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, Andrea E. DeBarber, P. Barton Duell, Robert D. Steiner, Ioanna Laina, Yuqin Wang, William J. Griffiths

Research output: Contribution to journalArticle

6 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)86-98
Number of pages13
JournalBiochimie
Volume153
DOIs
StatePublished - Oct 2018

Keywords

  • Bile acid
  • Brain
  • Cerebrotendinous xanthomatosis
  • Cytochrome P450
  • Hereditary spastic paraplegia type 5
  • Oxysterol

ASJC Scopus subject areas

  • Biochemistry

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