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Computational modelling of amino acid exchange and facilitated transport in placental membrane vesicles

Computational modelling of amino acid exchange and facilitated transport in placental membrane vesicles
Computational modelling of amino acid exchange and facilitated transport in placental membrane vesicles
Placental amino acid transport is required for fetal development and impaired transport has been associated with poor fetal growth. It is well known that placental amino acid transport is mediated by a broad array of specific membrane transporters with overlapping substrate specificity. However, it is not fully understood how these transporters function, both individually and as an integrated system. We propose that mathematical modelling could help in further elucidating the underlying mechanisms of how these transporters mediate placental amino acid transport.
The aim of this work is to model the sodium independent transport of serine, which has been assumed to follow an obligatory exchange mechanism. However, previous amino acid uptake experiments in human placental microvillous plasma membrane vesicles have persistently produced results that are seemingly incompatible with such a mechanism; i.e. transport has been observed under zero-trans conditions, in the absence of internal substrates inside the vesicles to drive exchange. This observation raises two alternative hypotheses; (i) either exchange is not fully obligatory, or (ii) exchange is indeed obligatory, but an unforeseen initial concentration of amino acid substrate is present within the vesicle which could drive exchange.
To investigate these possibilities, a mathematical model for tracer uptake was developed based on carrier mediated transport, which can represent either facilitated diffusion or obligatory exchange (also referred to as uniport and antiport mechanisms respectively). In vitro measurements of serine uptake by placental microvillous membrane vesicles were carried out and the model applied to interpret the results based on the measured apparent Michaelis-Menten parameters Km and Vmax. In addition, based on model predictions, a new time series experiment was implemented to distinguish the hypothesised transporter mechanisms. Analysis of the results indicated the presence of a facilitated transport component, while based on the model no evidence for substantial levels of endogenous amino acids within the vesicle was found.
0022-5193
352-364
Pantichob, N.
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Widdows, K.L.
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Crocker, I.P.
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Hanson, Mark A.
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Johnstone, E.D.
354bf081-807b-4ca9-8956-7be1287f834c
Please, C.P.
118dffe7-4b38-4787-a972-9feec535839e
Sibley, C.P.
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Glazier, J.D.
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Lewis, R.M.
caaeb97d-ea69-4f7b-8adb-5fa25e2d3502
Sengers, Bram G.
d6b771b1-4ede-48c5-9644-fa86503941aa
Pantichob, N.
b6ac00e6-f55f-494f-9a7d-ec7cb3933379
Widdows, K.L.
25faab47-b4fc-4837-99fb-fa6b0e15398e
Crocker, I.P.
b8686961-d199-4a28-bd16-bbf71821bd96
Hanson, Mark A.
1952fad1-abc7-4284-a0bc-a7eb31f70a3f
Johnstone, E.D.
354bf081-807b-4ca9-8956-7be1287f834c
Please, C.P.
118dffe7-4b38-4787-a972-9feec535839e
Sibley, C.P.
6e4ffcd0-f4b5-41c4-8360-9d78b9e9156c
Glazier, J.D.
db2aa1ae-5208-4a56-9213-4521128577e1
Lewis, R.M.
caaeb97d-ea69-4f7b-8adb-5fa25e2d3502
Sengers, Bram G.
d6b771b1-4ede-48c5-9644-fa86503941aa

Pantichob, N., Widdows, K.L., Crocker, I.P., Hanson, Mark A., Johnstone, E.D., Please, C.P., Sibley, C.P., Glazier, J.D., Lewis, R.M. and Sengers, Bram G. (2015) Computational modelling of amino acid exchange and facilitated transport in placental membrane vesicles. Journal of Theoretical Biology, 365, 352-364. (doi:10.1016/j.jtbi.2014.10.042).

Record type: Article

Abstract

Placental amino acid transport is required for fetal development and impaired transport has been associated with poor fetal growth. It is well known that placental amino acid transport is mediated by a broad array of specific membrane transporters with overlapping substrate specificity. However, it is not fully understood how these transporters function, both individually and as an integrated system. We propose that mathematical modelling could help in further elucidating the underlying mechanisms of how these transporters mediate placental amino acid transport.
The aim of this work is to model the sodium independent transport of serine, which has been assumed to follow an obligatory exchange mechanism. However, previous amino acid uptake experiments in human placental microvillous plasma membrane vesicles have persistently produced results that are seemingly incompatible with such a mechanism; i.e. transport has been observed under zero-trans conditions, in the absence of internal substrates inside the vesicles to drive exchange. This observation raises two alternative hypotheses; (i) either exchange is not fully obligatory, or (ii) exchange is indeed obligatory, but an unforeseen initial concentration of amino acid substrate is present within the vesicle which could drive exchange.
To investigate these possibilities, a mathematical model for tracer uptake was developed based on carrier mediated transport, which can represent either facilitated diffusion or obligatory exchange (also referred to as uniport and antiport mechanisms respectively). In vitro measurements of serine uptake by placental microvillous membrane vesicles were carried out and the model applied to interpret the results based on the measured apparent Michaelis-Menten parameters Km and Vmax. In addition, based on model predictions, a new time series experiment was implemented to distinguish the hypothesised transporter mechanisms. Analysis of the results indicated the presence of a facilitated transport component, while based on the model no evidence for substantial levels of endogenous amino acids within the vesicle was found.

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e-pub ahead of print date: 22 November 2014
Published date: 21 January 2015
Organisations: Faculty of Medicine, Faculty of Engineering and the Environment

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Local EPrints ID: 372066
URI: http://eprints.soton.ac.uk/id/eprint/372066
ISSN: 0022-5193
PURE UUID: f47331dd-e020-4559-a9b3-63fc7bc8effa
ORCID for Mark A. Hanson: ORCID iD orcid.org/0000-0002-6907-613X
ORCID for R.M. Lewis: ORCID iD orcid.org/0000-0003-4044-9104
ORCID for Bram G. Sengers: ORCID iD orcid.org/0000-0001-5859-6984

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Date deposited: 26 Nov 2014 15:02
Last modified: 18 Feb 2021 17:07

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Contributors

Author: N. Pantichob
Author: K.L. Widdows
Author: I.P. Crocker
Author: Mark A. Hanson ORCID iD
Author: E.D. Johnstone
Author: C.P. Please
Author: C.P. Sibley
Author: J.D. Glazier
Author: R.M. Lewis ORCID iD
Author: Bram G. Sengers ORCID iD

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