scholarly journals DHODH and cancer: promising prospects to be explored

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Yue Zhou ◽  
Lei Tao ◽  
Xia Zhou ◽  
Zeping Zuo ◽  
Jin Gong ◽  
...  
Keyword(s):  
Biological Function ◽  
De Novo ◽  
Mitochondrial Respiratory Chain ◽  
Cancer Therapies ◽  
Dihydroorotate Dehydrogenase ◽  
Specific Mechanism ◽  
Pyrimidine Synthesis ◽  
The Past ◽  
De Novo Pyrimidine Synthesis ◽  
Fourth Step

AbstractHuman dihydroorotate dehydrogenase (DHODH) is a flavin-dependent mitochondrial enzyme catalyzing the fourth step in the de novo pyrimidine synthesis pathway. It is originally a target for the treatment of the non-neoplastic diseases involving in rheumatoid arthritis and multiple sclerosis, and is re-emerging as a validated therapeutic target for cancer therapy. In this review, we mainly unravel the biological function of DHODH in tumor progression, including its crucial role in de novo pyrimidine synthesis and mitochondrial respiratory chain in cancer cells. Moreover, various DHODH inhibitors developing in the past decades are also been displayed, and the specific mechanism between DHODH and its additional effects are illustrated. Collectively, we detailly discuss the association between DHODH and tumors in recent years here, and believe it will provide significant evidences and potential strategies for utilizing DHODH as a potential target in preclinical and clinical cancer therapies.

scholarly journals Identification of 3,4-Dihydro-2H,6H-pyrimido[1,2-c][1,3]benzothiazin-6-imine Derivatives as Novel Selective Inhibitors of Plasmodium falciparum Dihydroorotate Dehydrogenase

2021 ◽  
Vol 22 (13) ◽  
pp. 7236
Author(s):  
Endah Dwi Hartuti ◽  
Takaya Sakura ◽  
Mohammed S. O. Tagod ◽  
Eri Yoshida ◽  
Xinying Wang ◽  
...  
Keyword(s):  
Drug Target ◽  
De Novo ◽  
Dihydroorotate Dehydrogenase ◽  
Chemical Library ◽  
New Class ◽  
De Novo Biosynthesis ◽  
Starting Point ◽  
Novel Drugs ◽  
Low Toxicity ◽  
Fourth Step

Plasmodium falciparum’s resistance to available antimalarial drugs highlights the need for the development of novel drugs. Pyrimidine de novo biosynthesis is a validated drug target for the prevention and treatment of malaria infection. P. falciparum dihydroorotate dehydrogenase (PfDHODH) catalyzes the oxidation of dihydroorotate to orotate and utilize ubiquinone as an electron acceptor in the fourth step of pyrimidine de novo biosynthesis. PfDHODH is targeted by the inhibitor DSM265, which binds to a hydrophobic pocket located at the N-terminus where ubiquinone binds, which is known to be structurally divergent from the mammalian orthologue. In this study, we screened 40,400 compounds from the Kyoto University chemical library against recombinant PfDHODH. These studies led to the identification of 3,4-dihydro-2H,6H-pyrimido[1,2-c][1,3]benzothiazin-6-imine and its derivatives as a new class of PfDHODH inhibitor. Moreover, the hit compounds identified in this study are selective for PfDHODH without inhibition of the human enzymes. Finally, this new scaffold of PfDHODH inhibitors showed growth inhibition activity against P. falciparum 3D7 with low toxicity to three human cell lines, providing a new starting point for antimalarial drug development.

scholarly journals Cellular pyrimidine imbalance triggers mitochondrial DNA–dependent innate immunity

2021 ◽  
Author(s):  
Hans-Georg Sprenger ◽  
Thomas MacVicar ◽  
Amir Bahat ◽  
Kai Uwe Fiedler ◽  
Steffen Hermans ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Cultured Cells ◽  
De Novo ◽  
Metabolic Response ◽  
Interferon Response ◽  
Type I ◽  
Nucleotide Synthesis ◽  
Pyrimidine Synthesis ◽  
Pyrimidine Nucleotide ◽  
De Novo Pyrimidine Synthesis

