Aldehyde Oxidase Contributes to All-Trans-Retinoic Acid Biosynthesis in Human Liver

Area of Science:

• Biochemistry and Molecular Biology
• Hepatology
• Nutritional Biochemistry

Background:

• All-trans-retinoic acid (atRA) is a crucial signaling molecule derived from vitamin A.
• Aldehyde dehydrogenase 1A1 (ALDH1A1) is the primary enzyme for atRA synthesis from retinaldehyde.
• The potential contribution of aldehyde oxidase (AOX) to atRA biosynthesis remained unclear.

Purpose of the Study:

• To investigate the role of aldehyde oxidase (AOX) in all-trans-retinoic acid (atRA) formation in human liver.
• To quantify the relative contributions of AOX and ALDH1A1 to hepatic atRA biosynthesis.

Main Methods:

• In vitro enzymatic assays using human recombinant AOX and human liver S9 fractions.
• Enzyme kinetics (K_m, k_cat) and inhibition studies with specific enzyme inhibitors.
• Quantification of AOX and ALDH1A1 protein expression using LC-MS/MS.

Main Results:

• Human recombinant AOX demonstrated the capacity to convert retinaldehyde to atRA.
• AOX and ALDH1A1 were identified as key enzymes in human liver atRA formation, with AOX contributing 20%-50%.
• ALDH1A1 functions as a high-affinity, low-capacity enzyme, while AOX acts as a low-affinity, high-capacity enzyme.

Conclusions:

• Both AOX and ALDH1A1 significantly contribute to hepatic all-trans-retinoic acid (atRA) biosynthesis.
• AOX plays a vital role in regulating vitamin A homeostasis, especially under conditions of ALDH1A1 dysfunction or vitamin A excess.
• Modulation of AOX activity could impact hepatic atRA levels and signaling pathways.