Genes of the thymidine salvage pathway: Thymine-7-hydroxylase from a Rhodotorula glutinis cDNA library and iso-orotate decarboxylase from Neurospora crassa

Smiley, Jeffrey A.; Kundracik, Melisa; Landfried, Daniel A.; Barnes, Vincient R.; Axhemi, Armend

doi:10.1016/j.bbagen.2005.02.001

Cited by 55 publications

(70 citation statements)

References 19 publications

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“…future science group in yeast [60], but no such carboxylase has yet been identified in mammals. Alternatively, it has been suggested that demethylation occurs through deamination of 5hmC to 5-hydroxymethyluracil with subsequent base-excision repair, resulting in a nonmodified CpG dinucleotide [61][62][63].…”

Section: Function and Distributionmentioning

confidence: 99%

5-Hydroxymethylcytosine Profiling as an Indicator of Cellular State

et al. 2013

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DNA methylation is widely studied in the context of cancer. However, the rediscovery of 5-hydroxymethylation of DNA adds a new layer of complexity to understanding the epigenetic basis of development and disease, including carcinogenesis. There have been significant advances in techniques for the detection of 5-hydroxymethylcytosine and, with this, greater insight into the distribution, regulation and function of this mark, which are reviewed here. Better understanding of the associated pathways involved in regulation of, and by, 5-hydroxymethylcytosine may give promise to new therapeutic targets. We discuss evidence to support the view of 5-hydroxymethylcytosine as a unique and dynamic mark of cellular state. These 5-hydroxymethylcytosine profiles may offer optimism for the development of diagnostic, prognostic and predictive biomarkers.

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Section: Function and Distributionmentioning

confidence: 99%

5-Hydroxymethylcytosine Profiling as an Indicator of Cellular State

et al. 2013

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“…Thymine 7-hydroxylase (THase), also a member of 2OG-dependent dioxygenases, acts as a key enzyme in the thymidine salvage pathway in fungi (e.g., Neurospora crassa) and catalyzes three sequential oxidation reactions to convert thymine (T) to iso-orotate, which is subsequently processed by a decarboxylase to produce uracil (U) (Smiley et al 2005;Neidigh et al 2009). Based on the similar chemistry between 5mC oxidation and the T-to-U conversion, we previously hypothesized that, in theory, Tet proteins should be able to further oxidize 5hmC to 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC) .…”

Section: Enzymatic Activity Of Tet Proteinsmentioning

confidence: 99%

Mechanisms and functions of Tet protein-mediated 5-methylcytosine oxidation

Wu¹,

Zhang²

2011

Genes Dev.

586

497

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Ten-eleven translocation 1-3 (Tet1-3) proteins have recently been discovered in mammalian cells to be members of a family of DNA hydroxylases that possess enzymatic activity toward the methyl mark on the 5-position of cytosine (5-methylcytosine [5mC]), a well-characterized epigenetic modification that has essential roles in regulating gene expression and maintaining cellular identity. Tet proteins can convert 5mC into 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC) through three consecutive oxidation reactions. These modified bases may represent new epigenetic states in genomic DNA or intermediates in the process of DNA demethylation. Emerging biochemical, genetic, and functional evidence suggests that Tet proteins are crucial for diverse biological processes, including zygotic epigenetic reprogramming, pluripotent stem cell differentiation, hematopoiesis, and development of leukemia. Insights into how Tet proteins contribute to dynamic changes in DNA methylation and gene expression will greatly enhance our understanding of epigenetic regulation of normal development and human diseases.

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“…2). The gene encoding T7H was recently identified, 18 and sequence comparisons reveal many homologues outside of the fungal kingdom including bacteria (e.g., Pseudomonas species and Xanthomonas campestris) and protists (e.g., Trypanosoma brucei). It is not known whether these gene products possess T7H activity.…”

Section: Pyrimidine and Purine Hydroxylases 21 Thymine 7-hydroxylasementioning

confidence: 99%

FeII/α-ketoglutarate hydroxylases involved in nucleobase, nucleoside, nucleotide, and chromatin metabolism

2008

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Fe II /α-ketoglutarate-dependent hydroxylases uniformly possess a double-stranded β-helix fold with two conserved histidines and one carboxylate coordinating their mononuclear ferrous ions. Oxidative decomposition of the α-keto acid is proposed to generate a ferryl-oxo intermediate capable of hydroxylating unactivated carbon atoms in a myriad of substrates. This perspective focuses on a subgroup of these enzymes that are involved in pyrimidine salvage, purine decomposition, nucleoside and nucleotide hydroxylation, DNA/RNA repair, and chromatin modification. The varied reaction schemes are presented, and selected structural and kinetic information is summarized. IntroductionFerrous ion and α-ketoglutarate (αKG)-dependent dioxygenases comprise an enzyme superfamily with members present in animals, plants, protists, fungi, bacteria and even viruses. Most representatives of this large group of enzymes couple the oxidative decarboxylation of αKG to various hydroxylation reactions ( Fig. 1), but others are capable of catalyzing desaturation, epoxidation, halogenation, ring formation, or ring expansion reactions, which allows them to fill a wide variety of biological roles including antibiotic biosynthesis, hypoxic sensing, DNA repair, and various types of metabolite transformations. [1][2][3] Not surprisingly, the primary substrates also are diverse and include proteins, lipids, nucleic acids, and a myriad of small molecules that can be used for synthesis or undergo degradation.The sequences of Fe II /αKG dioxygenases show little overall identity, yet the diverse reactions all are catalyzed by proteins with the same core fold and use similar chemistries. 4 The hallmark of these enzymes is their use of Fe II to activate molecular oxygen according to a mechanism (Scheme 1) first proposed by Hanauske-Abel and Günzler in 1982 for prolyl 4-hydroxylase. 5 (A) In the absence of substrates, a "facial triad" (usually two His plus one Asp or Glu occurring in a His-X-Asp/Glu-X n -His motif) weakly bind one face of the hexacoordinate metal. 6,7 (B) The αKG co-substrate displaces two waters and coordinates Fe II in a bidentate fashion with its C1 carboxyl and C2 keto oxygens. The binding of αKG is Correspondence to: Robert P. Hausinger, hausinge@msu.edu. NIH Public Access Author ManuscriptDalton Trans. Author manuscript; available in PMC 2010 July 20. This perspective focuses on the modification of nucleobases, nucleosides, nucleotides, and chromatin by the Fe II and αKG dependent hydroxylases (Table 1). We discuss the degradation and salvage of free bases by the fungal enzymes thymine 7-hydroxylase and xanthine hydroxylase. Next, nucleoside hydroxylases are briefly described. We then examine the developmental modification of DNA in kinetoplastid protozoans and summarize evidence that the JBP1 and JBP2 proteins possess thymidine hydroxylase activity. The oxidative repair of DNA by Escherichia coli AlkB is discussed, and the properties of mammalian homologues are summarized. Finally, we present emerging evidence pointing to...

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Genes of the thymidine salvage pathway: Thymine-7-hydroxylase from a Rhodotorula glutinis cDNA library and iso-orotate decarboxylase from Neurospora crassa

Cited by 55 publications

References 19 publications

5-Hydroxymethylcytosine Profiling as an Indicator of Cellular State

5-Hydroxymethylcytosine Profiling as an Indicator of Cellular State

Mechanisms and functions of Tet protein-mediated 5-methylcytosine oxidation

FeII/α-ketoglutarate hydroxylases involved in nucleobase, nucleoside, nucleotide, and chromatin metabolism

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