Structural insights into E. coli porphobilinogen deaminase during synthesis and exit of 1-hydroxymethylbilane.

Porphobilinogen deaminase (PBGD) catalyzes the formation of 1-hydroxymethylbilane (HMB), a crucial intermediate in tetrapyrrole biosynthesis, through a step-wise polymerization of four molecules of porphobilinogen (PBG), using a unique dipyrromethane (DPM) cofactor. Structural and biochemical studie...

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Autores principales:	Navneet Bung, Meenakshi Pradhan, Harini Srinivasan, Gopalakrishnan Bulusu
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2014
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/c8c9168196824c70b45fefa530f6d593
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spelling	oai:doaj.org-article:c8c9168196824c70b45fefa530f6d5932021-11-18T05:53:06ZStructural insights into E. coli porphobilinogen deaminase during synthesis and exit of 1-hydroxymethylbilane.1553-734X1553-735810.1371/journal.pcbi.1003484https://doaj.org/article/c8c9168196824c70b45fefa530f6d5932014-03-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24603363/?tool=EBIhttps://doaj.org/toc/1553-734Xhttps://doaj.org/toc/1553-7358Porphobilinogen deaminase (PBGD) catalyzes the formation of 1-hydroxymethylbilane (HMB), a crucial intermediate in tetrapyrrole biosynthesis, through a step-wise polymerization of four molecules of porphobilinogen (PBG), using a unique dipyrromethane (DPM) cofactor. Structural and biochemical studies have suggested residues with catalytic importance, but their specific role in the mechanism and the dynamic behavior of the protein with respect to the growing pyrrole chain remains unknown. Molecular dynamics simulations of the protein through the different stages of pyrrole chain elongation suggested that the compactness of the overall protein decreases progressively with addition of each pyrrole ring. Essential dynamics showed that domains move apart while the cofactor turn region moves towards the second domain, thus creating space for the pyrrole rings added at each stage. Residues of the flexible active site loop play a significant role in its modulation. Steered molecular dynamics was performed to predict the exit mechanism of HMB from PBGD at the end of the catalytic cycle. Based on the force profile and minimal structural changes the proposed path for the exit of HMB is through the space between the domains flanking the active site loop. Residues reported as catalytically important, also play an important role in the exit of HMB. Further, upon removal of HMB, the structure of PBGD gradually relaxes to resemble its initial stage structure, indicating its readiness to resume a new catalytic cycle.Navneet BungMeenakshi PradhanHarini SrinivasanGopalakrishnan BulusuPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Computational Biology, Vol 10, Iss 3, p e1003484 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Navneet Bung Meenakshi Pradhan Harini Srinivasan Gopalakrishnan Bulusu Structural insights into E. coli porphobilinogen deaminase during synthesis and exit of 1-hydroxymethylbilane.
description	Porphobilinogen deaminase (PBGD) catalyzes the formation of 1-hydroxymethylbilane (HMB), a crucial intermediate in tetrapyrrole biosynthesis, through a step-wise polymerization of four molecules of porphobilinogen (PBG), using a unique dipyrromethane (DPM) cofactor. Structural and biochemical studies have suggested residues with catalytic importance, but their specific role in the mechanism and the dynamic behavior of the protein with respect to the growing pyrrole chain remains unknown. Molecular dynamics simulations of the protein through the different stages of pyrrole chain elongation suggested that the compactness of the overall protein decreases progressively with addition of each pyrrole ring. Essential dynamics showed that domains move apart while the cofactor turn region moves towards the second domain, thus creating space for the pyrrole rings added at each stage. Residues of the flexible active site loop play a significant role in its modulation. Steered molecular dynamics was performed to predict the exit mechanism of HMB from PBGD at the end of the catalytic cycle. Based on the force profile and minimal structural changes the proposed path for the exit of HMB is through the space between the domains flanking the active site loop. Residues reported as catalytically important, also play an important role in the exit of HMB. Further, upon removal of HMB, the structure of PBGD gradually relaxes to resemble its initial stage structure, indicating its readiness to resume a new catalytic cycle.
format	article
author	Navneet Bung Meenakshi Pradhan Harini Srinivasan Gopalakrishnan Bulusu
author_facet	Navneet Bung Meenakshi Pradhan Harini Srinivasan Gopalakrishnan Bulusu
author_sort	Navneet Bung
title	Structural insights into E. coli porphobilinogen deaminase during synthesis and exit of 1-hydroxymethylbilane.
title_short	Structural insights into E. coli porphobilinogen deaminase during synthesis and exit of 1-hydroxymethylbilane.
title_full	Structural insights into E. coli porphobilinogen deaminase during synthesis and exit of 1-hydroxymethylbilane.
title_fullStr	Structural insights into E. coli porphobilinogen deaminase during synthesis and exit of 1-hydroxymethylbilane.
title_full_unstemmed	Structural insights into E. coli porphobilinogen deaminase during synthesis and exit of 1-hydroxymethylbilane.
title_sort	structural insights into e. coli porphobilinogen deaminase during synthesis and exit of 1-hydroxymethylbilane.
publisher	Public Library of Science (PLoS)
publishDate	2014
url	https://doaj.org/article/c8c9168196824c70b45fefa530f6d593
work_keys_str_mv	AT navneetbung structuralinsightsintoecoliporphobilinogendeaminaseduringsynthesisandexitof1hydroxymethylbilane AT meenakshipradhan structuralinsightsintoecoliporphobilinogendeaminaseduringsynthesisandexitof1hydroxymethylbilane AT harinisrinivasan structuralinsightsintoecoliporphobilinogendeaminaseduringsynthesisandexitof1hydroxymethylbilane AT gopalakrishnanbulusu structuralinsightsintoecoliporphobilinogendeaminaseduringsynthesisandexitof1hydroxymethylbilane
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Structural insights into E. coli porphobilinogen deaminase during synthesis and exit of 1-hydroxymethylbilane.

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