Research

Jump to: Review

14 pages, 2289 KiB

Open AccessArticle

Therapeutic Potential of a Novel Vitamin D₃ Oxime Analogue, VD1-6, with CYP24A1 Enzyme Inhibitory Activity and Negligible Vitamin D Receptor Binding

by Ali K. Alshabrawy, Yingjie Cui, Cyan Sylvester, Dongqing Yang, Emilio S. Petito, Kate R. Barratt, Rebecca K. Sawyer, Jessica K. Heatlie, Ruhi Polara, Matthew J. Sykes, Gerald J. Atkins, Shane M. Hickey, Michael D. Wiese, Andrea M. Stringer, Zhaopeng Liu and Paul H. Anderson

Biomolecules 2022, 12(7), 960; https://doi.org/10.3390/biom12070960 - 08 Jul 2022

Cited by 4 | Viewed by 1956

Abstract

The regulation of vitamin D₃ actions in humans occurs mainly through the Cytochrome P450 24-hydroxylase (CYP24A1) enzyme activity. CYP24A1 hydroxylates both 25-hydroxycholecalciferol (25(OH)D₃) and 1,25-dihydroxycholecalciferol (1,25(OH)₂D₃), which is the first step of vitamin D catabolism. An [...] Read more.

The regulation of vitamin D₃ actions in humans occurs mainly through the Cytochrome P450 24-hydroxylase (CYP24A1) enzyme activity. CYP24A1 hydroxylates both 25-hydroxycholecalciferol (25(OH)D₃) and 1,25-dihydroxycholecalciferol (1,25(OH)₂D₃), which is the first step of vitamin D catabolism. An abnormal status of the upregulation of CYP24A1 occurs in many diseases, including chronic kidney disease (CKD). CYP24A1 upregulation in CKD and diminished activation of vitamin D₃ contribute to secondary hyperparathyroidism (SHPT), progressive bone deterioration, and soft tissue and cardiovascular calcification. Previous studies have indicated that CYP24A1 inhibition may be an effective strategy to increase endogenous vitamin D activity and decrease SHPT. This study has designed and synthesized a novel C-24 O-methyloxime analogue of vitamin D₃ (VD1-6) to have specific CYP24A1 inhibitory properties. VD1-6 did not bind to the vitamin D receptor (VDR) in concentrations up to 10⁻⁷ M, assessed by a VDR binding assay. The absence of VDR binding by VD1-6 was confirmed in human embryonic kidney HEK293T cultures through the lack of CYP24A1 induction. However, in silico docking experiments demonstrated that VD1-6 was predicted to have superior binding to CYP24A1, when compared to that of 1,25(OH)₂D₃. The inhibition of CYP24A1 by VD1-6 was also evident by the synergistic potentiation of 1,25(OH)₂D₃-mediated transcription and reduced 1,25(OH)₂D₃ catabolism over 24 h. A further indication of CYP24A1 inhibition by VD1-6 was the reduced accumulation of the 24,25(OH)D₃, the first metabolite of 25(OH)D catabolism by CYP24A1. Our findings suggest the potent CYP24A1 inhibitory properties of VD1-6 and its potential for testing as an alternative therapeutic candidate for treating SHPT. Full article

(This article belongs to the Special Issue Biochemistry and Molecular Biology of Vitamin D and Its Analog)

► Show Figures

Figure 1

16 pages, 1880 KiB

Open AccessArticle

Lithocholic Acid Amides as Potent Vitamin D Receptor Agonists

by Ayana Yoshihara, Haru Kawasaki, Hiroyuki Masuno, Koki Takada, Nobutaka Numoto, Nobutoshi Ito, Naoya Hirata, Yasunari Kanda, Michiyasu Ishizawa, Makoto Makishima, Hiroyuki Kagechika and Aya Tanatani

Biomolecules 2022, 12(1), 130; https://doi.org/10.3390/biom12010130 - 14 Jan 2022

Cited by 5 | Viewed by 2337

Abstract

1α,25-Dihydroxyvitamin D₃ [1α,25(OH)₂D₃, 1] is an active form of vitamin D₃ and regulates various biological phenomena, including calcium and phosphate homeostasis, bone metabolism, and immune response via binding to and activation of vitamin D receptor (VDR). [...] Read more.

