Physiological insights into all-trans-retinoic acid biosynthesis

Area of Science:

• Biochemistry
• Molecular Biology
• Physiology

Background:

• All-trans-retinoic acid (atRA) is essential for numerous biological systems and processes.
• Historically, research focused on atRA's role in epithelial differentiation, cancer, and embryogenesis.
• Recent interest highlights atRA's function in the nervous and immune systems, energy balance, and obesity, particularly postnatal functions.

Purpose of the Study:

• To review the biochemical and genetic data identifying key enzymes in all-trans-retinoic acid biosynthesis.
• To elucidate the complex interactions between retinoid-binding proteins and enzymes in regulating atRA production.
• To discuss the physiological significance of specific enzymes in atRA-mediated biological processes.

Main Methods:

• Review of biochemical, physiological, and genetic data.
• Identification of key enzymes: retinol dehydrogenases (RDH1, RDH10, DHRS9) and retinal dehydrogenases (RALDH1, RALDH2, RALDH3).
• Analysis of the role of retinoid-binding proteins, such as CRBP1, in modulating substrate availability.

Main Results:

• RDH enzymes catalyze the first step, and RALDH enzymes catalyze the second, irreversible step of atRA biosynthesis.
• Specific enzymes are linked to distinct atRA-mediated biological processes, with limited redundancy.
• A model of enzyme and retinoid-binding protein interactions, including feedback regulation, is supported by cumulative data.

Conclusions:

• Physiological atRA biosynthesis is a regulated process involving complex interactions of enzymes and binding proteins.
• The apo-CRBP1/holo-CRBP1 ratio influences retinol flux, impacting substrate availability for atRA synthesis.
• atRA biosynthesis requires both RDH and RALDH enzymes; the absence of a single isozyme does not necessarily abolish atRA production at a given site.