Biochemistry and Molecular Biology of Vitamin D and Its Analog II

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Chemical Biology".

Deadline for manuscript submissions: 31 May 2024 | Viewed by 4966

Special Issue Editors

Department of Pharmaceutical Engineering, Toyama Prefectural University, Toyama 939-0398, Japan
Interests: structure–function analysis and application of cytochromes P450; metabolism and molecular mechanism of vitamin D; production of functional foods; gene therapy; genome editing
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Following a very successful first run, we are pleased to announce the launch of the second edition of a Special Issue on ‘Biochemistry and Molecular Biology of Vitamin D and Its Analog’.

Previous studies have shown that vitamin D exerts vitamin D receptor (VDR)-mediated genomic and non-genomic actions, as well as VDR-independent effects. Recently, VDR-independent effects of 25(OH)D3 on lipid metabolism by inducing degradation of SREBP/SCAP have been reported, as have ligand-independent effects of the VDR on the hair cycle. Thus, at least five types of effects of vitamin D and/or the VDR should be considered, namely: (1) VDR-dependent effects of 1,25D (VDR-1,25(OH)2D3), (2) VDR-independent effects of 1,25D (non VDR-1,25(OH)2D3), (3) VDR-dependent effects of 25D (VDR-25(OH)D3), (4) VDR-independent effects of 25D (non VDR-25(OH)D3), and (5) ligand-independent effects of VDR (VDR-no ligand).

Several thousand vitamin D analogs have been synthesized, and many have been studied in clinical trials, including for treating type I rickets, osteoporosis, psoriasis, renal osteodystrophy, leukemia, and pancreatic, prostate, and breast cancers. However, in many cases, their precise molecular mechanisms, which may include VDR-dependent and/or -independent pathways, are not fully understood.

In this Special Issue, we focus on the molecular mechanisms of vitamin D, its analogs and/or VDR actions leading to drug discovery, and nutritional supplements for disease prevention in the future.

Prof. Dr. Toshiyuki Sakaki
Prof. Dr. Naoko Tsugawa
Guest Editors

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Keywords

  • vitamin D
  • vitamin D receptor
  • vitamin D analog
  • genomic action
  • non-genomic action
  • bone formation
  • immune response
  • cancer
  • rickets
  • osteoporosis
  • psoriasis
  • drug discovery
  • disease prevention
  • nutrition improvement metabolism of vitamin D or its analogs cytochrome P450

Published Papers (5 papers)

