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The Role of 2-Oxoglutarate Dependent Dioxygenases in Gliomas and Glioblastomas: A Review of Epigenetic Reprogramming and Hypoxic Response.

ABSTRACT: Gliomas are a heterogeneous group of cancers that predominantly arise from glial cells in the brain, but may also arise from neural stem cells, encompassing low-grade glioma and high-grade glioblastoma. Whereas better diagnosis and new treatments have improved patient survival for many cancers, glioblastomas remain challenging with a highly unfavorable prognosis. This review discusses a super-family of enzymes, the 2-oxoglutarate dependent dioxygenase enzymes (2-OGDD) that control numerous processes including epigenetic modifications and oxygen sensing, and considers their many roles in the pathology of gliomas. We specifically describe in more detail the DNA and histone demethylases, and the hypoxia-inducible factor hydroxylases in the context of glioma, and discuss the substrate and cofactor requirements of the 2-OGDD enzymes. Better understanding of how these enzymes contribute to gliomas could lead to the development of new treatment strategies.

SUBMITTER: Crake RLI

PROVIDER: S-EPMC8027507 | biostudies-literature |

REPOSITORIES: biostudies-literature

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2-Oxoglutarate-dependent dioxygenases in the biosynthesis of simple coumarins.

Project description:Coumarins are natural plant products that have been the subject of extensive phytochemical and pharmacological research studies in the past few decades. The core structure of coumarins is derived from the respective cinnamates via ortho-hydroxylation of the aromatic ring, trans/cis isomerization, and lactonization. Various substitution patterns of coumarins have been reported, whereas the biosynthesis of coumarins remains elusive. Ortho-hydroxylation is a key step in simple coumarin biosynthesis as a branch point from the lignin biosynthetic pathway. 2-Oxoglutarate-dependent dioxygenases (2OGDs) from plants convert cinnamate derivatives into simple coumarins through the process of ortho-hydroxylation. This review describes the 2OGDs involved in coumarin biosynthesis and their substrate specificities.

| S-EPMC4217350 | biostudies-literature

Distribution and prediction of catalytic domains in 2-oxoglutarate dependent dioxygenases.

Project description:BackgroundThe 2-oxoglutarate dependent superfamily is a diverse group of non-haem dioxygenases, and is present in prokaryotes, eukaryotes, and archaea. The enzymes differ in substrate preference and reaction chemistry, a factor that precludes their classification by homology studies and electronic annotation schemes alone. In this work, I propose and explore the rationale of using substrates to classify structurally similar alpha-ketoglutarate dependent enzymes.FindingsDifferential catalysis in phylogenetic clades of 2-OG dependent enzymes, is determined by the interactions of a subset of active-site amino acids. Identifying these with existing computational methods is challenging and not feasible for all proteins. A clustering protocol based on validated mechanisms of catalysis of known molecules, in tandem with group specific hidden markov model profiles is able to differentiate and sequester these enzymes. Access to this repository is by a web server that compares user defined unknown sequences to these pre-defined profiles and outputs a list of predicted catalytic domains. The server is free and is accessible at the following URL (http://comp-biol.theacms.in/H2OGpred.html).ConclusionsThe proposed stratification is a novel attempt at classifying and predicting 2-oxoglutarate dependent function. In addition, the server will provide researchers with a tool to compare their data to a comprehensive list of HMM profiles of catalytic domains. This work, will aid efforts by investigators to screen and characterize putative 2-OG dependent sequences. The profile database will be updated at regular intervals.

| S-EPMC3475032 | biostudies-literature

Functional diversity of 2-oxoglutarate/Fe(II)-dependent dioxygenases in plant metabolism.

Project description:Oxidative enzymes catalyze many different reactions in plant metabolism. Among this suite of enzymes are the 2-oxoglutarate/Fe(II)-dependent dioxygenases (2-ODDs). Cytochromes P450 (CYPs) as often considered the most versatile oxidative enzymes in nature, but the diversity and complexity of reactions catalyzed by 2-ODDs is superior to the CYPs. The list of oxidative reactions catalyzed by 2-ODDs includes hydroxylations, demethylations, desaturations, ring closure, ring cleavage, epimerization, rearrangement, halogenation, and demethylenation. Furthermore, recent work, including the discovery of 2-ODDs involved in epigenetic regulation, and others catalyzing several characteristic steps in specialized metabolic pathways, support the argument that 2-ODDs are among the most versatile and important oxidizing biological catalysts. In this review, we survey and summarize the pertinent literature with a focus on several key reactions catalyzed by 2-ODDs, and discuss the significance and impact of these enzymes in plant metabolism.

| S-EPMC4191161 | biostudies-literature

2-oxoglutarate-dependent dioxygenases: A renaissance in attention for ascorbic acid in plants.

Project description:L-Ascorbic acid (ascorbate, Vitamin C) is an essential human micronutrient that is predominantly obtained from plants. It is known to work as the major antioxidant in plants, and it underpins several environmentally induced stresses due to its use as a co-factor by certain 2-oxoglutarate-dependent (2-OG) dioxygenases [2(OG)-dioxygenases]. It is important to understand the role of 2(OG)-dioxygenases in the biosynthesis of ascorbate. The present study examined contents of ascorbate and protein-protein interaction in nine T-DNA mutants of Arabidopsis containing an insert in their respective (2-OG) dioxygenase genes (At1g20270, At1g68080, At2g17720, At3g06290, At3g28490, At4g35810, At4g35820, At5g18900, At5g66060). In this study, the amount of ascorbate in five of the mutants was shown to be almost two-fold or more than two-fold higher than in the wild type. This result may be a consequence of the insertion of the T-DNA. The prediction of possible protein interactions between 2(OG)-dioxygenases and relevant ascorbate-function players may indicate the oxidative effects of certain dioxygenase proteins in plants. It is expected that certain dioxygenases are actively involved in the metabolic and biosynthetic pathways of ascorbate. This involvement may be of importance to increase ascorbate amounts in plants for human nutrition, and to protect plant species against stress conditions.

