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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
Online Access: Check full text

URI: https://cronfa.swan.ac.uk/Record/cronfa40916
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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 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.
Keywords: oxysterol, hereditary spastic paraplegia type 5, cerebrotendinous xanthomatosis, cytochrome P450, bile acid, brain
College: Faculty of Medicine, Health and Life Sciences

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