Functions, Therapeutic Applications, and Synthesis of Retinoids and Carotenoids

Álvarez, Rosana; Vaz, Belén; Gronemeyer, Hinrich; Lera, Ángel R. de

doi:10.1021/cr400126u

Cited by 196 publications

(194 citation statements)

References 890 publications

(1,334 reference statements)

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“…The specific programs can be activated by RARA (neuronal) and RARG (endodermal)-selective retinoids (Alvarez et al 2014), which both activate the common program (Fig. 5E).…”

Section: Ra Induces Modular Gene Programs In Committed Ec Cellsmentioning

confidence: 99%

“…The complexity of the RA signaling is largely increased by the expression of three RXR and three RAR isotypes (alpha, beta, and gamma), as each RAR/RXR combination could regulate cognate gene programs (Chiba et al 1997). Interestingly, particular isotype-selective RAR ligands (Alvarez et al 2014) induced specific cell fate transitions: F9 cells show similar morphological cell differentiation phenotypes when treated with RA or the RARG-selective ligand BMS961, but not with the RARA-selective ligand BMS753. In contrast, in P19 cells BMS753 and RA induce the same morphological differentiation, while BMS961 has no such effect (Taneja et al 1996).…”

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confidence: 99%

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Reconstructed cell fate–regulatory programs in stem cells reveal hierarchies and key factors of neurogenesis

Mendoza-Parra¹,

Malysheva²,

Saleem³

et al. 2016

Genome Res.

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Cell lineages, which shape the body architecture and specify cell functions, derive from the integration of a plethora of cell intrinsic and extrinsic signals. These signals trigger a multiplicity of decisions at several levels to modulate the activity of dynamic gene regulatory networks (GRNs), which ensure both general and cell-specific functions within a given lineage, thereby establishing cell fates. Significant knowledge about these events and the involved key drivers comes from homogeneous cell differentiation models. Even a single chemical trigger, such as the morphogen all-trans retinoic acid (RA), can induce the complex network of gene-regulatory decisions that matures a stem/precursor cell to a particular step within a given lineage. Here we have dissected the GRNs involved in the RA-induced neuronal or endodermal cell fate specification by integrating dynamic RXRA binding, chromatin accessibility, epigenetic promoter epigenetic status, and the transcriptional activity inferred from RNA polymerase II mapping and transcription profiling. Our data reveal how RA induces a network of transcription factors (TFs), which direct the temporal organization of cognate GRNs, thereby driving neuronal/endodermal cell fate specification. Modeling signal transduction propagation using the reconstructed GRNs indicated critical TFs for neuronal cell fate specification, which were confirmed by CRISPR/Cas9-mediated genome editing. Overall, this study demonstrates that a systems view of cell fate specification combined with computational signal transduction models provides the necessary insight in cellular plasticity for cell fate engineering. The present integrated approach can be used to monitor the in vitro capacity of (engineered) cells/tissues to establish cell lineages for regenerative medicine.

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“…The specific programs can be activated by RARA (neuronal) and RARG (endodermal)-selective retinoids (Alvarez et al 2014), which both activate the common program (Fig. 5E).…”

Section: Ra Induces Modular Gene Programs In Committed Ec Cellsmentioning

confidence: 99%

mentioning

confidence: 99%

Reconstructed cell fate–regulatory programs in stem cells reveal hierarchies and key factors of neurogenesis

Mendoza-Parra¹,

Malysheva²,

Saleem³

et al. 2016

Genome Res.

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“…embryonic development, growth, immunology, reproduction, and vision (1)(2)(3)(4). However, because of their lipophilic nature, free retinoids exist only at extremely low concentrations in plasma or cytosol, making diffusion kinetics between sites of action inefficient.…”

mentioning

confidence: 99%

Ligand Binding Induces Conformational Changes in Human Cellular Retinol-binding Protein 1 (CRBP1) Revealed by Atomic Resolution Crystal Structures

