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Nutrient Metabolism and Fetal Brain Development
Published in Emilio Herrera, Robert H. Knopp, Perinatal Biochemistry, 2020
George E. Shambaugh, Boyd E. Metzger, James A. Radosevich
In the fetal brain, amino acids are utilized for biosynthesis of purines, pyrimidines, and polyamines. The de novo pathway for pyrimidine biosynthesis is summarized in Figure 3 and begins with the combination of nitrogen from glutamine with bicarbonate, a reaction catalyzed by carbamyl phosphate synthetase. Carbamyl phosphate is converted to carbamyl aspartate and dihydro orotic acid. The capacity for glutamine synthesis in the fetal brain and the low KM for glutamine make the synthesis of carbamyl phosphate an effective means for reutilizing ammonia derived from maternal gluconeogenesis or transamination of branched-chain amino acids.14 The de novo pathway for purine biosynthesis also fixes nitrogen that is spared from urea synthesis.
Diamond-Blackfan Anemia
Published in Stephen A. Feig, Melvin H. Freedman, Clinical Disorders and Experimental Models of Erythropoietic Failure, 2019
Jeffrey M. Lipton, Blanche P. Alter
The observation of abnormalities in purine or pyrimidine biosynthesis has not as yet been helpful in understanding the pathophysiology of DBA. RBCs of some patients with acute leukemia, adult chronic myelogenous leukemia, myeloproliferative disorder with Down syndrome, dyskeratosis with pancytopenia, and megaloblastic anemia were also found to have increased ADA activity.103 This suggests an association of elevated ADA activity with abnormal progenitor function, supporting the concept that DBA is the consequence of an intrinsic progenitor defect. Also of interest is the observation that W/Wv and S1/S1D mice with genetically determined RBC failure have elevated erythrocyte nucleoside deaminase levels.106 Further advances in this area must await a detailed understanding of the biochemistry of hematopoiesis. From a practical perspective, ADA activity levels provide a reasonably useful means for distinction of DBA from TEC (see Section VI). Laboratory investigations continue in search of abnormalities that will suggest pathophysiology or be of predictive value in distinguishing steroid responders from non-responders in DBA.
History of antifungals
Published in Mahmoud A. Ghannoum, John R. Perfect, Antifungal Therapy, 2019
Emily L. Larkin, Ali Abdul Lattif Ali, Kim Swindell
F901318 impedes pyrimidine biosynthesis by inhibiting the fungal enzyme dihydroorotate dehydrogenase [95]. This new antifungal is ineffective against Candida species but is highly active against molds such as Aspergillus, Scedosporium, and Lomentospora, including azole-resistant types [95–97]. Like APX001, humans have their own version of dihydroorotate dehydrogenase, which is not inhibited by F901318, indicating that it will have a low toxicity that has been demonstrated in in vivo models [95]. Clinical trials to evaluate its tolerability and safety have been undertaken.
Mirvetuximab soravtansine for platinum-resistant epithelial ovarian cancer
Published in Expert Review of Anticancer Therapy, 2023
Rebecca L. Porter, Ursula A. Matulonis
Folates are essential for purine and pyrimidine biosynthesis and in turn for DNA synthesis and repair [36,37]. The predominant mechanism for transporting reduced folates into normal cells is via the constitutively expressed low affinity reduced folate carrier [38]. Folates are also transported unidirectionally via receptor-mediated endocytosis by the high-affinity folate receptor family of glycoproteins [39], of which FRα is the most well characterized. FRα expression in normal cells is restricted to polarized epithelial tissues such as in the choroid plexus, kidney, uterus, ovary, lung, and placenta [40], but it is aberrantly expressed in several epithelial cancer types including EOC, endometrial, and non-small cell lung cancer [41]. In EOC, 80% or more of tumors have shown aberrant constitutive expression of FRα across studies [42–44], most notably in HGSOC [45]. Further, overexpression correlates with worse prognosis [46,47], rationalizing this as a potential therapeutic target in HGSOC.
Lipidic cubic-phase leflunomide nanoparticles (cubosomes) as a potential tool for breast cancer management
Published in Drug Delivery, 2022
Mariam Zewail, Passent M. E. Gaafar, Mai M. Ali, Haidy Abbas
Leflunomide (LEF) is an isoxazole derivative prodrug that was first approved for rheumatoid arthritis treatment at 1998. It showed promising results for its application as an anti-tumor agent. Upon administration, LEF is completely metabolized to its active metabolite teriflunomide (A771726) (Zhang & Chu, 2018). The prodrug activation was even confirmed in the skin upon topical administration (Bae & Park, 2016). LEF exerts its pharmacological anti-tumor effects by several mechanisms. It can act by inhibiting the de novo pyrimidine biosynthesis through suppression of mitochondrial dihydroorotatedehydrogenase (DHODH) enzyme which plays a vital role in cancer cells apoptosis through suppression of B and T cells (Sanders & Harisdangkul, 2002; Keen et al., 2013; Zhang & Chu, 2018; Zewail, 2021). Also, LEF can act as a tyrosine kinase inhibitor and was used for the treatment of several types of tumors (Pytel, Sliwinski et al., 2009). In addition, LEF showed selective inhibition of platelet-derived growth factor (PDGF) mediated phosphorylation. Signals through PDGF stimulate numerous functions such as cell growth, proliferation, and differentiation (Zhang & Chu, 2018). Furthermore, LEF can act as aryl hydrocarbon receptor (AhR) agonist by stimulating AhR which can inhibit cancer cells’ proliferation and act as a tumor suppressor in cancer animal models (O’Donnell et al., 2010). Furthermore, it was reported that LEF can inhibit stemness of cancer stem cells (White et al., 2011).
Targeted drug therapy in non-small cell lung cancer: Clinical significance and possible solutions-Part I
Published in Expert Opinion on Drug Delivery, 2021
Archana Upadhya, Khushwant S. Yadav, Ambikanandan Misra
Pemetrexed is a multi-targeted antifolate that inhibits enzymes involved in folate metabolism and inhibits purine, pyrimidine biosynthesis. The inhibited enzymes are thymidylate synthetase (TS), dihydrofolate reductase (DHFR) and glycinamide ribonucleotide formyltransferase (GARFT) [126]. Pemetrexed is transported within the cell through a reduced folate carrier (RFc). In the cell, pemetrexed is polyglutamated by folypolyglutamate synthetase (FPGS). Polyglutamated pemetrexed is a strong inhibitor of enzymes involved in purine synthesis such as TS, GRAFT and to a lesser extent of AICARFT and DHFR [127]. Pemetrexed resistance is mainly associated with increased levels of TS, decreased levels of FPGS, increased levels of folypolyglutamate hydrolase, elevated levels of GRAFT, RRMI, and MTHFR (methylenetetrahydrofolate reductase) [128]. Additionally, a higher status of DNA repair systems such as BER, NER, as well as CHK1, MSH2, and Ku protein may contribute to resistance to pemetrexed in NSCLC [128].