Figure 2

Bile salt synthetic pathways. The enzymatic pathways involved in bile salt synthesis have so far been elucidated only in humans and rodents. The pathway shown is the 'neutral' pathway, as opposed to the 'acidic' pathway that modifies the side-chain before the steroid nucleus [6, 7]. The ultimate production of the default C₂₄ bile acid chenodeoxycholic acid (CDCA) requires multiple changes to the original cholesterol structure including 7α-hydroxylation, isomerization of the C-5 - C-6 double bond (from cholesterol) to form a Δ⁴ compound coupled with oxidation of the 3β-hydroxy group to a 3-oxo group, stereospecific reduction of the 3-oxo group to a 3α-hydroxy group, hydroxylation of the terminal carbon atom of the side-chain, oxidation of the side-chain (to form a C₂₇ bile acid), and shortening of the side-chain. Animals using C₂₇ bile alcohols or C₂₇ bile acids as their primary bile salts presumably require fewer enzymatic steps than those synthesizing C₂₄ bile acids. The enzymes involved in 5α-reduction leading to 5α-bile salts are currently unknown. The stem C₂₇ 5β-bile alcohol would be 3α,7α,27-trihydroxy-5β-cholestan, while the stem C₂₇ 5β-bile acid would be 3α,7α-dihydroxy-5β-cholestan-27-oic acid. Note that some steps in the pathway require more than one enzyme (e.g., isomerization of the 3β-hydroxy group of cholesterol to the 3α configuration), whereas some enzymes (e.g., CYP27A1) can catalyze more than one reaction. Double bonds or additional hydroxyl groups may be added to the nucleus or side-chain, either on an intermediate or on the completed stem bile alcohol or acid.