Introduction to Telomere Biology
Sara C. Zapico in Mechanisms Linking Aging, Diseases and Biological Age Estimation, 2017
During cellular replication, the lineal chromosome of eukaryotes suffers from a telomere shortening on each mitosis estimated at 100 bp in humans, due to the DNA replication process. DNA replication in eukaryotes is a semiconservative process, which means that it is carried out by copying the parental DNA strand, as originally suggested by Watson and Crick model (Watson and Crick 1953a). DNA replication starts by separating both strands of the double helix of DNA, which leaves one strand oriented in 5’-3’ sense and the other in reverse sense. The enzyme responsible for the de novo synthesis of DNA, the DNA polymerase, can only synthesize in the 5’-3’ sense, requiring a small oligonucleotide sequence (RNA primer) to start replication. The strand synthesized in that sense, called leading strand, is continuously synthesized to the end of the template strand. The end replication problem arises in the complementary strand, oriented in 3’-5’ sense. On this strand, the nascent DNA strand, called lagging strand, requires to be synthesized by small and discontinuous fragments, named Okazaki fragments, which are later bound by a ligase, replacing the RNA primers by DNA. As ligase requires a DNA strand in front of the primer, the last RNA primer is removed and therefore, DNA polymerase is unable to replicate the 3’ end from the template strand and the sequence is shortened in each mitotic cycle (Fig. 1).
Histone Metabolism
Lubomir S. Hnilica in The Structure and Biological Function of Histones, 1972
The appearance of protamines during spermatogenesis in fish was first studied by Miescher, who discovered this peculiar group of proteins almost a century ago. In the yet unpolluted river Rhine, the salmon fish (Salmo salar) were born in fresh water, matured in the ocean and, sexually mature, started their upstream journey back to the breeding grounds along the Rhine river. During this period, the fish accepted no food and their originally small testes enlarged many fold, filling with ripe spermatozoa. During the six to nine months of their upstream travel, the final stages of sperm maturation took place. The histones originally present in the spermatocytes were completely replaced by more primitive protamine. This replacement which occurs in many fish species was observed by Miescher and confirmed by others. Felix et al.636 analyzed the basic protein contents in testes of the brook char Salmo fontinalis at 10-day intervals during the sperm maturation, which begins approximately 90 days before spawning. The nucleoprotamine appeared suddenly, about 40 days before spawning. The late appearance of protamines replacing histone protein during maturation of spermatozoa was confirmed in Chinook salmon (Oncorhynchus tshawytscha) by Alfert.637 The protamines are biosynthesized after the cessation of DNA synthesis. It was assumed by early investigators that protamines represent the degradation products of more complex somatic proteins and histones. More recent investigations demonstrated however, that their de novo synthesis is regulated by mechanisms common to other cellular proteins.
Emerging ergogenic aids for strength/power development
Jay R Hoffman in Dietary Supplementation in Sport and Exercise, 2019
PA is a biosynthetic precursor to membrane glycerophospholipids and triacylglycerol. It can be synthesized via three major ways: 1) most commonly via de novo synthesis originating from glycerol-3-phosphate (a molecule formed during glycolysis). Two acylation reactions take place via the enzymes glycerol-3-phosphate acyltransferase and lysophosphatidic acid acyltransferase to form PA; 2) hydrolysis of phosphatidylcholine – the enzyme phospholipase D catalyzes the cleavage of the phosphodiester bond forming PA and choline; and 3) phosphorylation of diacylglycerol (DAG) by DAG kinase – DAG may be generated from triacylglycerol (from stored fat) or from the phospholipid phosphatidylinositol (6).
Pharmacokinetics, metabolism and off-target effects in the rat of 8-[(1H- benzotriazol-1-yl)amino]octanoic acid, a selective inhibitor of human cytochrome P450 4Z1: β-oxidation as a potential augmenting pathway for inhibition
Published in Xenobiotica, 2021
John P. Kowalski, Robert D. Pelletier, Matthew G. McDonald, Edward J. Kelly, Allan E. Rettie
Scaling in vitro data for the prediction of drug-drug interactions due to mechanism-based inactivation of CYPs for drug candidates has become common practice (Obach et al.2007). We previously characterized the MBI parameters in vitro for the inactivation of CYP4Z1 by 8-BOA, resulting in a KI = 2.2 µM and a kinact = 0.15 min−1 (Kowalski et al.2020). These values, taken together with the pharmacokinetic profile, allowed for an estimation of the potential CYP4Z1 inactivation that would occur in a xenograft model where the tumour expresses this enzyme. Contrary to an in vitro setting where the target enzyme can become virtually all depleted, de novo synthesis occurring in vivo will regenerate the enzyme pool concurrently. The turnover half-lives that have been determined for CYPs vary widely due to both isoform differences as well as the technically challenging, and indirect methods of measurement that are employed. As this information is clearly lacking for CYP4Z1, we used a t1/2, CYP range of 1–4 days to encompass the spectrum that has been reported for this constant (Zhang and Wong 2005, Yang et al.2008). Furthermore, for this simple exercise, intratumoral exposure to the unbound fraction of 8-BOA (2%) was modelled as occurring in the central compartment, ignoring both the lag-time to reach a peripheral tumour, and the potential for the concentration to build inside the tumour.
Cannabis for cancer – illusion or the tip of an iceberg: a review of the evidence for the use of Cannabis and synthetic cannabinoids in oncology
Published in Expert Opinion on Investigational Drugs, 2019
Ilit Turgeman, Gil Bar-Sela
Ceramides are a family of lipid molecules found within cell membranes that take part in regulating differentiation, proliferation and programmed cell death of cells. Cell lines of prostate cancer treated with the cannabinoid AEA demonstrated accumulation of ceramide alongside downregulation of epidermal growth factor, and a CB2 agonist triggered its de novo synthesis, leading to induction of cell death [52]. Ceramide also has a role in cannabinoid-induced apoptosis in pancreatic cancer cell lines via the CB2 receptor and ceramide dependent gene upregulation [53]. Additionally, antineoplastic effects of cannabinoids on gliomas appear vitally tied to ceramide levels. Highly aggressive, malignant and treatment-resistant brain tumors, gliomas express endocannabinoid receptors abundantly and are thereby common targets for cannabinoid research. Studies have shown that growth inhibitory effects of both selective and nonselective agonists are prevented by blocking ceramide synthesis [54]. Lastly, apoptosis associated with ceramide accumulation is also implicated in lymphoma cell lines [55].
An overview of late-stage functionalization in today’s drug discovery
Published in Expert Opinion on Drug Discovery, 2019
Michael Moir, Jonathan J. Danon, Tristan A. Reekie, Michael Kassiou
The importance of aryl fluorides in the pharmaceutical industry has seen the development of numerous methods for their synthesis through the conversion of various functional groups. However, there is a paucity of general methods for direct aromatic C–H fluorination. Yamaoto and coworkers have reported an undirected, palladium catalyzed method for C–H aromatic fluorination using a mild fluorine source (Selectfluor or NSFI) (Figure 5(f)) [65]. The reaction proceeds via a transition metal-fluoride electrophile that is reactive enough for the fluorination of otherwise inert arenes. The LSF of drug candidates is demonstrated (for example butyl ciprobrate) without the need for prefunctionalization or laborious de novo synthesis.