AbstractCytosolic mitochondrial DNA (mtDNA) elicits a type I interferon response, but signals triggering the release of mtDNA from mitochondria remain enigmatic. Here, we show that mtDNA-dependent immune signalling via the cyclic GMP–AMP synthase‒stimulator of interferon genes‒TANK-binding kinase 1 (cGAS–STING–TBK1) pathway is under metabolic control and is induced by cellular pyrimidine deficiency. The mitochondrial protease YME1L preserves pyrimidine pools by supporting de novo nucleotide synthesis and by proteolysis of the pyrimidine nucleotide carrier SLC25A33. Deficiency of YME1L causes inflammation in mouse retinas and in cultured cells. It drives the release of mtDNA and a cGAS–STING–TBK1-dependent inflammatory response, which requires SLC25A33 and is suppressed upon replenishment of cellular pyrimidine pools. Overexpression of SLC25A33 is sufficient to induce immune signalling by mtDNA. Similarly, depletion of cytosolic nucleotides upon inhibition of de novo pyrimidine synthesis triggers mtDNA-dependent immune responses in wild-type cells. Our results thus identify mtDNA release and innate immune signalling as a metabolic response to cellular pyrimidine deficiencies.

scholarly journals ASLAN003, a potent dihydroorotate dehydrogenase inhibitor for differentiation of acute myeloid leukemia

Haematologica ◽  
2019 ◽  
Vol 105 (9) ◽  
pp. 2286-2297 ◽  
Author(s):  
Jianbiao Zhou ◽  
Jessie Yiying Quah ◽  
Yvonne Ng ◽  
Jing-Yuan Chooi ◽  
Sabrina Hui-Min Toh ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Acute Promyelocytic Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Leukemia Cell ◽  
Promyelocytic Leukemia ◽  
Dihydroorotate Dehydrogenase ◽  
Isocitrate Dehydrogenase 1 ◽  
Pyrimidine Synthesis ◽  
Acute Myeloid

Differentiation therapies achieve remarkable success in acute promyelocytic leukemia, a subtype of acute myeloid leukemia. However, excluding acute promyelocytic leukemia, clinical benefits of differentiation therapies are negligible in acute myeloid leukemia except for mutant isocitrate dehydrogenase 1/2. Dihydroorotate dehydrogenase catalyses the fourth step of the de novo pyrimidine synthesis pathway. ASLAN003 is a highly potent dihydroorotate dehydrogenase inhibitor that induces differentiation, as well as reduces cell proliferation and viability, of acute myeloid leukemia cell lines and primary acute myeloid leukemia blasts including in chemo-resistant cells. Apoptotic pathways are triggered by ASLAN003, and it also significantly inhibits protein synthesis and activates AP-1 transcription, contributing to its differentiation promoting capacity. Finally, ASLAN003 substantially reduces leukemic burden and prolongs survival in acute myeloid leukemia xenograft mice and acute myeloid leukemia patient-derived xenograft models. Notably, the drug has no evident effect on normal hematopoietic cells and exhibits excellent safety profiles in mice, even after a prolonged period of administration. Our results, therefore, suggest that ASLAN003 is an agent targeting dihydroorotate dehydrogenase with potential in the treatment of acute myeloid leukemia. ASLAN003 is currently being evaluated in phase 2a clinical trial in acute myeloid leukemia patients.

scholarly journals Function and Evolution of Plasmid-Borne Genes for Pyrimidine Biosynthesis in Borrelia spp

2006 ◽  
Vol 188 (3) ◽  
pp. 909-918 ◽  
Author(s):  
Jianmin Zhong ◽  
Stephane Skouloubris ◽  
Qiyuan Dai ◽  
Hannu Myllykallio ◽  
Alan G. Barbour
Keyword(s):  
Thymidylate Synthase ◽  
De Novo ◽  
Linear Plasmid ◽  
Borrelia Hermsii ◽  
Borrelia Garinii ◽  
E Coli ◽  
Pyrimidine Synthesis ◽  
De Novo Pyrimidine Synthesis

