Cloning and Characterization of the CYP2D1-Binding Protein, Retinol Dehydrogenase

Imaoka, Shingi; Wan, Jie; Chow, T. L.; Hiroi, Toyoko; Eyanagi, Reiko; Shigematsu, Hidenari; Funae, Yoshihiko

doi:10.1006/abbi.1998.0644

Cited by 15 publications

(11 citation statements)

References 19 publications

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“…It is reasonable to expect that the composition and stoichiometry of smooth endoplasmic reticulum membrane phospholipids are crucial to RDH activity and any interaction with holo-CRBP1. For example, RDH1 activity during purification was maintained only with phosphotidylcholine—no other phospholipid tested produced the same reaction rate—and only when RDH1 was bound with the membrane protein, CYP2D [48, 53, 65]. In other words, the membrane context of RDH affects function.…”

Section: Retinol Dehydrogenasesmentioning

confidence: 99%

Physiological insights into all-trans-retinoic acid biosynthesis

Napoli

2012

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

283

336

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All-trans-retinoic acid (atRA) provides essential support to diverse biological systems and physiological processes. Epithelial differentiation and its relationship to cancer and embryogenesis have typified intense areas of interest into atRA function. Recently, however, interest in atRA action in the nervous system, the immune system, energy balance and obesity has increased considerably, especially concerning postnatal function. atRA action depends on atRA biosynthesis: defects in retinoid-dependent processes increasingly relate to defects in atRA biogenesis. Considerable evidence indicates that physiological atRA biosynthesis occurs via a regulated process, consisting of a complex interaction of retinoid binding-proteins and retinoid recognizing enzymes. An accrual of biochemical, physiological and genetic data have identified specific functional outcomes for the retinol dehydrogenases, RDH1, RDH10, and DHRS9, as physiological catalysts of the first step in atRA biosynthesis, and for the retinal dehydrogenases RALDH1, RALDH2, and RALDH3, as catalysts of the second and irreversible step. Each of these enzymes associates with explicit biological processes mediated by atRA. Redundancy occurs, but seems limited. Cumulative data supports a model of interactions among these enzymes with retinoid binding-proteins, with feedback regulation and/or control by atRA via modulating gene expression of multiple participants. The ratio apo-CRBP1/holo-CRBP1 participates by influencing retinol flux into and out of storage as retinyl esters, thereby modulating substrate to support atRA biosynthesis. atRA biosynthesis requires presence of both an RDH and an RALDH: conversely, absence of one isozyme of either step does not indicate lack of atRA biosynthesis at the site.

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Section: Retinol Dehydrogenasesmentioning

confidence: 99%

Physiological insights into all-trans-retinoic acid biosynthesis

Napoli

2012

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

283

336

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“…Another form of interaction may be through direct binding to other proteins. During purification, rat RDH activity required binding to a 54 kDa protein, identified as CYP2D1 [29, 98]. In another example, recombinant tagged RDH10 and DHRS3 expressed in HEK293 cells form a heterodimer that enhances activities of both [1].…”

Section: Current State Of the Fieldmentioning

confidence: 99%

“…Membrane-associated proteins depend on membrane composition and their stoichiometry with membrane lipids and proteins for activity and function [2, 35, 92, 126]. Rat RODH activity during purification was maintained only with phosphatidylcholine (no other phospholipids were as effective), and required binding to the membrane protein CYP2D1, illustrating the importance of the membrane environment to activity [29, 30, 98]. This suggests that RDH expressed in insect cells might have inherently low activity because of the unnatural environment and/or stoichiometry.…”

Section: Current State Of the Fieldmentioning

confidence: 99%

Functions of Intracellular Retinoid Binding-Proteins

Napoli

2016

Subcellular Biochemistry

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Multiple binding and transport proteins facilitate many aspects of retinoid biology through effects on retinoid transport, cellular uptake, metabolism, and nuclear delivery. These include the serum retinol binding protein sRBP (aka Rbp4), the plasma membrane sRBP receptor Stra6, and the intracellular retinoid binding-proteins such as cellular retinol-binding proteins (CRBP) and cellular retinoic acid binding-proteins (CRABP). sRBP transports the highly lipophilic retinol through an aqueous medium. The major intracellular retinol-binding protein, CRBP1, likely enhances efficient retinoid use by providing a sink to facilitate retinol uptake from sRBP through the plasma membrane or via Stra6, delivering retinol or retinal to select enzymes that generate retinyl esters or retinoic acid, and protecting retinol/retinal from excess catabolism or opportunistic metabolism. Intracellular retinoic acid binding-proteins (CRABP1 and 2, and FABP5) seem to have more diverse functions distinctive to each, such as directing retinoic acid to catabolism, delivering retinoic acid to specific nuclear receptors, and generating non-canonical actions. Gene ablation of intracellular retinoid binding-proteins does not cause embryonic lethality or gross morphological defects. Metabolic and functional defects manifested in knockouts of CRBP1, CRBP2 and CRBP3, however, illustrate their essentiality to health, and in the case of CRBP2, to survival during limited dietary vitamin A. Future studies should continue to address the specific molecular interactions that occur between retinoid binding-proteins and their targets and their precise physiologic contributions to retinoid homeostasis and function.

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“…The consistent pattern through two purification steps suggests that the isolated proteins are binding with high affinity which would be consistent with specific binding. Third, some of the identified proteins had been reported to interact with CYPs, including other CYPs, PGRMC1 22, retinol dehydrogenase 35, and mEH, and UGT 19. Fourth, the enrichment of the identified proteins in the 2C2/Flag/His samples was similar to that of known CYP‐binding proteins.…”

Section: Discussionmentioning

confidence: 78%

Identification of cytochrome P450 2C2 protein complexes in mouse liver

Yau

Kemper

2011

Proteomics

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Interactions of microsomal cytochromes P450 (CYPs) with other proteins in the microsomal membrane are important for their function. In addition to their redox partners, CYPs have been reported to interact with other proteins not directly involved in their enzymatic function. In this study, proteins were identified that interact with CYP2C2 in vivo in mouse liver. Flag-tagged CYP2C2 was expressed exogenously in mouse liver and was affinity purified, along with associated proteins which were identified by MS and confirmed by western blotting. Over 20 proteins reproducibly co-purified with CYP2C2. The heterogeneous sedimentation velocity of CYP2C2 and associated proteins by centrifugation in sucrose gradients and sequential immunoprecipitation analysis were consistent with multiple CYP2C2 complexes of differing composition. The abundance of CYPs and other drug metabolizing enzymes and NAD/NADP requiring enzymes associated with CYP2C2 suggest that complexes of these protein may improve enzymatic efficiency or facilitate sequential metabolic steps. Chaperones, which may be important for maintaining CYP function, and reticulons, endoplasmic reticulum proteins that shape the morphology of the endoplasmic reticulum and are potential endoplasmic reticulum retention proteins for CYPs, were also associated with CYP2C2.

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Cloning and Characterization of the CYP2D1-Binding Protein, Retinol Dehydrogenase

Cited by 15 publications

References 19 publications

Physiological insights into all-trans-retinoic acid biosynthesis

Physiological insights into all-trans-retinoic acid biosynthesis

Functions of Intracellular Retinoid Binding-Proteins

Identification of cytochrome P450 2C2 protein complexes in mouse liver

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