1α,25-Dihydroxyvitamin D₃ [1α,25(OH)₂D₃, 1] is an active form of vitamin D₃ and regulates various biological phenomena, including calcium and phosphate homeostasis, bone metabolism, and immune response via binding to and activation of vitamin D receptor (VDR). Lithocholic acid (LCA, 2) was identified as a second endogenous agonist of VDR, though its potency is very low. However, the lithocholic acid derivative 3 (Dcha-20) is a more potent agonist than 1α,25(OH)₂D₃, (1), and its carboxyl group has similar interactions to the 1,3-dihydroxyl groups of 1 with amino acid residues in the VDR ligand-binding pocket. Here, we designed and synthesized amide derivatives of 3 in order to clarify the role of the carboxyl group. The synthesized amide derivatives showed HL-60 cell differentiation-inducing activity with potency that depended upon the substituent on the amide nitrogen atom. Among them, the N-cyanoamide 6 is more active than either 1 or 3. Full article

(This article belongs to the Special Issue Biochemistry and Molecular Biology of Vitamin D and Its Analog)

► Show Figures

Graphical abstract

11 pages, 1267 KiB

Open AccessArticle

Synthesis of C2-Alkoxy-Substituted 19-Nor Vitamin D₃ Derivatives: Stereoselectivity and Biological Activity

by Yuka Mizumoto, Ryota Sakamoto, Akiko Nagata, Suzuka Sakane, Atsushi Kittaka, Minami Odagi, Masayuki Tera and Kazuo Nagasawa

Biomolecules 2022, 12(1), 69; https://doi.org/10.3390/biom12010069 - 04 Jan 2022

Cited by 1 | Viewed by 1787

Abstract

The active form of vitamin D₃ (D₃), 1a,25-dihydroxyvitamn D₃ (1,25D₃), plays a central role in calcium and bone metabolism. Many structure–activity relationship (SAR) studies of D₃ have been conducted, with the aim of separating the biological [...] Read more.

The active form of vitamin D₃ (D₃), 1a,25-dihydroxyvitamn D₃ (1,25D₃), plays a central role in calcium and bone metabolism. Many structure–activity relationship (SAR) studies of D₃ have been conducted, with the aim of separating the biological activities of 1,25D₃ or reducing its side effects, such as hypercalcemia, and SAR studies have shown that the hypercalcemic activity of C2-substituted derivatives and 19-nor type derivatives is significantly suppressed. In the present paper, we describe the synthesis of 19-nor type 1,25D₃ derivatives with alkoxy groups at C2, by means of the Julia–Kocienski type coupling reaction between a C2 symmetrical A ring ketone and a CD ring synthon. The effect of C2 substituents on the stereoselectivity of the coupling reaction was evaluated. The biological activities of the synthesized derivatives were evaluated in an HL-60 cell-based assay. The a-methoxy-substituted C2α-7a was found to show potent cell-differentiating activity, with an ED₅₀ value of 0.38 nM, being 26-fold more potent than 1,25D₃. Full article

(This article belongs to the Special Issue Biochemistry and Molecular Biology of Vitamin D and Its Analog)

► Show Figures

Figure 1

13 pages, 1295 KiB

Open AccessEditor’s ChoiceArticle

New Variants of the Cytochrome P450 2R1 (CYP2R1) Gene in Individuals with Severe Vitamin D-Activating Enzyme 25(OH)D Deficiency

by Martyna Fronczek, Joanna Katarzyna Strzelczyk, Krzysztof Biernacki, Silvia Salatino, Tadeusz Osadnik and Zofia Ostrowska

Biomolecules 2021, 11(12), 1867; https://doi.org/10.3390/biom11121867 - 12 Dec 2021

Cited by 5 | Viewed by 2689

Abstract

Background: Vitamin D is a fat-soluble cholesterol derivative found in two forms, vitamin D2, and vitamin D3. Cytochrome P450 2R1 (CYP2R1) encoded by the CYP2R1 gene is the major hydroxylase that activates vitamin D by catalyzing the formation of 25-hydroxyvitamin D (25(OH)D). Methods: [...] Read more.

Background: Vitamin D is a fat-soluble cholesterol derivative found in two forms, vitamin D2, and vitamin D3. Cytochrome P450 2R1 (CYP2R1) encoded by the CYP2R1 gene is the major hydroxylase that activates vitamin D by catalyzing the formation of 25-hydroxyvitamin D (25(OH)D). Methods: We collected 89 (100%) subjects, 46 of which (51.69%) had a documented severe deficiency of 25(OH)D (<10 ng/mL) and 43 (48.31%) in the control group with documented optimum levels of 25(OH)D (>30 ng/mL). We performed Sanger sequencing of three selected fragments of the CYP2R1 gene (Ch11: 14878000–14878499; Ch11: 14880058–14880883 and Ch11: 14885321–14886113) that affect the binding of substrates to this enzyme and analyzed the possible involvement of genetic variation in these regions with an increased risk of vitamin D deficiency in healthy Polish individuals. Results: Two substitutions were found within the three fragments. Bioinformatic analysis suggested that one of these (NC_000011.10: g.14878291G>A) may influence the structure and function of CYP2R1. Conclusions: Variant NC_000011.10: g.14878291G>A may have a perturbing effect on heme binding in the active site of CYP2R1 and on the function of 25-hydroxylase and probably affects the concentration of 25(OH)D in vivo. We intend to perform functional verification in a larger patient population to confirm and extend these results. Full article

