Biological synthesis of ursodeoxycholic acid

Abstract

Ursodeoxycholic acid (UDCA) is a fundamental treatment drug for numerous hepatobiliary diseases that also has adjuvant therapeutic effects on certain cancers and neurological diseases. Chemical UDCA synthesis is environmentally unfriendly with low yields. Biological UDCA synthesis by free-enzyme catalysis or whole-cell synthesis using inexpensive and readily available chenodeoxycholic acid (CDCA), cholic acid (CA), or lithocholic acid (LCA) as substrates is being developed. The free enzyme-catalyzed one-pot, one-step/two-step method uses hydroxysteroid dehydrogenase (HSDH); whole-cell synthesis, mainly uses engineered bacteria (mainly Escherichia coli) expressing the relevant HSDHs. To further develop these methods, HSDHs with specific coenzyme dependence, high enzyme activity, good stability, and high substrate loading concentration, P450 monooxygenase with C-7 hydroxylation activity and engineered strain harboring HSDHs must be exploited.

High Enantioselective and Large-Scale Production of Ursodeoxycholic Acid by Combination of Pd- and Hydroxysteroid Dehydrogenase-Catalyzed Hydrogenation

“…Previous reports have identified two main categories of synthetic methods for UDCA. − The first category comprises chemical synthesis, , chemoenzymatic synthesis, − and biological conversion . These methods utilize animal-sourced materials obtained from the bile of domestic animals, including cholic, lithocholic, and chenodeoxycholic acids, as starting materials.…”

Dietary polyphenols maintain homeostasis via regulating bile acid metabolism: a review of possible mechanisms

“…12 CDCA is converted to lithocholic acid (LCA), while CA is converted to deoxycholic acid (DCA). 16 Primary BAs (T-/G-CA/CDCA) and secondary BAs (DCA and LCA) can be converted into oxycholic acid analogs by hydroxysteroid dehydrogenase (HSDH) produced by Clostridium clusters XIVa IV (i.e., C. scindens, C. hiranonis, and C. hylemonae) and XI. [17][18][19] Secondary BAs also include secondary conjugated BAs and secondary unconjugated BAs.…”

“…1,12 Furthermore, certain secondary BAs, which are transformed by intestinal flora, may not be effectively reabsorbed and are excreted in feces. 3,4 This can potentially stimulate increased BA biosyn- 16 (D) The predicted binding position of kaempferol with mouse FXR. 18 Food & Function Review thesis in the liver, thereby resulting in enhanced cholesterol utilization and excretion.…”

“…The oxygen atom is red and the hydrogen atom is white in color. The green line indicates the hydrogen bond interaction 16. (D) The predicted binding position of kaempferol with mouse FXR 18.…”

Not exclusively the activity, but the sweet spot: a dehydrogenase point mutation synergistically boosts activity, substrate tolerance, thermal stability and yield

“…It catalyzes the redox reaction of bile acids to convert primary bile acids into secondary bile acids. [11][12][13][14] For example, it catalyzes the conversion of chenodeoxycholic acid (CDCA) into 7-ketolithocholic acid (7-KLCA), a key intermediate for production of ursodeoxycholic acid (UDCA), thereby participating in regulation of the composition and concentration of bile acids. 15 11β-HSDHs play a critical part in the metabolic regulation of corticosteroid hormones.…”