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Systemic Lupus Erythematosus
Published in Vincenzo Berghella, Maternal-Fetal Evidence Based Guidelines, 2022
Maria A. Giraldo-Isaza, Bettina F. Cuneo
Antimetabolite, blocks pyrimidine synthesis by inhibiting the dihydroorotate dehydrogenase. Avoid as no data available and long half-life of its metabolite, teriflunomide, is of concern. Wait 2 years after discontinuation of therapy to attempt conception. Cholestyramine washout is recommended if detectable levels prior to a planned pregnancy or once pregnant to accelerate clearance. This is achieved with a level of <0.02 mg/L documented in 2 occasions 14 days apart. The risk of congenital anomalies does not appear increased in those pregnancies exposed to leflunomide following cholestyramine washout [67].
Antimetabolites
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Ribonucleotide reductase, also known as nucleoside diphosphate reductase (or RNR), is involved late in both the purine and the pyrimidine synthesis pathways (see Figure 3.1). Only one ribonucleotide reductase (RNR) inhibitor, hydroxycarbamide (HydreaTM), is presently in clinical use, although two other inhibitors, triapine and tezacitabine, are in clinical development.
Nutritional Deficiencies
Published in Philip B. Gorelick, Fernando D. Testai, Graeme J. Hankey, Joanna M. Wardlaw, Hankey's Clinical Neurology, 2020
Deepa Bhupali, Fernando D. Testai
Dietary methionine is metabolized to S-adenosylmethionine, which is necessary for the methylation of myelin sheath products. Downstream, S-adenosylmethionine is converted to homocysteine, and this may enter the remethylation or the transsulfuration pathway. In the remethylation pathway, the methionine synthase, which requires methylcobalamin as a cofactor, catalyzes the reaction of homocysteine and methyltetrahydrofolate to produce methionine and tetrahydrofolate. Tetrahydrofolate is the precursor required for purine and pyrimidine synthesis (Figure 10.9). Adenosylcobalamin is necessary for the conversion of l-methylmalonyl-CoA to succinyl-CoA in the mitochondria (Figure 17.1).
Porphyromonas gingivalis diffusible signaling molecules enhance Fusobacterium nucleatum biofilm formation via gene expression modulation
Published in Journal of Oral Microbiology, 2023
Yukiko Yamaguchi-Kuroda, Yuichiro Kikuchi, Eitoyo Kokubu, Kazuyuki Ishihara
Eighty-seven genes were downregulated (Table 2), including those encoding protein involved in de novo synthesis of purine (phosphoribosyl amine-glucine ligase, purH, class I SAM-dependent methyltransferase, phosphoribosyl glycinamide formyl transferase, purM, amidophosphoribosyltransferase, phosphoribosylaminoimidazole-succinocarboxamide synthase, purE, and phosphoribosylformylglycinamidine synthetase), proteins involved in de novo pyrimidine synthesis (bifunctional pyr operon transcriptional regulator/uracil phosphoribosyltransferase PyrR, aspartate carbamoyltransferase, dihydroorotase, glutamine-hydrolyzing carbamoyl-phosphate synthase small subunit, carbamoyl-phosphate synthase large subunit, dihydroorotate dehydrogenase electron transfer subunit, dihydroorotate dehydrogenase, orotidine 5’-phosphate decarboxylase, and orotate phosphoribosyltransferase), bioA involved in biotin metabolism, and TonB-dependent receptor.
The role of biomarkers in stage III non-small cell lung cancer
Published in Expert Review of Respiratory Medicine, 2023
Rafael Rosell, María González-Cao, Masaoki Ito, Mariacarmela Santarpia, Andrés Aguilar, Jordi Codony-Servat
De novo synthesis of pyrimidines is cardinal in cancer-specific metabolic dependencies. De novo synthesis of pyrimidine nucleotides is a targetable vulnerability in many tumors, including lung cancer, targeting the gatekeeper DHODH expression, the rate-limiting step in de novo pyrimidine synthesis pathway. Treatment of cancer cells with GPX4 inhibitors leads to acute depletion of N-carbamoyl-aspartate, a pyrimidine biosynthesis intermediate, with accumulation of uridine. Importantly, inactivation of DHODH provokes mitochondrial lipid peroxidation and ferroptosis in cancer cells with low GPX4 expression, while there is synergism with ferroptosis inducers in cancer cells with high GPX4 expression [50]. DHODH prevents ferroptosis regardless of cytosolic GPX4 or ferroptosis suppressor protein 1 (FSP1). FSP1 acts in parallel to GPX4 to inhibit ferroptosis [51] (Figure 2). DHODH inhibits ferroptosis in the mitochondrial inner membrane by reducing ubiquinone to ubiquinol (a radical trapping antioxidant with anti-ferroptosis action). The DHODH inhibitor brequinar suppresses tumor growth with GPX4 low expression by inducing ferroptosis. Brequinar in combination with sulfasalazine (a SLC17A11 inhibitor) also caused ferroptosis in tumors with high expression of GPX4 [50].
Immune Response and Safety of Viral Vaccines in Children with Autoimmune Diseases on Immune Modulatory Drug Therapy
Published in Expert Review of Vaccines, 2020
Hiu Nam Tse, Ray Borrow, Peter D. Arkwright
Azathioprine (AZA), 6-mercaptopurine (MCP), mycophenolate mofetil (MMF), methotrexate (MTX), and leflunomide are antimetabolites that inhibit de novo DNA synthesis. Active drug metabolites inhibit Rac-1 activities by binding GTPases, which then leads to mitochondrial-driven T-cell apoptosis. 6-thio-GTP also triggers T-lymphocytes apoptosis by inhibiting CD28, a co-stimulatory signal that is required for T-cell activation [4,10]. Mycophenolate mofetil (MMF) inhibits purine metabolism and blocks inosine monophosphate dehydrogenase (IMPDH) and thus DNA replication [4]. Leflunomide blocks de novo pyrimidine synthesis. Activated T- and B-cells are arrested in the G1 phase of the cell cycle, inhibiting T-cell proliferation and B-cell antibody production [11]. MTX inhibits both purine and pyrimidine synthesis by blocking several key enzymes in de novo DNA synthesis [12]. It is also a folate antagonist and increases adenosine, activating an intracellular cascade that promotes an anti-inflammatory response [13]. Cyclophosphamide (CYCLO) is an alkylating agent that inhibits protein synthesis through DNA and RNA crosslinking after being metabolized to aldophosphamide and then phosphoramide and acrolein. Phospharamide cross-links adjacent DNA strands, inhibiting T- and B-cell proliferation [14].