Biochemical and physiological importance of the CYP26 retinoic acid hydroxylases

Abstract

The Cytochrome P450 (CYP) family 26 enzymes contribute to retinoic acid (RA) metabolism and homeostasis in humans, mammals and other chordates. The three CYP26 family enzymes, CYP26A1, CYP26B1 and CYP26C1 have all been shown to metabolize all-trans-retinoic acid (atRA) it's 9-cisRA and 13-cisRA isomers and primary metabolites 4-OH-RA and 4-oxo-RA with high efficiency. While no crystal structures of CYP26 enzymes are available, the binding of various ligands has been extensively explored via homology modeling. All three CYP26 enzymes are inducible by treatment with atRA in various prenatal and postnatal tissues and cell types. However, current literature shows that in addition to regulation by atRA, CYP26 enzyme expression is also regulated by other endogenous processes and inflammatory cytokines. In humans and in animal models the expression patterns of CYP26 enzymes have been shown to be tissue and cell type specific, and the expression of the CYP26 enzymes is believed to regulate the formation of critical atRA concentration gradients in various tissue types. Yet, very little data exists on direct disease associations of altered CYP26 expression or activity. Nevertheless, data is emerging describing a variety of human genetic variations in the CYP26 enzymes that are associated with different pathologies. Interestingly, some of these genetic variants result in increased activity of the CYP26 enzymes potentially leading to complex gene-environment interactions due to variability in dietary intake of retinoids. This review highlights the current knowledge of structure-function of CYP26 enzymes and focuses on their role in human retinoid metabolism in different tissues.

Keywords: Cytochrome P450; Retinoic acid; Structure-function; Vitamin A.

Figure 1.

Metabolic network of vitamin A homeostasis shown with cellular localization of known retinoid metabolizing enzymes. ALDH, aldehyde dehydrogenase; REH, retinyl ester hydrolase; LRAT, lecithin retinol acyltransferase; RDH, retinaldehyde dehydrogenase; AO, aldehyde oxidase; ADH, alcohol dehydrogenase; CRBP, cellular retinol binding protein; CRABP, cellular retinoic acid binding protein. LRAT, RDHs, AO and RDHs function as dimers while ALDH1As function as tetramers and CYP26s as monomers.

Figure 2.

chemical structures of the key retinoids. Numbers shown on 4-oxo-atRA structure represent positions of carbon atoms in all retinoid chemical structures.

Figure 3.

CYP26 enzyme phylogenetic tree constructed with protein sequences. All CYP26 protein sequences were obtained from NCBI protein data base except that human CYP26B1 (*) protein sequence is from published works (Foti, Isoherranen, et al., 2016). Evolutionary analyses were conducted in MEGA X (Kumar et al., 2018). The evolutionary history was inferred using the UPGMA method (Sneath and Sokal, 1973) and the evolutionary distances were computed using the Poisson correction method (Zuckerkandl and Pauling, 1965). CYP26A1 GeneBank accession numbers: NP_000774.2, NP_031837.2, NP_569092.2, RLQ71010.1, AKO62658.1, AAI49356.1, OWK07689.1, NP_571221.2, AHY95171.1, NP_001265772.1, NP_001001129.1, AAI71087.1; CYP26B1 GeneBank accession numbers: AAH59246.1 NP_851601.1, AAQ82596.1, NP_001179722.1, XP_015141554.1, RLQ56656.1, OWK10279.1 NP_001072655.1, PNI38749.1, OWK56765.1; CYP26C1 GeneBank accession numbers: NP_899230.2, OWK58156.1, AAI51107.1, AGN04289.1, AHH39274.1, PNI82309.1, AAI29132.1, RLQ71011.1, PNJ89455.1.

Figure 4.

Protein sequence alignment of human CYP26 enzymes. CYP26A1 (NP_000774.2) and CYP26C1 (NP_899230.2) sequences are from NCBI protein database while CYP26B1 sequence is as previously published work (Foti, Isoherranen, et al., 2016). Hydrophobic residues are shown in black color, hydrophilic residues as green, acidic residues (negatively charged) as red and basic residues (positively charged) as blue. Bar graphs indicate the degree of amino acid conservation. Black boxes indicate sequence regions involved in atRA binding based on homology models as indicated in the text. Amino acids proposed to interact with atRA are indicated by symbols a for CYP26A1, b for CYP26B1, c for CYP26C1 and * for all three CYP26 enzymes. Amino acids which can change due to SNPs (Table 1) are marked by red boxes.