-
International Journal of Molecular... Sep 2020Vitamin D is a steroid hormone classically involved in the calcium metabolism and bone homeostasis. Recently, new and interesting aspects of vitamin D metabolism has... (Review)
Review
Vitamin D is a steroid hormone classically involved in the calcium metabolism and bone homeostasis. Recently, new and interesting aspects of vitamin D metabolism has been elucidated, namely the special role of the skin, the metabolic control of liver hydroxylase CYP2R1, the specificity of 1α-hydroxylase in different tissues and cell types and the genomic, non-genomic and epigenomic effects of vitamin D receptor, which will be addressed in the present review. Moreover, in the last decades, several extraskeletal effects which can be attributed to vitamin D have been shown. These beneficial effects will be here summarized, focusing on the immune system and cardiovascular system.
Topics: 25-Hydroxyvitamin D3 1-alpha-Hydroxylase; Animals; Bone and Bones; Calcitriol; Cytochrome P-450 Enzyme System; Cytochrome P450 Family 2; Homeostasis; Humans; Lipid Metabolism; Mixed Function Oxygenases; Receptors, Calcitriol; Skin; Vitamin D; Vitamin D3 24-Hydroxylase
PubMed: 32911795
DOI: 10.3390/ijms21186573 -
Cellular and Molecular Life Sciences :... Jun 2022The ten-eleven translocation (TET) family of dioxygenases consists of three members, TET1, TET2, and TET3. All three TET enzymes have Fe and α-ketoglutarate... (Review)
Review
The ten-eleven translocation (TET) family of dioxygenases consists of three members, TET1, TET2, and TET3. All three TET enzymes have Fe and α-ketoglutarate (α-KG)-dependent dioxygenase activities, catalyzing the 1st step of DNA demethylation by converting 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), and further oxidize 5hmC to 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC). Gene knockout studies demonstrated that all three TET proteins are involved in the regulation of fetal organ generation during embryonic development and normal tissue generation postnatally. TET proteins play such roles by regulating the expression of key differentiation and fate-determining genes via (1) enzymatic activity-dependent DNA methylation of the promoters and enhancers of target genes; and (2) enzymatic activity-independent regulation of histone modification. Interacting partner proteins and post-translational regulatory mechanisms regulate the activities of TET proteins. Mutations and dysregulation of TET proteins are involved in the pathogenesis of human diseases, specifically cancers. Here, we summarize the research on the interaction partners and post-translational modifications of TET proteins. We also discuss the molecular mechanisms by which these partner proteins and modifications regulate TET functioning and target gene expression. Such information will help in the design of medications useful for targeted therapy of TET-mutant-related diseases.
Topics: 5-Methylcytosine; Cytosine; DNA Methylation; DNA-Binding Proteins; Dioxygenases; Humans; Mixed Function Oxygenases; Promoter Regions, Genetic; Proto-Oncogene Proteins
PubMed: 35705880
DOI: 10.1007/s00018-022-04396-x -
Tidsskrift For Den Norske Laegeforening... Sep 2021Trimethylaminuria is a rare disorder characterised by foul odour from bodily fluids and breath. The condition is caused by a homozygous mutation in the FMO3 (flavin...
BACKGROUND
Trimethylaminuria is a rare disorder characterised by foul odour from bodily fluids and breath. The condition is caused by a homozygous mutation in the FMO3 (flavin monooxygenase 3) gene coding for the enzyme that converts TMA (trimethylamine) to trimethylamine N-oxide. The result is elevated levels of secreted trimethylamine, which has a strong odour. The condition is likely to affect mental, emotional and social health. The diagnosis is reached by testing of free TMA (trimethylamine) and percentage N-oxidation in urine samples or by genetic testing.
CASE PRESENTATION
A man in his fifties had from childhood occasionally been told that his breath resembled rotten fish. He had searched for a diagnosis on the internet and was referred to testing for trimethylaminuria, and the diagnosis was confirmed.