ABSTRACT The thyX gene for thymidylate synthase of the Lyme borreliosis (LB) agent Borrelia burgdorferi is located in a 54-kb linear plasmid. In the present study, we identified an orthologous thymidylate synthase gene in the relapsing fever (RF) agent Borrelia hermsii, located it in a 180-kb linear plasmid, and demonstrated its expression. The functions of the B. hermsii and B. burgdorferi thyX gene products were evaluated both in vivo, by complementation of a thymidylate synthase-deficient Escherichia coli mutant, and in vitro, by testing their activities after purification. The B. hermsii thyX gene complemented the thyA mutation in E. coli, and purified B. hermsii ThyX protein catalyzed the conversion of dTMP from dUMP. In contrast, the B. burgdorferi ThyX protein had only weakly detectable activity in vitro, and the B. burgdorferi thyX gene did not provide complementation in vivo. The lack of activity of B. burgdorferi's ThyX protein was associated with the substitution of a cysteine for a highly conserved arginine at position 91. The B. hermsii thyX locus was further distinguished by the downstream presence in the plasmid of orthologues of nrdI, nrdE, and nrdF, which encode the subunits of ribonucleoside diphosphate reductase and which are not present in the LB agents B. burgdorferi and Borrelia garinii. Phylogenetic analysis suggested that the nrdIEF cluster of B. hermsii was acquired by horizontal gene transfer. These findings indicate that Borrelia spp. causing RF have a greater capability for de novo pyrimidine synthesis than those causing LB, thus providing a basis for some of the biological differences between the two groups of pathogens.

scholarly journals Missense mutation of the COQ2 gene causes defects of bioenergetics and de novo pyrimidine synthesis

2007 ◽  
Vol 16 (9) ◽  
pp. 1091-1097 ◽  
Author(s):  
José M. López-Martín ◽  
Leonardo Salviati ◽  
Eva Trevisson ◽  
Giovanni Montini ◽  
Salvatore DiMauro ◽  
...  
Keyword(s):  
Missense Mutation ◽  
De Novo ◽  
Pyrimidine Synthesis ◽  
De Novo Pyrimidine Synthesis

scholarly journals Diversion of aspartate in ASS1-deficient tumours fosters de novo pyrimidine synthesis

Nature ◽  
2015 ◽  
Vol 527 (7578) ◽  
pp. 379-383 ◽  
Author(s):  
Shiran Rabinovich ◽  
Lital Adler ◽  
Keren Yizhak ◽  
Alona Sarver ◽  
Alon Silberman ◽  
...  
Keyword(s):  
De Novo ◽  
Pyrimidine Synthesis ◽  
De Novo Pyrimidine Synthesis

scholarly journals Pyrimidine nucleotide availability is essential for efficient photosynthesis, ROS scavenging, and organelle development

2021 ◽  
Author(s):  
Leo Bellin ◽  
Michael Melzer ◽  
Alexander Hilo ◽  
Diana Laura Garza Amaya ◽  
Isabel Keller ◽  
...  
Keyword(s):  
De Novo ◽  
Energy State ◽  
Chloroplast Ultrastructure ◽  
Low Energy ◽  
Ros Scavenging ◽  
Nucleotide Synthesis ◽  
Knock Down ◽  
Pyrimidine Synthesis ◽  
Pyrimidine Nucleotide ◽  
De Novo Pyrimidine Synthesis

ABSTRACTDe novo synthesis of pyrimidines is an essential and highly conserved pathway in all organisms. A peculiarity in plants is the localization of the first committed step, catalyzed by aspartate transcarbamoylase (ATC), in chloroplasts. By contrast, the third step in the pathway is catalyzed by dihydroorotate dehydrogenase (DHODH) localized in mitochondria in eukaryotes, including plants. To unravel pathway- and organelle specific functions, we analyzed knock-down mutants in ATC and DHODH in detail. ATC knock-downs were most severely affected, exhibiting low levels of pyrimidine metabolites, a low energy state, reduced photosynthetic capacity and accumulated reactive oxygen species (ROS). Furthermore, we observed altered leaf morphology and chloroplast ultrastructure in the mutants. Although less affected, DHODH knock-down mutants showed impaired seed germination and altered mitochondrial ultrastructure. Our results point to an integration of de novo pyrimidine synthesis and cellular energy states via photosynthesis and mitochondrial respiration. These findings highlight the likelihood of further regulatory roles for ATC and DHODH in pathways located in the corresponding organelles.ONE-SENTENCE SUMMARYImpaired pyrimidine nucleotide synthesis results in a low energy state, affecting photosynthesis and organellar ultrastructure, thus leading to reduced growth, reproduction, and seed yield

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