BRCA Mutation and PARP Inhibitors
Sherry X. Yang, Janet E. Dancey in Handbook of Therapeutic Biomarkers in Cancer, 2021
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].
Lesch–Nyhan disease and variants
William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop in Atlas of Inherited Metabolic Diseases, 2020
The molecular defect in the Lesch–Nyhan disease is in the activity of the enzyme HPRT (E.C.2.4.2.8.) (see Figure 65.1). This enzyme catalyzes the reaction of hypoxanthine or guanine with phosphoribosyl pyrophosphate (PRPP) to form their respective nucleotides, inosinic, and guanylic acids. The enzyme is present in all cells of the body. It is particularly active in the basal ganglia and testis. The defect is readily detectable in erythrocyte hemolysates and in cultured fibroblasts. In the erythrocyte, quantitative assays reveal no activity in patients with classic phenotype.
Mechanisms of Resistance to Antineoplastic Drugs
Robert I. Glazer in Developments in Cancer Chemotherapy, 2019
Phosphoribosyl pyrophosphate (PRPP) is another important intracellular cofactor whose levels influence the activation of several antineoplastic antimetabolites, such as 5-FU and 6-MP.97-98 Lowering of PRPP levels can lead to thiopurine resistance, while increased levels of PRPP enhance the efficacy of these agents. Indeed, the increased toxicity observed in vitro when MTX is administered before 5-FU is believed to be due to the antifolate-induced increase in PRPP levels and subsequent increased activation of 5-FU.
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.
Drug safety in thyroid eye disease – a systematic review
Published in Expert Opinion on Drug Safety, 2022
Jan Wolf, Kamila I. Mitka, Alicja Hubalewska-Dydejczyk, Irene Krämer, George J Kahaly
Azathioprine (Aza) is a nonspecific, cell-cycle dependent immunosuppressive agent. Aza is converted in vivo in its active form 6-mercaptopurin (6-MP). As a prodrug, Aza has a higher bioavailability and is more frequently administered than 6-MP [79,80]. Aza inhibits early the de novo synthesis of purine bases. 6-MP inhibits the conversion of inosine monophosphate (IMP) into adenosine monophosphate (AMP) and guanosine monophosphate (GMP). In addition, 6-MP has a negative pseudo feedback on the synthesis of IMP, out of 5-phosphoribosyl-pyrophosphate (PRPP). A less relevant mechanism of 6-MP is the incorporation in the deoxyribonucleic acid (DNA) or ribonucleic acid (RNA) [81]. Since not all immunosuppressive effects result from the above mechanisms, other involved metabolites than 6-MP are presumed. Aza may beneficially impact TED signs and symptoms [82] and may prevent the development of exophthalmos [83]. In uncontrolled case-series [82], five patients received Aza (2 mg/kg). Treatment duration was 8–11 weeks, while one patient was treated for 36 weeks. Two patients received additionally OGC (50–60 mg/d prednisone). Nausea was the only SE reported.
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.
Related Knowledge Centers
- DNA
- Nucleotide
- Purine
- Pyrimidine
- Rna
- Thiamine
- Tryptophan
- Vitamin B12
- Sugar Phosphates
- Inosinic Acid