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

Autor: Jonas, Abdel-Khalik, Peter J, Crick, Eylan, Yutuc, Andrea E, DeBarber, P Barton, Duell, Robert D, Steiner, Ioanna, Laina, Yuqin, Wang, William J, Griffiths
Rok vydání: 2018
Předmět:
Zdroj: Biochimie
ISSN: 1638-6183
Popis: 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.
Graphical abstract Image 1
Highlights • Dihydroxy-3-oxocholest-5-en-26-oic are found in human CSF and plasma. • Hydroxy groups may be at 7α,24, 7α,25, or 7α,12α. • Another acid is hydroxylated at 7α and in the side-chain probably at C-22 or C-23. • In patients with CTX acids with 25 R or 25 S stereochemistry are found. • In patients with SPG5 the concentrations of acids in CSF are reduced.
Databáze: OpenAIRE
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