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Research

10 pages, 4298 KiB  
Article
Efficient Stereo-Selective Fluorination on Vitamin D3 Side-Chain Using Electrophilic Fluorination
by Fumihiro Kawagoe, Sayuri Mototani and Atsushi Kittaka
Biomolecules 2024, 14(1), 37; https://doi.org/10.3390/biom14010037 - 26 Dec 2023
Viewed by 835
Abstract
Our research regarding side-chain fluorinated vitamin D3 analogues has explored a series of efficient fluorination methods. In this study, a new electrophilic stereo-selective fluorination methodology at C24 and C22 positions of the vitamin D3 side-chain was developed using N-fluorobenzenesulfonimide (NFSI) [...] Read more.
Our research regarding side-chain fluorinated vitamin D3 analogues has explored a series of efficient fluorination methods. In this study, a new electrophilic stereo-selective fluorination methodology at C24 and C22 positions of the vitamin D3 side-chain was developed using N-fluorobenzenesulfonimide (NFSI) and CD-ring imides with an Evans chiral auxiliary (26,27,30). Full article
(This article belongs to the Special Issue Biochemistry and Molecular Biology of Vitamin D and Its Analog II)
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11 pages, 1741 KiB  
Article
Characterization of Rickets Type II Model Rats to Reveal Functions of Vitamin D and Vitamin D Receptor
by Yuichiro Iwai, Ayano Iijima, Satoko Kise, Chika Nagao, Yuto Senda, Kana Yabu, Hiroki Mano, Miyu Nishikawa, Shinichi Ikushiro, Kaori Yasuda and Toshiyuki Sakaki
Biomolecules 2023, 13(11), 1666; https://doi.org/10.3390/biom13111666 - 19 Nov 2023
Viewed by 839
Abstract
Vitamin D has been known to exert a wide range of physiological effects, including calcemic, osteogenic, anticancer, and immune responses. We previously generated genetically modified (GM) rats and performed a comparative analysis of their physiological properties to elucidate the roles of vitamin D [...] Read more.
Vitamin D has been known to exert a wide range of physiological effects, including calcemic, osteogenic, anticancer, and immune responses. We previously generated genetically modified (GM) rats and performed a comparative analysis of their physiological properties to elucidate the roles of vitamin D and vitamin D receptor (VDR). In this study, our primary goal was to investigate the manifestations of type II rickets in rats with the VDR(H301Q) mutation, analogous to the human VDR(H305Q). Additionally, we created a double-mutant rat with the VDR(R270L/H301Q) mutation, resulting in almost no affinity for 1,25-dihydroxy-vitamin D3 (1,25D3) or 25-hydroxy-vitamin D3 (25D3). Notably, the plasma calcium concentration in Vdr(R270L/H301Q) rats was significantly lower than in wild-type (WT) rats. Meanwhile, Vdr(H301Q) rats had calcium concentrations falling between those of Vdr(R270L/H301Q) and WT rats. GM rats exhibited markedly elevated plasma parathyroid hormone and 1,25D3 levels compared to those of WT rats. An analysis of bone mineral density in the cortical bone of the femur in both GM rats revealed significantly lower values than in WT rats. Conversely, the bone mineral density in the trabecular bone was notably higher, indicating abnormal bone formation. This abnormal bone formation was more pronounced in Vdr(R270L/H301Q) rats than in Vdr(H301Q) rats, highlighting the critical role of the VDR-dependent function of 1,25D3 in bone formation. In contrast, neither Vdr(H301Q) nor Vdr(R270L/H301Q) rats exhibited symptoms of alopecia or cyst formation in the skin, which were observed in the Vdr-KO rats. These findings strongly suggest that unliganded VDR is crucial for maintaining the hair cycle and normal skin. Our GM rats hold significant promise for comprehensive analyses of vitamin D and VDR functions in future research. Full article
(This article belongs to the Special Issue Biochemistry and Molecular Biology of Vitamin D and Its Analog II)
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12 pages, 2667 KiB  
Article
An N-Cyanoamide Derivative of Lithocholic Acid Co-Operates with Lysophosphatidic Acid to Promote Human Osteoblast (MG63) Differentiation
by Jason P. Mansell, Aya Tanatani and Hiroyuki Kagechika
Biomolecules 2023, 13(7), 1113; https://doi.org/10.3390/biom13071113 - 13 Jul 2023
Viewed by 892
Abstract
Less-calcaemic vitamin D receptor (VDR) agonists have the potential to promote osteoblast maturation in a bone regenerative setting. The emergence of lithocholic acid (LCA) as a bona fide VDR agonist holds promise as an adjunct for arthroplasty following reports that it was less [...] Read more.