Silvaroli¹,

Arne²,

Chełstowska

et al. 2016

Journal of Biological Chemistry

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Important in regulating the uptake, storage, and metabolism of retinoids, cellular retinol-binding protein 1 (CRBP1) is essential for trafficking vitamin A through the cytoplasm. However, the molecular details of ligand uptake and targeted release by CRBP1 remain unclear. Here we report the first structure of CRBP1 in a ligand-free form as well as ultra-high resolution structures of this protein bound to either all-trans-retinol or retinylamine, the latter a therapeutic retinoid that prevents light-induced retinal degeneration. Superpositioning of human apo-and holo-CRBP1 revealed major differences within segments surrounding the entrance to the retinoid-binding site. These included ␣-helix II and hairpin turns between ␤-strands ␤C-␤D and ␤E-␤F as well as several side chains, such as Phe-57, Tyr-60, and Ile-77, that change their orientations to accommodate the ligand. Additionally, we mapped hydrogen bond networks inside the retinoid-binding cavity and demonstrated their significance for the ligand affinity. Analyses of the crystallographic B-factors indicated several regions with higher backbone mobility in the apoprotein that became more rigid upon retinoid binding. This conformational flexibility of human apo-CRBP1 facilitates interaction with the ligands, whereas the more rigid holoprotein structure protects the labile retinoid moiety during vitamin A transport. These findings suggest a mechanism of induced fit upon ligand binding by mammalian cellular retinol-binding proteins.Effective distribution of vitamin A (all-trans-retinol) and its derivatives (called "retinoids") throughout the body and cellular compartments determines their essential functions in embryonic development, growth, immunology, reproduction, and vision (1-4). However, because of their lipophilic nature, free retinoids exist only at extremely low concentrations in plasma or cytosol, making diffusion kinetics between sites of action inefficient. This solubility limitation is overcome by specialized retinoid-binding proteins that regulate retinoid metabolism and physiological functions (5). Thus, an appreciation of the molecular basis for ligand uptake and targeted release by retinoid-binding proteins is critical for understanding retinoid homeostasis, yet current knowledge of this process is very limited.Three classes of retinoid-binding proteins named for their selectivity (i.e. cellular retinol-binding protein (CRBP), 3 cellular retinoic acid-binding protein, and cis-retinoid-specific cellular retinal-binding proteins) carry vitamin A and its metabolites within cells (5-7). All representatives of CRBPs and cellular retinoic acid-binding proteins are members of intracellular lipid-binding proteins (8), whereas cellular retinal-binding protein belongs to the Sec14 protein family (9). Four CRBPs (CRBP1, -2, -3, and -4) are encoded in the human genome (10, 11). Among them, CRBP1 is the most widely expressed in numerous tissues, with the highest abundance in the liver, kidney, lung, and retinal pigment epithelium cells of the eye (12)(13)(14)...

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“…In metazoans, vitamin A (all-trans-retinol) and its metabolites, collectively referred to as retinoids, participate in many essential physiological processes, including embryonic development, growth, immune function, reproduction, and vision (1)(2)(3)(4). Therefore, a sustainable supply of vitamin A is critical to fulfill the diverse biological functions associated with retinoids.…”

mentioning

confidence: 99%

Key Residues for Catalytic Function and Metal Coordination in a Carotenoid Cleavage Dioxygenase

Sui

Zhang

Golczak

et al. 2016

Journal of Biological Chemistry

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Carotenoid cleavage dioxygenases (CCDs) are non-heme iron-containing enzymes found in all domains of life that generate biologically important apocarotenoids. Prior studies have revealed a critical role for a conserved 4-His motif in forming the CCD iron center. By contrast, the roles of other active site residues in catalytic function, including maintenance of the stringent regio-and stereo-selective cleavage activity, typically exhibited by these enzymes have not been thoroughly investigated. Here, we examined the functional and structural importance of active site residues in an apocarotenoid-cleaving oxygenase (ACO) from Synechocystis. Most active site substitutions variably lowered maximal catalytic activity without markedly affecting the K m value for the all-trans-8-apocarotenol substrate. Native C15-C15 cleavage activity was retained in all ACO variants examined suggesting that multiple active site residues contribute to the enzyme's regioselectivity. Crystallographic analysis of a nearly inactive W149A-substituted ACO revealed marked disruption of the active site structure, including loss of iron coordination by His-238 apparently from an altered conformation of the conserved second sphere Glu-150 residue. Gln-and Asp-150-substituted versions of ACO further confirmed the structural/functional requirement for a Glu side chain at this position, which is homologous to Glu-148 in RPE65, a site in which substitution to Asp has been associated with loss of enzymatic function in Leber congenital amaurosis. The novel links shown here between ACO active site structure and catalytic activity could be broadly applicable to other CCD members and provide insights into the molecular pathogenesis of vision loss associated with an RPE65 point mutation.

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Functions, Therapeutic Applications, and Synthesis of Retinoids and Carotenoids

Cited by 196 publications

References 890 publications

Reconstructed cell fate–regulatory programs in stem cells reveal hierarchies and key factors of neurogenesis

Reconstructed cell fate–regulatory programs in stem cells reveal hierarchies and key factors of neurogenesis

Ligand Binding Induces Conformational Changes in Human Cellular Retinol-binding Protein 1 (CRBP1) Revealed by Atomic Resolution Crystal Structures

Key Residues for Catalytic Function and Metal Coordination in a Carotenoid Cleavage Dioxygenase

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