(This article belongs to the Special Issue Biochemistry and Molecular Biology of Vitamin D and Its Analog)

► Show Figures

Figure 1

23 pages, 20961 KiB

Open AccessArticle

Impact of Vitamin D₃ Deficiency on Phosphatidylcholine-/Ethanolamine, Plasmalogen-, Lyso-Phosphatidylcholine-/Ethanolamine, Carnitine- and Triacyl Glyceride-Homeostasis in Neuroblastoma Cells and Murine Brain

by Anna Andrea Lauer, Lea Victoria Griebsch, Sabrina Melanie Pilz, Daniel Janitschke, Elena Leoni Theiss, Jörg Reichrath, Christian Herr, Christoph Beisswenger, Robert Bals, Teresa Giovanna Valencak, Dorothea Portius, Heike Sabine Grimm, Tobias Hartmann and Marcus Otto Walter Grimm

Biomolecules 2021, 11(11), 1699; https://doi.org/10.3390/biom11111699 - 15 Nov 2021

Cited by 2 | Viewed by 3712

Abstract

Vitamin D₃ hypovitaminosis is associated with several neurological diseases such as Alzheimer’s disease, Parkinson’s disease or multiple sclerosis but also with other diseases such as cancer, diabetes or diseases linked to inflammatory processes. Importantly, in all of these diseases lipids have at [...] Read more.

Vitamin D₃ hypovitaminosis is associated with several neurological diseases such as Alzheimer’s disease, Parkinson’s disease or multiple sclerosis but also with other diseases such as cancer, diabetes or diseases linked to inflammatory processes. Importantly, in all of these diseases lipids have at least a disease modifying effect. Besides its well-known property to modulate gene-expression via the VDR-receptor, less is known if vitamin D hypovitaminosis influences lipid homeostasis and if these potential changes contribute to the pathology of the diseases themselves. Therefore, we analyzed mouse brain with a mild vitamin D hypovitaminosis via a targeted shotgun lipidomic approach, including phosphatidylcholine, plasmalogens, lyso-phosphatidylcholine, (acyl-/acetyl-) carnitines and triglycerides. Alterations were compared with neuroblastoma cells cultivated in the presence and with decreased levels of vitamin D. Both in cell culture and in vivo, decreased vitamin D level resulted in changed lipid levels. While triglycerides were decreased, carnitines were increased under vitamin D hypovitaminosis suggesting an impact of vitamin D on energy metabolism. Additionally, lyso-phosphatidylcholines in particular saturated phosphatidylcholine (e.g., PC aa 48:0) and plasmalogen species (e.g., PC ae 42:0) tended to be increased. Our results suggest that vitamin D hypovitaminosis not only may affect gene expression but also may directly influence cellular lipid homeostasis and affect lipid turnover in disease states that are known for vitamin D hypovitaminosis. Full article

(This article belongs to the Special Issue Biochemistry and Molecular Biology of Vitamin D and Its Analog)

► Show Figures

Graphical abstract

11 pages, 791 KiB

Open AccessArticle

A Novel Method for the Determination of Vitamin D Metabolites Assessed at the Blood-Cerebrospinal Fluid Barrier

by Sieglinde Zelzer, Andreas Meinitzer, Markus Herrmann, Walter Goessler and Dietmar Enko

Biomolecules 2021, 11(9), 1288; https://doi.org/10.3390/biom11091288 - 29 Aug 2021

Cited by 5 | Viewed by 1914

Abstract

The brain’s supply with vitamin D is poorly understood. Therefore, the present study aimed to determine 25-hydroxy vitamin D3 (25(OH)D) and 24,25-dihydroxy vitamin D (24,25(OH)₂D₃) in serum and cerebrospinal fluid (CSF) from individuals with intact and disturbed brain-CSF-barrier (BCB) [...] Read more.

