Enhancing human spermine synthase activity by engineered mutations.

Spermine synthase (SMS) is an enzyme which function is to convert spermidine into spermine. It was shown that gene defects resulting in amino acid changes of the wild type SMS cause Snyder-Robinson syndrome, which is a mild-to-moderate mental disability associated with osteoporosis, facial asymmetry...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Zhe Zhang, Yueli Zheng, Margo Petukh, Anthony Pegg, Yoshihiko Ikeguchi, Emil Alexov
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/d392bb2700c147568b12dea3d086815a
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:d392bb2700c147568b12dea3d086815a
record_format	dspace
spelling	oai:doaj.org-article:d392bb2700c147568b12dea3d086815a2021-11-18T05:52:25ZEnhancing human spermine synthase activity by engineered mutations.1553-734X1553-735810.1371/journal.pcbi.1002924https://doaj.org/article/d392bb2700c147568b12dea3d086815a2013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23468611/?tool=EBIhttps://doaj.org/toc/1553-734Xhttps://doaj.org/toc/1553-7358Spermine synthase (SMS) is an enzyme which function is to convert spermidine into spermine. It was shown that gene defects resulting in amino acid changes of the wild type SMS cause Snyder-Robinson syndrome, which is a mild-to-moderate mental disability associated with osteoporosis, facial asymmetry, thin habitus, hypotonia, and a nonspecific movement disorder. These disease-causing missense mutations were demonstrated, both in silico and in vitro, to affect the wild type function of SMS by either destabilizing the SMS dimer/monomer or directly affecting the hydrogen bond network of the active site of SMS. In contrast to these studies, here we report an artificial engineering of a more efficient SMS variant by transferring sequence information from another organism. It is confirmed experimentally that the variant, bearing four amino acid substitutions, is catalytically more active than the wild type. The increased functionality is attributed to enhanced monomer stability, lowering the pKa of proton donor catalytic residue, optimized spatial distribution of the electrostatic potential around the SMS with respect to substrates, and increase of the frequency of mechanical vibration of the clefts presumed to be the gates toward the active sites. The study demonstrates that wild type SMS is not particularly evolutionarily optimized with respect to the reaction spermidine → spermine. Having in mind that currently there are no variations (non-synonymous single nucleotide polymorphism, nsSNP) detected in healthy individuals, it can be speculated that the human SMS function is precisely tuned toward its wild type and any deviation is unwanted and disease-causing.Zhe ZhangYueli ZhengMargo PetukhAnthony PeggYoshihiko IkeguchiEmil AlexovPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Computational Biology, Vol 9, Iss 2, p e1002924 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Zhe Zhang Yueli Zheng Margo Petukh Anthony Pegg Yoshihiko Ikeguchi Emil Alexov Enhancing human spermine synthase activity by engineered mutations.
description	Spermine synthase (SMS) is an enzyme which function is to convert spermidine into spermine. It was shown that gene defects resulting in amino acid changes of the wild type SMS cause Snyder-Robinson syndrome, which is a mild-to-moderate mental disability associated with osteoporosis, facial asymmetry, thin habitus, hypotonia, and a nonspecific movement disorder. These disease-causing missense mutations were demonstrated, both in silico and in vitro, to affect the wild type function of SMS by either destabilizing the SMS dimer/monomer or directly affecting the hydrogen bond network of the active site of SMS. In contrast to these studies, here we report an artificial engineering of a more efficient SMS variant by transferring sequence information from another organism. It is confirmed experimentally that the variant, bearing four amino acid substitutions, is catalytically more active than the wild type. The increased functionality is attributed to enhanced monomer stability, lowering the pKa of proton donor catalytic residue, optimized spatial distribution of the electrostatic potential around the SMS with respect to substrates, and increase of the frequency of mechanical vibration of the clefts presumed to be the gates toward the active sites. The study demonstrates that wild type SMS is not particularly evolutionarily optimized with respect to the reaction spermidine → spermine. Having in mind that currently there are no variations (non-synonymous single nucleotide polymorphism, nsSNP) detected in healthy individuals, it can be speculated that the human SMS function is precisely tuned toward its wild type and any deviation is unwanted and disease-causing.
format	article
author	Zhe Zhang Yueli Zheng Margo Petukh Anthony Pegg Yoshihiko Ikeguchi Emil Alexov
author_facet	Zhe Zhang Yueli Zheng Margo Petukh Anthony Pegg Yoshihiko Ikeguchi Emil Alexov
author_sort	Zhe Zhang
title	Enhancing human spermine synthase activity by engineered mutations.
title_short	Enhancing human spermine synthase activity by engineered mutations.
title_full	Enhancing human spermine synthase activity by engineered mutations.
title_fullStr	Enhancing human spermine synthase activity by engineered mutations.
title_full_unstemmed	Enhancing human spermine synthase activity by engineered mutations.
title_sort	enhancing human spermine synthase activity by engineered mutations.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/d392bb2700c147568b12dea3d086815a
work_keys_str_mv	AT zhezhang enhancinghumansperminesynthaseactivitybyengineeredmutations AT yuelizheng enhancinghumansperminesynthaseactivitybyengineeredmutations AT margopetukh enhancinghumansperminesynthaseactivitybyengineeredmutations AT anthonypegg enhancinghumansperminesynthaseactivitybyengineeredmutations AT yoshihikoikeguchi enhancinghumansperminesynthaseactivitybyengineeredmutations AT emilalexov enhancinghumansperminesynthaseactivitybyengineeredmutations
_version_	1718424757320286208

Enhancing human spermine synthase activity by engineered mutations.

Ejemplares similares