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Antimetabolites
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Mercaptopurine (Puri-NetholTM; 6MP) is given orally and used almost exclusively as maintenance therapy for acute leukemias and chronic myeloid leukemia and in the management of inflammatory bowel diseases such as ulcerative colitis and Crohn’s disease. The free-base form of mercaptopurine is converted by hypoxanthine-guanine 5-phosphoribosyl transferase (HGPRT) in sensitive tumor cells to 6-thio-inosine monophosphate (T-IMP), also called ribonucleotide 6-mercaptopurin-9-yl (MPRP). Although 6MP inhibits several enzymatic pathways in the biosynthesis of purine nucleotides, including ribonucleotide reductase mediated conversion of inosine-5′-phosphate to adenosine/guanosine-5′-phosphate, the main inhibitory action appears to occur at an earlier stage in de novo purine synthesis, when the conversion of 5′-phosphoribosylpyrophosphate to phosphoribosylamine by phosphoribosylpyrophosphate amidotransferase is inhibited by T-IMP. 6MP is also metabolized by ribonucleotide reductase to 6-thio-2′-deoxyguanosine-5′-triphosphate, which is incorporated into DNA and recognized by repair enzymes, thus leading to apoptosis. Resistance to mercaptopurine usually arises due to partial or complete down regulation of 5-phosphoribosyl transferase (HGPRT) within tumor cells.
BRCA Mutation and PARP Inhibitors
Published in Sherry X. Yang, Janet E. Dancey, Handbook of Therapeutic Biomarkers in Cancer, 2021
Arjun Mittra, James H. Doroshow, Alice P. Chen
PAR is degraded by Poly (ADP-ribose) glycohydrolase and possibly ADP-ribose hydrolase 3, into ADP-ribose molecules, which are metabolized further to AMP. The increased AMP: ATP ratio catalyzes the metabolic sensor AMP-activated protein kinase (AMPKs). Mammalian target of rapamycin complex 1 (MTORC1) is thereby inhibited, inducing autophagy [50]. Thus, cellular energy homeostasis is regulated. In the process of making PAR, NAD+ is converted to nicotinamide. To replenish the NAD+ from nicotinamide, phosphoribosyl pyrophosphate and ATP are converted to AMP and pyrophosphate (Fig. 15.1). In the case of extreme DNA damage, as with ischemia, PARP 1 hyperactivation results in depletion of NAD+ and ATP, resulting in cell death by necrosis or apoptosis [108].
Phosphoribosylpyrophosphate synthetase and its abnormalities
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop
5-Phosphoribosylpyrophosphate synthetase (EC 2.7. 6.2) (Figure 67.1) catalyzes the initial step in the de novo synthesis of purines in which ribose-5-P reacts with adenosine triphosphate (ATP) to form PRPP. The PRPP formed, provides the substrate for the first rate-limiting step in the ten-step purine de novo pathway. Increased quantities of intracellular PRPP lead to overproduction of purine de novo and of uric acid. PRPP synthetase is coded for by two genes on opposite arms the X chromosome at Xq22-24 and Xp22.2-22.3 [14, 15]. The genes have been cloned and sequenced [16] and referred to as PRPS1 and S2 [17]. A small number of point mutations have been defined in PRPS1 in patients with overactivity and altered allosteric properties of the enzyme.
Novel amides of mycophenolic acid and some heterocyclic derivatives as immunosuppressive agents
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Juliusz Maksymilian Walczak, Dorota Iwaszkiewicz-Grześ, Michalina Ziomkowska, Magdalena Śliwka-Kaszyńska, Mateusz Daśko, Piotr Trzonkowski, Grzegorz Cholewiński
Inosine-5′-monophosphate dehydrogenase (IMPDH) is an enzyme responsible for oxidation of inosine-5′-monophosphate into xanthine-5′-monophosphate (XMP) exploiting water molecule as well as NAD+ redox potential. This biotransformation is crucial for proper cell growth due to the fact that it triggers guanyl nucleotides formation which serve as RNA and DNA precursors, the energy reservoir for translation process, the cofactor for G-proteins as well as glycosylation precursor. Depletion of guanine-based nucleotides, which is induced by redirecting biosynthesis into adenine-based nucleotides pathway, results in impairment of de novo and salvage route of purine and pyrimidine nucleotides biosynthesis. This misregulation proceeds from phosphoribosyl pyrophosphate synthetase (PRPP) and ribonucleotides reductase (RNR) stimulation dependence accruing from guanine and adenine nucleotides. When the previous one activates enzymes’ bioactivities, the latter one inhibits them. Eventually, enhancement of adenosine nucleotides pool effects in malfunctioning of rapidly proliferating human cells1.
A metabolomic study on the anti-depressive effects of two active components from Chrysanthemum morifolium
Published in Artificial Cells, Nanomedicine, and Biotechnology, 2020
Tong Liu, Ning Zhou, Ruihao Xu, Yangang Cao, Yanli Zhang, Zhen Liu, Xiaoke Zheng, Weisheng Feng
Niacin is one of the 13 essential vitamins, and it can be converted to nicotinamide in the human body [38]. Niacin deficit symptoms include several nervous system pathologies, such as dementia and depression, as well as other symptoms resembling those observed in other neurodegenerative diseases [39]. In our study, a low level of niacin in depressed mice was detected. After the administration of Chr and its two active components, the level of nicotinuric acid increased significantly. In terms of energy metabolism, nicotinamide and phosphoribosyl- pyrophosphate combine to generate nicotinamide mononucleotide, which can continue to react with adenosine triphosphate (ATP) to generate coenzyme I. The generation of coenzyme II (NADP) is the result of the combination of coenzyme I and ATP. Coenzyme I and coenzyme II are coenzymes of dehydrogenase and indispensable substance transfer carriers in the human body that participate in the process of lipid metabolism and saccharide anaerobic decomposition. The symptoms of energy deficiency or fatigue in patients with major depression have been described above [36]. Chr and its two active components could increase the level of nicotinuric acid. Furthermore, as a direct metabolite of niacin, the level of nicotinuric acid increased after Chr/Nar/Api treatment, indicating that more niacin exerts its biological activity in the body. Thus, Chr/Nar/Api improved the energy supply by accelerating the niacin and niacinamide metabolism in depressed mice.
Late diagnosis of Lesch–Nyhan disease complicated with end-stage renal disease and tophi burst: a case report
Published in Renal Failure, 2020
Cahyani Gita Ambarsari, Daffodilone Cahyadi, Lenny Sari, Oryza Satria, Felly Sahli, Thyrza Laudamy Darmadi, Agustina Kadaristiana
LND is the most severe manifestation of HPRT deficiency. The spectrum of the clinical manifestations of HPRT deficiency varies depending on enzymatic activity. In LND, motor delay is accompanied by uric acid overproduction and behavioral disorders, as with the present case. Recurrent self-injurious behaviors (SIBs), such as biting of the fingers, hands, lips, and cheek, which can be accompanied with banging of head or legs, are hallmarks of LND. SIBs usually occur between the ages of 2 and 3 years, but almost always before the age of 4 years. Nevertheless, the onset of SIBs can be delayed up to the age of 20 years, which could delay or complicate a diagnosis of LND [7]. In partial HPRT deficiency (Kelly-Seegmiller syndrome), only uric acid overproduction occurs without neurological involvement [8]. Phosphoribosylpyrophosphate synthetase superactivity also presents with hyperuricemia, kidney stone, and neurological symptoms, however it exhibits hearing impairment, differing it from HPRT deficiency [9].