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 (25 R)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 25 R- and 25 S-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.
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Authors | Jonas Abdel-Khalik, Peter J Crick, Eylan Yutuc, Andrea E DeBarber, P Barton Duell, Robert D Steiner, Ioanna Laina, Yuqin Wang, William J Griffiths |
Journal | Biochimie
(Biochimie)
Vol. 153
Pg. 86-98
(Oct 2018)
ISSN: 1638-6183 [Electronic] France |
PMID | 29960034
(Publication Type: Journal Article)
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Copyright | Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved. |
Chemical References |
- Bile Acids and Salts
- Cholestenes
- CYP27A1 protein, human
- Cholestanetriol 26-Monooxygenase
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Topics |
- Bile Acids and Salts
(biosynthesis)
- Cholestanetriol 26-Monooxygenase
(metabolism)
- Cholestenes
(blood, cerebrospinal fluid, chemistry, standards)
- Chromatography, Liquid
- Humans
- Hydroxylation
- Mass Spectrometry
- Spastic Paraplegia, Hereditary
(blood, cerebrospinal fluid)
- Stereoisomerism
- Xanthomatosis, Cerebrotendinous
(blood, cerebrospinal fluid)
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