Less-calcaemic vitamin D receptor (VDR) agonists have the potential to promote osteoblast maturation in a bone regenerative setting. The emergence of lithocholic acid (LCA) as a bona fide VDR agonist holds promise as an adjunct for arthroplasty following reports that it was less calcaemic than calcitriol (1,25D). However, LCA and some earlier derivatives, e.g., LCA acetate, had to be used at much higher concentrations than 1,25D to elicit comparable effects on osteoblasts. However, recent developments have led to the generation of far more potent LCA derivatives that even outperform the efficacy of 1,25D. These new compounds include the cyanoamide derivative, Dcha-150 (also known as AY2-79). In light of this significant development, we sought to ascertain the ability of Dcha-150 to promote human osteoblast maturation by monitoring alkaline phosphatase (ALP) and osteocalcin (OC) expression. The treatment of MG63 cells with Dcha-150 led to the production of OC. When Dcha-150 was co-administered with lysophosphatidic acid (LPA) or an LPA analogue, a synergistic increase in ALP activity occurred, with Dcha-150 showing greater potency compared to 1,25D. We also provide evidence that this synergy is likely attributed to the actions of myocardin-related transcription factor (MRTF)–serum response factor (SRF) gene transcription following LPA-receptor-induced cytoskeletal reorganisation. Full article
(This article belongs to the Special Issue Biochemistry and Molecular Biology of Vitamin D and Its Analog II)
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22 pages, 4673 KiB  
Article
Syntheses of 25-Adamantyl-25-alkyl-2-methylidene-1α,25-dihydroxyvitamin D3 Derivatives with Structure–Function Studies of Antagonistic and Agonistic Active Vitamin D Analogs
by Kazuki Maekawa, Michiyasu Ishizawa, Takashi Ikawa, Hironao Sajiki, Taro Matsumoto, Hiroaki Tokiwa, Makoto Makishima and Sachiko Yamada
Biomolecules 2023, 13(7), 1082; https://doi.org/10.3390/biom13071082 - 06 Jul 2023
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Abstract
The active form of vitamin D3, 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3], is a major regulator of calcium homeostasis through activation of the vitamin D receptor (VDR). We have previously synthesized vitamin D derivatives with large adamantane (AD) rings [...] Read more.
The active form of vitamin D3, 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3], is a major regulator of calcium homeostasis through activation of the vitamin D receptor (VDR). We have previously synthesized vitamin D derivatives with large adamantane (AD) rings at position 24, 25, or 26 of the side chain to study VDR agonist and/or antagonist properties. One of them—ADTK1, with an AD ring and 23,24-triple bond—shows a high VDR affinity and cell-selective VDR activity. In this study, we synthesized novel vitamin D derivatives (ADKM1-6) with an alkyl group substituted at position 25 of ADTK1 to develop more cell-selective VDR ligands. ADKM2, ADKM4, and ADKM6 had VDR transcriptional activity comparable to 1,25(OH)2D3 and ADTK1, although their VDR affinities were weaker. Interestingly, ADKM2 has selective VDR activity in kidney- and skin-derived cells—a unique phenotype that differs from ADTK1. Furthermore, ADKM2, ADKM4, and ADKM6 induced osteoblast differentiation in human dedifferentiated fat cells more effectively than ADTK1. The development of vitamin D derivatives with bulky modifications such as AD at position 24, 25, or 26 of the side chain is useful for increased stability and tissue selectivity in VDR-targeting therapy. Full article
(This article belongs to the Special Issue Biochemistry and Molecular Biology of Vitamin D and Its Analog II)
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13 pages, 1936 KiB  
Article
Differential Metabolic Stability of 4α,25- and 4β,25-Dihydroxyvitamin D3 and Identification of Their Metabolites
by Yuka Mizumoto, Ryota Sakamoto, Kazuto Iijima, Naoto Nakaya, Minami Odagi, Masayuki Tera, Takatsugu Hirokawa, Toshiyuki Sakaki, Kaori Yasuda and Kazuo Nagasawa
Biomolecules 2023, 13(7), 1036; https://doi.org/10.3390/biom13071036 - 24 Jun 2023
Viewed by 858
Abstract
Vitamin D3 (1) is metabolized by various cytochrome P450 (CYP) enzymes, resulting in the formation of diverse metabolites. Among them, 4α,25-dihydroxyvitamin D3 (6a) and 4β,25-dihydroxyvitamin D3 (6b) are both produced from 25-hydroxyvitamin D3 [...] Read more.
Vitamin D3 (1) is metabolized by various cytochrome P450 (CYP) enzymes, resulting in the formation of diverse metabolites. Among them, 4α,25-dihydroxyvitamin D3 (6a) and 4β,25-dihydroxyvitamin D3 (6b) are both produced from 25-hydroxyvitamin D3 (2) by CYP3A4. However, 6b is detectable in serum, whereas 6a is not. We hypothesized that the reason for this is a difference in the susceptibility of 6a and 6b to CYP24A1-mediated metabolism. Here, we synthesized 6a and 6b, and confirmed that 6b has greater metabolic stability than 6a. We also identified 4α,24R,25- and 4β,24R,25-trihydroxyvitamin D3 (16a and 16b) as metabolites of 6a and 6b, respectively, by HPLC comparison with synthesized authentic samples. Docking studies suggest that the β-hydroxy group at C4 contributes to the greater metabolic stability of 6b by blocking a crucial hydrogen-bonding interaction between the C25 hydroxy group and Leu325 of CYP24A1. Full article
(This article belongs to the Special Issue Biochemistry and Molecular Biology of Vitamin D and Its Analog II)
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