INTERPRETATION
Urine test samples with high levels of free TMA and subnormal percentage of trimethylamine N-oxide revealed the diagnosis of trimethylaminuria. There is no causal treatment. Patients are advised to avoid choline-rich foods and take hygienic measures.
Topics: Animals; Child; Fishes; Humans; Male; Metabolism, Inborn Errors; Methylamines; Mutation; Oxygenases
PubMed: 34597008
DOI: 10.4045/tidsskr.21.0142 -
Molecular Plant Dec 2023The diterpenoid paclitaxel (Taxol) is a chemotherapy medication widely used as a first-line treatment against several types of solid cancers. The supply of paclitaxel...
The diterpenoid paclitaxel (Taxol) is a chemotherapy medication widely used as a first-line treatment against several types of solid cancers. The supply of paclitaxel from natural sources is limited. However, missing knowledge about the genes involved in several specific metabolic steps of paclitaxel biosynthesis has rendered it difficult to engineer the full pathway. In this study, we used a combination of transcriptomics, cell biology, metabolomics, and pathway reconstitution to identify the complete gene set required for the heterologous production of paclitaxel. We identified the missing steps from the current model of paclitaxel biosynthesis and confirmed the activity of most of the missing enzymes via heterologous expression in Nicotiana benthamiana. Notably, we identified a new C4β-C20 epoxidase that could overcome the first bottleneck of metabolic engineering. We used both previously characterized and newly identified oxomutases/epoxidases, taxane 1β-hydroxylase, taxane 9α-hydroxylase, taxane 9α-dioxygenase, and phenylalanine-CoA ligase, to successfully biosynthesize the key intermediate baccatin III and to convert baccatin III into paclitaxel in N. benthamiana. In combination, these approaches establish a metabolic route to taxoid biosynthesis and provide insights into the unique chemistry that plants use to generate complex bioactive metabolites.
Topics: Synthetic Biology; Taxoids; Paclitaxel; Mixed Function Oxygenases
PubMed: 37897038
DOI: 10.1016/j.molp.2023.10.016 -
Archives of Biochemistry and Biophysics May 2020
Topics: Congresses as Topic; Heme Oxygenase (Decyclizing)
PubMed: 32105660
DOI: 10.1016/j.abb.2020.108321 -
Nature Mar 2022Activated T cells secrete interferon-γ, which triggers intracellular tryptophan shortage by upregulating the indoleamine 2,3-dioxygenase 1 (IDO1) enzyme. Here we show...
Activated T cells secrete interferon-γ, which triggers intracellular tryptophan shortage by upregulating the indoleamine 2,3-dioxygenase 1 (IDO1) enzyme. Here we show that despite tryptophan depletion, in-frame protein synthesis continues across tryptophan codons. We identified tryptophan-to-phenylalanine codon reassignment (W>F) as the major event facilitating this process, and pinpointed tryptophanyl-tRNA synthetase (WARS1) as its source. We call these W>F peptides 'substitutants' to distinguish them from genetically encoded mutants. Using large-scale proteomics analyses, we demonstrate W>F substitutants to be highly abundant in multiple cancer types. W>F substitutants were enriched in tumours relative to matching adjacent normal tissues, and were associated with increased IDO1 expression, oncogenic signalling and the tumour-immune microenvironment. Functionally, W>F substitutants can impair protein activity, but also expand the landscape of antigens presented at the cell surface to activate T cell responses. Thus, substitutants are generated by an alternative decoding mechanism with potential effects on gene function and tumour immunoreactivity.
