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Identification of 7α,24-dihydroxy-3-oxocholest-4-en-26-oic and 7α,25-dihydroxy-3-oxocholest-4-en-26-oic acids in human cerebrospinal fluid and plasma

Jonas Abdel-Khalik, Peter J. Crick, Eylan Yutuc Orcid Logo, Andrea E. DeBarber, P. Barton Duell, Robert D. Steiner, Ioanna Laina, Yuqin Wang Orcid Logo, William Griffiths Orcid Logo

Biochimie

Swansea University Authors: Eylan Yutuc Orcid Logo, Yuqin Wang Orcid Logo, William Griffiths Orcid Logo

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DOI (Published version): 10.1016/j.biochi.2018.06.020

Abstract

Dihydroxyoxocholestenoic acids are intermediates in bile acid biosynthesis. Here, using liquid chromatography – mass spectrometry, we confirm the identification of 7α,24-dihydroxy-3-oxocholest-4-en-26-oic and 7α,25-dihydroxy-3-oxocholest-4-en-26-oic acids in cerebrospinal fluid (CSF) based on compar...

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Published in: Biochimie
ISSN: 03009084
Published: 2018
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URI: https://cronfa.swan.ac.uk/Record/cronfa40916
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spelling 2018-09-24T12:24:11.2845807 v2 40916 2018-07-03 Identification of 7α,24-dihydroxy-3-oxocholest-4-en-26-oic and 7α,25-dihydroxy-3-oxocholest-4-en-26-oic acids in human cerebrospinal fluid and plasma 99332f073ce913a9b7d8b6441b17516d 0000-0001-9971-1950 Eylan Yutuc Eylan Yutuc true false c92729b58622f9fdf6a0e7d8f4ce5081 0000-0002-3063-3066 Yuqin Wang Yuqin Wang true false 3316b1d1b524be1831790933eed1c26e 0000-0002-4129-6616 William Griffiths William Griffiths true false 2018-07-03 MEDS Dihydroxyoxocholestenoic acids are intermediates in bile acid biosynthesis. Here, using liquid chromatography – mass spectrometry, we confirm the identification of 7α,24-dihydroxy-3-oxocholest-4-en-26-oic and 7α,25-dihydroxy-3-oxocholest-4-en-26-oic acids in cerebrospinal fluid (CSF) based on comparisons to authentic standards and of 7α,12α-dihydroxy-3-oxocholest-4-en-26-oic and 7α,x-dihydroxy-3-oxocholest-4-en-26-oic (where hydroxylation is likely on C-22 or C-23) based on exact mass measurement and multistage fragmentation. Surprisingly, patients suffering from the inborn error of metabolism cerebrotendinous xanthomatosis, where the enzyme CYP27A1, which normally introduces the (25R)26-carboxylic acid group to the sterol side-chain, is defective still synthesise 7α,24-dihydroxy-3-oxocholest-4-en-26-oic acid and also both 25R- and 25S-epimers of 7α,12α-dihydroxy-3-oxocholest-4-en-26-oic acid. We speculate that the enzymes CYP46A1 and CYP3A4 may have C-26 carboxylase activity to generate these acids. In patients suffering from hereditary spastic paraplegia type 5 the CSF concentrations of the 7α,24- and 7α,25-dihydroxy acids are reduced, suggesting an involvement of CYP7B1 in their biosynthesis in brain. Journal Article Biochimie 03009084 oxysterol, hereditary spastic paraplegia type 5, cerebrotendinous xanthomatosis, cytochrome P450, bile acid, brain 31 12 2018 2018-12-31 10.1016/j.biochi.2018.06.020 COLLEGE NANME Medical School COLLEGE CODE MEDS Swansea University RCUK, BB/N015932/1 2018-09-24T12:24:11.2845807 2018-07-03T11:49:37.5983616 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine Jonas Abdel-Khalik 1 Peter J. Crick 2 Eylan Yutuc 0000-0001-9971-1950 3 Andrea E. DeBarber 4 P. Barton Duell 5 Robert D. Steiner 6 Ioanna Laina 7 Yuqin Wang 0000-0002-3063-3066 8 William Griffiths 0000-0002-4129-6616 9 0040916-24092018122131.pdf APCE011.Griffiths.1-s2.0-S0300908418301792-main.pdf 2018-09-24T12:21:31.1430000 Output 3699247 application/pdf Version of Record true 2018-09-24T00:00:00.0000000 Distributed under the terms of a Creative Commons CC-BY 4.0 Licence. true eng
