate has been reported to inhibit an ICL from Mycobacterium tuberculosis (tbICL). To elucidate the molecular mechanism of ICL inhibition, we determined the crystal structure of tbICL in complex with itaconate. Unexpectedly, succinate and itaconate were found to bind to the respective active sites in the dimeric form of tbICL. Our structure revealed the active site architecture as an open form, although the substrate and inhibitor were bound to the active sites. Our findings provide novel insights into the conformation of tbICL upon its binding to a substrate or inhibitor, along with molecular details of the inhibitory mechanism of itaconate.
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spelling pubmed-80990912021-05-17 Heterogeneous multimeric structure of isocitrate lyase in complex with succinate and itaconate provides novel insights into its inhibitory mechanism Kwon, Sunghark Chun, Hye Lin Ha, Hyun Ji Lee, So Yeon Park, Hyun Ho PLoS One Research Article During the glyoxylate cycle, isocitrate lyases (ICLs) catalyze the lysis of isocitrate to glyoxylate and succinate. Itaconate has been reported to inhibit an ICL from Mycobacterium tuberculosis (tbICL). To elucidate the molecular mechanism of ICL inhibition, we determined the crystal structure of tbICL in complex with itaconate. Unexpectedly, succinate and itaconate were found to bind to the respective active sites in the dimeric form of tbICL. Our structure revealed the active site architecture as an open form, although the substrate and inhibitor were bound to the active sites. Our findings provide novel insights into the conformation of tbICL upon its binding to a substrate or inhibitor, along with molecular details of the inhibitory mechanism of itaconate. Public Library of Science 2021-05-05 /pmc/articles/PMC8099091/ /pubmed/33951112 http://dx.doi.org/10.1371/journal.pone.0251067 Text en © 2021 Kwon et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://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
Kwon, Sunghark
Chun, Hye Lin
Ha, Hyun Ji
Lee, So Yeon
Park, Hyun Ho
Heterogeneous multimeric structure of isocitrate lyase in complex with succinate and itaconate provides novel insights into its inhibitory mechanism
title Heterogeneous multimeric structure of isocitrate lyase in complex with succinate and itaconate provides novel insights into its inhibitory mechanism
title_full Heterogeneous multimeric structure of isocitrate lyase in complex with succinate and itaconate provides novel insights into its inhibitory mechanism
title_fullStr Heterogeneous multimeric structure of isocitrate lyase in complex with succinate and itaconate provides novel insights into its inhibitory mechanism
title_full_unstemmed Heterogeneous multimeric structure of isocitrate lyase in complex with succinate and itaconate provides novel insights into its inhibitory mechanism
title_short Heterogeneous multimeric structure of isocitrate lyase in complex with succinate and itaconate provides novel insights into its inhibitory mechanism
title_sort heterogeneous multimeric structure of isocitrate lyase in complex with succinate and itaconate provides novel insights into its inhibitory mechanism
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099091/
https://www.ncbi.nlm.nih.gov/pubmed/33951112
http://dx.doi.org/10.1371/journal.pone.0251067
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