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Roles of HIF and 2-Oxoglutarate-Dependent Dioxygenases in Controlling Gene Expression in Hypoxia.

Project description:Hypoxia-reduction in oxygen availability-plays key roles in both physiological and pathological processes. Given the importance of oxygen for cell and organism viability, mechanisms to sense and respond to hypoxia are in place. A variety of enzymes utilise molecular oxygen, but of particular importance to oxygen sensing are the 2-oxoglutarate (2-OG) dependent dioxygenases (2-OGDs). Of these, Prolyl-hydroxylases have long been recognised to control the levels and function of Hypoxia Inducible Factor (HIF), a master transcriptional regulator in hypoxia, via their hydroxylase activity. However, recent studies are revealing that dioxygenases are involved in almost all aspects of gene regulation, including chromatin organisation, transcription and translation. We highlight the relevance of HIF and 2-OGDs in the control of gene expression in response to hypoxia and their relevance to human biology and health.

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Epigenetic Reprogramming for Targeting IDH-Mutant Malignant Gliomas.

Project description:Targeting the epigenome has been considered a compelling treatment modality for several cancers, including gliomas. Nearly 80% of the lower-grade gliomas and secondary glioblastomas harbor recurrent mutations in isocitrate dehydrogenase (IDH). Mutant IDH generates high levels of 2-hydroxyglutarate (2-HG) that inhibit various components of the epigenetic machinery, including histone and DNA demethylases. The encouraging results from current epigenetic therapies in hematological malignancies have reinvigorated the interest in solid tumors and gliomas, both preclinically and clinically. Here, we summarize the recent advancements in epigenetic therapy for lower-grade gliomas and discuss the challenges associated with current treatment options. A particular focus is placed on therapeutic mechanisms underlying favorable outcome with epigenetic-based drugs in basic and translational research of gliomas. This review also highlights emerging bridges to combination treatment with respect to epigenetic drugs. Given that epigenetic therapies, particularly DNA methylation inhibitors, increase tumor immunogenicity and antitumor immune responses, appropriate drug combinations with immune checkpoint inhibitors may lead to improvement of treatment effectiveness of immunotherapy, ultimately leading to tumor cell eradication.

| S-EPMC6826741 | biostudies-literature

Unity in diversity, a systems approach to regulating plant cell physiology by 2-oxoglutarate-dependent dioxygenases.

Project description:Could a disjoint group of enzymes synchronize their activities and execute a complex multi-step, measurable, and reproducible response? Here, I surmise that the alpha-ketoglutarate dependent superfamily of non-haem iron (II) dioxygenases could influence cell physiology as a cohesive unit, and that the broad spectra of substrates transformed is an absolute necessity to this portrayal. This eclectic group comprises members from all major taxa, and participates in pesticide breakdown, hypoxia signaling, and osmotic stress neutralization. The oxidative decarboxylation of 2-oxoglutarate to succinate is coupled with a concomitant substrate hydroxylation and, in most cases, is followed by an additional specialized conversion. The domain profile of a protein sequence was used as an index of miscellaneous reaction chemistry and interpreted alongside existent kinetic data in a linear model of integrated function. Statistical parameters were inferred by the creation of a novel, empirically motivated flat-file database of over 3800 sequences (DB2OG) with putative 2-oxoglutarate dependent activity. The collated information was categorized on the basis of existing annotation schema. The data suggests that 2OG-dependent enzymes incorporate several desirable features of a systems level player. DB2OG, is free, accessible without a login to all users, and available at the following URL (http://comp-biol.theacms.in/DB2OG.html).

| S-EPMC4356072 | biostudies-literature

Functional Characterisation of Banana (<i>Musa</i> spp.) 2-Oxoglutarate-Dependent Dioxygenases Involved in Flavonoid Biosynthesis.

Project description:Bananas (Musa) are non-grass, monocotyledonous, perennial plants that are well known for their edible fruits. Their cultivation provides food security and employment opportunities in many countries. Banana fruits contain high levels of minerals and phytochemicals, including flavonoids, which are beneficial for human nutrition. To broaden the knowledge on flavonoid biosynthesis in this major crop plant, we aimed to identify and functionally characterise selected structural genes encoding 2-oxoglutarate-dependent dioxygenases, involved in the formation of the flavonoid aglycon. Musa candidates genes predicted to encode flavanone 3-hydroxylase (F3H), flavonol synthase (FLS) and anthocyanidin synthase (ANS) were assayed. Enzymatic functionalities of the recombinant proteins were confirmed in vivo using bioconversion assays. Moreover, transgenic analyses in corresponding Arabidopsis thaliana mutants showed that MusaF3H, MusaFLS and MusaANS were able to complement the respective loss-of-function phenotypes, thus verifying functionality of the enzymes in planta. Knowledge gained from this work provides a new aspect for further research towards genetic engineering of flavonoid biosynthesis in banana fruits to increase their antioxidant activity and nutritional value.

| S-EPMC8415913 | biostudies-literature

EZH2 promotes metabolic reprogramming in glioblastomas through epigenetic repression of EAF2-HIF1α signaling.

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| S-EPMC5216711 | biostudies-literature

Epigenetic Reprogramming of Kaposi's Sarcoma-Associated Herpesvirus during Hypoxic Reactivation.

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| S-EPMC9654037 | biostudies-literature

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