title Identification of 7α,24-dihydroxy-3-oxocholest-4-en-26-oic and 7α,25-dihydroxy-3-oxocholest-4-en-26-oic acids in human cerebrospinal fluid and plasma
spellingShingle Identification of 7α,24-dihydroxy-3-oxocholest-4-en-26-oic and 7α,25-dihydroxy-3-oxocholest-4-en-26-oic acids in human cerebrospinal fluid and plasma
Eylan Yutuc
Yuqin Wang
William Griffiths
title_short Identification of 7α,24-dihydroxy-3-oxocholest-4-en-26-oic and 7α,25-dihydroxy-3-oxocholest-4-en-26-oic acids in human cerebrospinal fluid and plasma
title_full Identification of 7α,24-dihydroxy-3-oxocholest-4-en-26-oic and 7α,25-dihydroxy-3-oxocholest-4-en-26-oic acids in human cerebrospinal fluid and plasma
title_fullStr Identification of 7α,24-dihydroxy-3-oxocholest-4-en-26-oic and 7α,25-dihydroxy-3-oxocholest-4-en-26-oic acids in human cerebrospinal fluid and plasma
title_full_unstemmed Identification of 7α,24-dihydroxy-3-oxocholest-4-en-26-oic and 7α,25-dihydroxy-3-oxocholest-4-en-26-oic acids in human cerebrospinal fluid and plasma
title_sort Identification of 7α,24-dihydroxy-3-oxocholest-4-en-26-oic and 7α,25-dihydroxy-3-oxocholest-4-en-26-oic acids in human cerebrospinal fluid and plasma
author_id_str_mv 99332f073ce913a9b7d8b6441b17516d
c92729b58622f9fdf6a0e7d8f4ce5081
3316b1d1b524be1831790933eed1c26e
author_id_fullname_str_mv 99332f073ce913a9b7d8b6441b17516d_***_Eylan Yutuc
c92729b58622f9fdf6a0e7d8f4ce5081_***_Yuqin Wang
3316b1d1b524be1831790933eed1c26e_***_William Griffiths
author Eylan Yutuc
Yuqin Wang
William Griffiths
author2 Jonas Abdel-Khalik
Peter J. Crick
Eylan Yutuc
Andrea E. DeBarber
P. Barton Duell
Robert D. Steiner
Ioanna Laina
Yuqin Wang
William Griffiths
format Journal article
container_title Biochimie
publishDate 2018
institution Swansea University
issn 03009084
doi_str_mv 10.1016/j.biochi.2018.06.020
college_str Faculty of Medicine, Health and Life Sciences
hierarchytype
hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Medicine{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Medicine
document_store_str 1
active_str 0
description Dihydroxyoxocholestenoic acids are intermediates in bile acid biosynthesis. Here, using liquid chromatography – mass spectrometry, we confirm the identification of 7α,24-dihydroxy-3-oxocholest-4-en-26-oic and 7α,25-dihydroxy-3-oxocholest-4-en-26-oic acids in cerebrospinal fluid (CSF) based on comparisons to authentic standards and of 7α,12α-dihydroxy-3-oxocholest-4-en-26-oic and 7α,x-dihydroxy-3-oxocholest-4-en-26-oic (where hydroxylation is likely on C-22 or C-23) based on exact mass measurement and multistage fragmentation. Surprisingly, patients suffering from the inborn error of metabolism cerebrotendinous xanthomatosis, where the enzyme CYP27A1, which normally introduces the (25R)26-carboxylic acid group to the sterol side-chain, is defective still synthesise 7α,24-dihydroxy-3-oxocholest-4-en-26-oic acid and also both 25R- and 25S-epimers of 7α,12α-dihydroxy-3-oxocholest-4-en-26-oic acid. We speculate that the enzymes CYP46A1 and CYP3A4 may have C-26 carboxylase activity to generate these acids. In patients suffering from hereditary spastic paraplegia type 5 the CSF concentrations of the 7α,24- and 7α,25-dihydroxy acids are reduced, suggesting an involvement of CYP7B1 in their biosynthesis in brain.
published_date 2018-12-31T19:26:46Z
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score 11.04748

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