Aldo–keto reductases in retinoid metabolism: Search for substrate specificity and inhibitor selectivity

Porté, Sergio; Ruiz, Francesc Xavier; Giménez, Joan; Molist, Iago; Álvarez, Susana; Domínguez, Marta; Álvarez, Rosana; Lera, Ángel R. de; Parés, Xavier; Farrés, Jaume

doi:10.1016/j.cbi.2012.11.014

“…The interactions between the 7-hydroxyl group and the benzylamide moiety of 26 and the enzyme catalytic residues Tyr-49, His-111 and Trp-220 are necessary for the potent inhibition. Recently, some aromatic retinoid (arotinoids) were synthesized and their inhibitory potency against AKR1B10 and AKR1B1 was explored [79]. Some of them bind to RXR (retinoid X receptors) and others to RAR (retinoic acid receptors), and even exhibit higher selectivity for AKR1B10.…”

Section: Akr1b10 Inhibitorsmentioning

confidence: 99%

“…UVI2008 ( 27 ) [120], a retinoic acid receptor (RAR) β/γ agonist, was a potent and selective inhibitor of AKR1B10 with its carboxyl group binding to the anion-binding pocket of the enzyme. It worked as both receptors' ligand and AKR inhibitor, and could be regarded as a lead agent in the design of bifunctional drugs [79]. Androstane-3β,5α,6β,19-tetraol ( 28 ) (CN104497086)[80], a polyhydroxysterol compound, has high inhibitory activity on AKR1B10 and exhibits good selectivity.…”

Section: Akr1b10 Inhibitorsmentioning

confidence: 99%

Aldo-Keto Reductase Family 1 Member B10 Inhibitors: Potential Drugs for Cancer Treatment

Huang¹,

He²,

Luo³

et al. 2016

PRA

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Cytosolic NADPH-dependent reductase AKR1B10 is a member of the aldo-keto reductase (AKR) superfamily. This enzyme is normally expressed in the gastrointestinal tract. However, it is overexpressed in many solid tumors, such as hepatocarcinoma, lung cancer and breast cancer. AKR1B10 may play a role in the formation and development of carcinomas through multiple mechanisms including detoxification of cytotoxic carbonyls, modulation of retinoic acid level, and regulation of cellular fatty acid synthesis and lipid metabolism. Studies have suggested that AKR1B10 may be a useful biomarker for cancer diagnosis and a potential target for cancer treatment. Over the last decade, a number of AKR1B10 inhibitors including aldose reductase inhibitors (ARIs), endogenous substances, natural-based derivatives and synthetic compounds have been developed, which could be novel anticancer drugs. This review provides an overview on related articles and patents about AKR1B10 inhibitors, with a focus on their inhibition selectivity and mechanism of function.

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“…UVI2008 (27) [120], a retinoic acid receptor (RAR) / agonist, was a potent and selective inhibitor of AKR1B10 with its carboxyl group binding to the anion-binding pocket of the enzyme. It worked as both receptors' ligand and AKR inhibitor, and could be regarded as a lead agent in the design of bifunctional drugs [79]. Androstane-3 ,5 ,6 ,19-tetraol (28) (CN104497086) [80], a polyhydroxysterol compound, has high inhibitory activity on AKR1B10 and exhibits good selectivity.…”

Section: Non-drug Synthetic Compoundsmentioning

confidence: 99%

Aldo-Keto Reductase Family 1 Member B10 Inhibitors: Potential Drugs for Cancer Treatment

Li¹,

He²,

Luo³

et al. 2016

PRA

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Cytosolic NADPH-dependent reductase AKR1B10 is a member of the aldo-keto reductase (AKR) superfamily. This enzyme is normally expressed in the gastrointestinal tract. However, it is overexpressed in many solid tumors, such as hepatocarcinoma, lung cancer and breast cancer. AKR1B10 may play a role in the formation and development of carcinomas through multiple mechanisms including detoxification of cytotoxic carbonyls, modulation of retinoic acid level, and regulation of cellular fatty acid synthesis and lipid metabolism. Studies have suggested that AKR1B10 may be a useful biomarker for cancer diagnosis and a potential target for cancer treatment. Over the last decade, a number of AKR1B10 inhibitors including aldose reductase inhibitors (ARIs), endogenous substances, natural-based derivatives and synthetic compounds have been developed, which could be novel anticancer drugs. This review provides an overview on related articles and patents about AKR1B10 inhibitors, with a focus on their inhibition selectivity and mechanism of function.

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“…The common feature of the SDR superfamily is a “Rossmann-fold” which is involved in the binding of dinucleotide cofactors including NADPH or NADH (Kavanagh et al, 2008). Oxidation reactions creating these various double bonds could be catalyzed by AKRs and SDRs as well because of the potential of these enzyme families to drive oxidations (Porté et al, 2013). 2-Oxoglutarate dependent dioxygenases and cytochrome P450 enzymes are well known for their ability to hydroxylate substrates thus making them good candidate gene families for the various hydroxylases in the biosynthesis of the Amaryllidaceae alkaloids (Lester et al, 1997; Nelson and Werck-Reichhart, 2011) (Figure 1, 2, 5, and 6).…”

Section: Amaryllidaceae Alkaloidsmentioning

confidence: 99%

The Amaryllidaceae alkaloids: biosynthesis and methods for enzyme discovery

Kilgore

¹

,

Kutchan

²

2015

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Amaryllidaceae alkaloids are an example of the vast diversity of secondary metabolites with great therapeutic promise. The identification of novel compounds in this group with over 300 known structures continues to be an area of active study. The recent identification of norbelladine 4′-O-methyltransferase (N4OMT), an Amaryllidaceae alkaloid biosynthetic enzyme, and the assembly of transcriptomes for Narcissus sp. aff. pseudonarcissus and Lycoris aurea highlight the potential for discovery of Amaryllidaceae alkaloid biosynthetic genes with new technologies. Recent technical advances of interest include those in enzymology, next generation sequencing, genetic modification, nuclear magnetic resonance spectroscopy (NMR), and mass spectrometry (MS).

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Aldo–keto reductases in retinoid metabolism: Search for substrate specificity and inhibitor selectivity

Cited by 32 publications

References 63 publications

Aldo-Keto Reductase Family 1 Member B10 Inhibitors: Potential Drugs for Cancer Treatment

Aldo-Keto Reductase Family 1 Member B10 Inhibitors: Potential Drugs for Cancer Treatment

Aldo-Keto Reductase Family 1 Member B10 Inhibitors: Potential Drugs for Cancer Treatment

The Amaryllidaceae alkaloids: biosynthesis and methods for enzyme discovery

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