The brain’s supply with vitamin D is poorly understood. Therefore, the present study aimed to determine 25-hydroxy vitamin D3 (25(OH)D) and 24,25-dihydroxy vitamin D (24,25(OH)₂D₃) in serum and cerebrospinal fluid (CSF) from individuals with intact and disturbed brain-CSF-barrier (BCB) function. In 292 pairs of serum and CSF samples the vitamin D metabolites were measured with liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). CSF/serum ratios (Q_ALB, Q_25(OH)D, Q_24,25(OH)2D3) were calculated. Median (IQR) serum concentrations of 25(OH)D and 24,25(OH)₂D₃ were 63.8 (43.4–83.9) nmol/L and 4.2 (2.2–6.2) nmol/L. The CSF concentrations of both metabolites accounted for 3.7 and 3.3% of the respective serum concentrations. Serum 25(OH)D correlated inversely with Q_25(OH)D and Q_24,25(OH)2D3 implying a more efficient transport of both metabolites across the BCB when the serum concentration of 25(OH)D is low. In patients with BCB dysfunction, the CSF concentrations and the CSF/serum ratios of both vitamin D metabolites were higher than in individuals with intact BCB. The CSF concentrations of 25(OH)D and 24,25(OH)₂D₃ depend on BCB function and the respective serum concentrations of both metabolites. Higher vitamin D metabolite concentrations in CSF of patients with impaired BCB function may be due to passive diffusion across the BCB. Full article

(This article belongs to the Special Issue Biochemistry and Molecular Biology of Vitamin D and Its Analog)

► Show Figures

Figure 1

Review

Jump to: Research

21 pages, 17965 KiB

Open AccessEditor’s ChoiceReview

The Synthesis and Biological Evaluation of D-Ring-Modified Vitamin D Analogues

by Fumihiro Kawagoe, Sayuri Mototani and Atsushi Kittaka

Biomolecules 2021, 11(11), 1639; https://doi.org/10.3390/biom11111639 - 04 Nov 2021

Cited by 6 | Viewed by 1884

Abstract

The vitamin D₃ structure consists of the A-ring, a linker originating from the B-ring, C-ring, D-ring, and side-chain moieties. Each unit has its unique role in expressing the biological activities of vitamin D₃. Many efforts have been made to date [...] Read more.

The vitamin D₃ structure consists of the A-ring, a linker originating from the B-ring, C-ring, D-ring, and side-chain moieties. Each unit has its unique role in expressing the biological activities of vitamin D₃. Many efforts have been made to date to assess the possible clinical use of vitamin D. Some organic chemists focused on the D-ring structure of vitamin D and synthesized D-ring-modified vitamin D analogues, and their biological activities were studied. This review summarizes the synthetic methodologies of D-ring-modified vitamin D analogues, except for seco-D, and their preliminary biological profiles. Full article

(This article belongs to the Special Issue Biochemistry and Molecular Biology of Vitamin D and Its Analog)

► Show Figures

Figure 1

9 pages, 718 KiB

Open AccessReview

The Effects of Vitamin D on Immune System and Inflammatory Diseases

by Tomoka Ao, Junichi Kikuta and Masaru Ishii

Biomolecules 2021, 11(11), 1624; https://doi.org/10.3390/biom11111624 - 03 Nov 2021

Cited by 117 | Viewed by 13031

Abstract

Immune cells, including dendritic cells, macrophages, and T and B cells, express the vitamin D receptor and 1α-hydroxylase. In vitro studies have shown that 1,25-dihydroxyvitamin D, the active form of vitamin D, has an anti-inflammatory effect. Recent epidemiological evidence has indicated a significant [...] Read more.

Immune cells, including dendritic cells, macrophages, and T and B cells, express the vitamin D receptor and 1α-hydroxylase. In vitro studies have shown that 1,25-dihydroxyvitamin D, the active form of vitamin D, has an anti-inflammatory effect. Recent epidemiological evidence has indicated a significant association between vitamin D deficiency and an increased incidence, or aggravation, of infectious diseases and inflammatory autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis. However, the impact of vitamin D on treatment and prevention, particularly in infectious diseases such as the 2019 coronavirus disease (COVID-19), remains controversial. Here, we review recent evidence associated with the relationship between vitamin D and inflammatory diseases and describe the underlying immunomodulatory effect of vitamin D. Full article

(This article belongs to the Special Issue Biochemistry and Molecular Biology of Vitamin D and Its Analog)

► Show Figures

Figure 1

Journal Menu

Journal Browser

Biochemistry and Molecular Biology of Vitamin D and Its Analog

Share This Special Issue

Special Issue Editors

Special Issue Information

Keywords

Published Papers (8 papers)

Research

Review

Further Information

Guidelines

MDPI Initiatives

Follow MDPI