Topics: Codon; Indoleamine-Pyrrole 2,3,-Dioxygenase; Interferon-gamma; Neoplasms; Phenylalanine; T-Lymphocytes; Tryptophan; Tryptophan Oxygenase; Tryptophan-tRNA Ligase
PubMed: 35264796
DOI: 10.1038/s41586-022-04499-2 -
The FEBS Journal Dec 2021Hypoxia has a significant impact on many physiological and pathological processes. Over the recent years, its role in modulation of epigenetic remodelling has also... (Review)
Review
Hypoxia has a significant impact on many physiological and pathological processes. Over the recent years, its role in modulation of epigenetic remodelling has also become clearer. In cancer, low oxygen environments and aberrant epigenomes often go hand in hand, and changes in DNA methylation are now commonly recognised as potential outcome indicators. TET (ten-eleven translocation) family enzymes are alpha-ketoglutarate-, iron- and oxygen-dependent DNA demethylases and are key players in these processes. Although TETs have historically been considered tumour suppressors, recent studies suggest that their functions in cancer might not be straightforward. Recently, inhibition of TETs has been reported to have positive impact in cancer immunotherapy and vaccination studies. This underlines the current interest in developing targeted pharmaceutical inhibitors of these enzymes. Here, we will survey the complexity of TET roles in cancer, and its hypoxic modulation, as well as highlight the potential of these enzymes as therapeutic targets.
Topics: Animals; Humans; Mixed Function Oxygenases; Neoplasms; Oxygen
PubMed: 33410283
DOI: 10.1111/febs.15695 -
Molecules (Basel, Switzerland) Sep 2023Catechols have important applications in the pharmaceutical, food, cosmetic, and functional material industries. 4-hydroxyphenylacetate-3-hydroxylase (4HPA3H), a... (Review)
Review
Catechols have important applications in the pharmaceutical, food, cosmetic, and functional material industries. 4-hydroxyphenylacetate-3-hydroxylase (4HPA3H), a two-component enzyme system comprising HpaB (monooxygenase) and HpaC (FAD oxidoreductase), demonstrates significant potential for catechol production because it can be easily expressed, is highly active, and exhibits -hydroxylation activity toward a broad spectrum of phenol substrates. HpaB determines the -hydroxylation efficiency and substrate spectrum of the enzyme; therefore, studying its structure-activity relationship, improving its properties, and developing a robust HpaB-conducting system are of significance and value; indeed, considerable efforts have been made in these areas in recent decades. Here, we review the classification, molecular structure, catalytic mechanism, primary efforts in protein engineering, and industrial applications of HpaB in catechol synthesis. Current trends in the further investigation of HpaB are also discussed.
Topics: Mixed Function Oxygenases; Catechols; Phenylacetates
PubMed: 37764475
DOI: 10.3390/molecules28186699 -
Archives of Biochemistry and Biophysics Sep 2019In this review we examine the effects of both over- and under-production of heme oxygenase-1 (HO-1) and HO activity on a broad spectrum of biological systems and on... (Review)
Review
In this review we examine the effects of both over- and under-production of heme oxygenase-1 (HO-1) and HO activity on a broad spectrum of biological systems and on vascular disease. In a few instances e.g., neonatal jaundice, overproduction of HO-1 and increased HO activity results in elevated levels of bilirubin requiring clinical intervention with inhibitors of HO activity. In contrast HO-1 levels and HO activity are low in obesity and the HO system responds to mitigate the deleterious effects of oxidative stress through increased levels of bilirubin (anti-inflammatory) and CO (anti-apoptotic) and decreased levels of heme (pro-oxidant). Site specific HO-1 overexpression diminishes adipocyte terminal differentiation and lipid accumulation of obesity mediated release of inflammatory molecules. A series of diverse strategies have been implemented that focus on increasing HO-1 and HO activity that are central to reversing the clinical complications associated with diseases including, obesity, metabolic syndrome and vascular disease.
Topics: Animals; Disease; Gene Expression Regulation, Enzymologic; Heme; Heme Oxygenase-1; Humans; Signal Transduction
PubMed: 31425676
DOI: 10.1016/j.abb.2019.108073 -
Indian Pediatrics Mar 2021
Topics: Anemia, Hemolytic; Growth Disorders; Heme Oxygenase-1; Humans; Iron Metabolism Disorders
PubMed: 33713076
DOI: 10.1007/s13312-021-2180-z