4.7 Article

CRABPs Alter all-trans-Retinoic Acid Metabolism by CYP26A1 via Protein-Protein Interactions

Journal

NUTRIENTS
Volume 14, Issue 9, Pages -

Publisher

MDPI
DOI: 10.3390/nu14091784

Keywords

cellular retinoic acid binding protein; fatty acid-binding protein; cytochrome P450 26; all-trans-retinoic acid; vitamin A metabolism; protein-protein interactions; free drug hypothesis

Funding

  1. National Institutes of Health [R01GM111772, T32 GM007750]

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Cellular retinoic acid binding proteins (CRABP1 and CRABP2) have a high affinity for all-trans-retinoic acid (atRA), and bind to atRA-clearing enzymes and nuclear receptors. This study shows that CRABP1 and CRABP2 also impact atRA metabolism by CYP26A1, suggesting their critical role in modulating atRA concentrations.
Cellular retinoic acid binding proteins (CRABP1 and CRABP2) bind all-trans-retinoic acid (atRA), the active metabolite of vitamin A, with high affinity. CRABP1 and CRABP2 have been shown to interact with the atRA-clearing cytochrome P450 enzymes CYP26B1 and CYP26C1 and with nuclear retinoic acid receptors (RARs). We hypothesized that CRABP1 and CRABP2 also alter atRA metabolism and clearance by CYP26A1, the third key atRA-metabolizing enzyme in the CYP26 family. Based on stopped-flow experiments, atRA bound CRABP1 and CRABP2 with K-d values of 4.7 nM and 7.6 nM, respectively. The unbound atRA K-m values for 4-OH-atRA formation by CYP26A1 were 4.7 +/- 0.8 nM with atRA, 6.8 +/- 1.7 nM with holo-CRABP1 and 6.1 +/- 2.7 nM with holo-CRABP2 as a substrate. In comparison, the apparent k(cat) value was about 30% lower (0.71 +/- 0.07 min(-1) for holo-CRABP1 and 0.75 +/- 0.09 min(-1) for holo-CRABP2) in the presence of CRABPs than with free atRA (1.07 +/- 0.08 min(-1)). In addition, increasing concentrations in apo-CRABPs decreased the 4-OH-atRA formation rates by CYP26A1. Kinetic analyses suggest that apo-CRABP1 and apo-CRABP2 inhibit CYP26A1 (K-i = 0.39 nM and 0.53 nM, respectively) and holo-CRABPs channel atRA for metabolism by CYP26A1. These data suggest that CRABPs play a critical role in modulating atRA metabolism and cellular atRA concentrations.

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