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Mode of Action of Artemisinin
Published in Tariq Aftab, M. Naeem, M. Masroor, A. Khan, Artemisia annua, 2017
Athar Ali, Abdul Qadir, Mather Ali Khan, Parul Saxena, Malik Zainul Abdin
In reductive scission, ferrous-heme/non-heme exogenous Fe2+ is first attached to artemisinin by a covalent bond, causing the reductive scission of the endoperoxide bridge. This leads to the generation of oxygen-centered radicals, which subsequently self-arrange to give carbon-centered radicals. In addition, iron–peroxide interaction occurs in different ways to form either primary carbon-centered radicals (via C3–C4 bond scission) or secondary carbon-centered radicals (via 1,5 H-shifts). The open peroxide model, on the other hand, suggests that the endoperoxide group of artemisinin produces secondary carbon-centered radicals via a Fenton reaction involving the Fe2+ of hemoglobin (Haynes et al., 2007). It is reported, however, that these secondary carbon-centered radicals, which damage the parasite’s essential biomolecules, are short-lived (Edikpo et al., 2013).
Acetylenes: cytochrome P450 oxidation and mechanism-based enzyme inactivation
Published in Drug Metabolism Reviews, 2019
A ring expansion also occurs in the oxidative metabolism of the AIDS drug efavirenz (Figure 8). In this reaction, the cyclopropyl ring expands to a cyclobutyl ring by migration of one of its carbon atoms to the outside carbon of the triple bond. The ring expansion is driven by release of ring strain and transfer of the incipient cation from a vinylic to a secondary carbon atom. The resulting conjugated ketone can then react with glutathione or thiol groups on proteins. The authors proposed the formation of an oxirene as the initial product formed by cytochrome P450-catalyzed oxidation of the acetylene function (Mutlib et al. 2000). However, as already discussed, oxirenes are not expected as actual metabolites due to their high energy. A shift of the cyclopropyl carbon atom to give the cyclobutyl ring concomitant with oxygen transfer to the triple bond, without formation of a stable intermediate, is a more attractive explanation of the observed reaction.
Proteomic response in Streptococcus gordonii DL1 biofilm cells during attachment to salivary MUC5B
Published in Journal of Oral Microbiology, 2021
Carolina Robertsson, Gunnel Svensäter, Zoltan Blum, Magnus E Jakobsson, Claes Wickström
The β-glucoside operon antiterminator LicT (UniProt accession number A8AXH7) was absent in the biofilm cells grown on MUC5B and present in all other cultures. LicT is a transcription factor belonging to the BglG family of transcriptional antiterminators, and it is present in a large variety of prokaryotes [27]. In the closely related S. mutans, the bgl regulon contains a set of genes that encode for a β-glucoside PTS carbohydrate uptake system [63]. β-glucosides include arbutin, salicin, cellobiose and aesculin, and represent secondary carbohydrates that are likely to be subject to catabolite repression in the presence of glucose [64]. LicT inhibits catabolite repression of β-glucosides and was found to enable continued transport and hydrolysis and thereby utilization of aesculin as a carbon source in S. mutans even in the presence of glucose, by maintaining expression of the β-glucoside PTS-specific Enzyme II and downstream metabolic enzymes expressed from the genes of the bgl regulon [63,65,66]. The ability to utilize secondary carbon sources even in the presence of glucose would possibly increase the acidity of the bacteria by providing access to a wider range of carbohydrates. bgl products were also associated with virulence factors in S. pyogenes related to soft tissue infection, such as blood dissemination and haemolysis [67], and in pneumococcal survival and virulence [68]. As opposed to in the other studied growth conditions, LicT was uniquely absent in S. gordonii DL1 biofilm cells grown on MUC5B. The absence of this transcription antiterminator results in continued repression of β-glucoside PTS-specific Enzyme II, and thereby reduction of acidity through reduced secondary carbohydrate uptake, and possibly also reduced expression of other putative bgl operon-related virulence factor proteins in the biofilm bacteria that bind to MUC5B.
Structure-activity relationship of atorvastatin derivatives for metabolic activation by hydrolases
Published in Xenobiotica, 2020
Kenta Mizoi, Masato Takahashi, Sachiko Sakai, Takuo Ogihara, Masami Haba, Masakiyo Hosokawa
Structure-activity relationships were examined using hCES1b (Figure 2(A)), hCES1c (Figure 2(B)), and hCES2 (Figure 2(C)). Moreover, points to be noted in the results of Figure 2 are summarized in Supplementary Table S1. The hydrolytic activity of hCES1b and hCES1c tended to decrease from 2a to 2j, i.e. as the carbon chain was extended from 1 to 10 carbons, while the hydrolytic activity of hCES2 was practically independent of the carbon number. Focusing on three carbon atoms, the hydrolytic activity of hCESs increased in the order of 2m, 2c, and 2k. As regards the carbon atom adjacent to the oxygen atom of the ester, the hydrolytic activity of hCESs increased in the order of 2o, 2m, and 2b, i.e. in the order of tertiary carbon, secondary carbon, and primary carbon. In similar structures, the hydrolytic activity of hCESs was lower for bulky esters such as 2l and 2n than for 2k and 2m, respectively. The hydrolytic activities of hCESs towards 2p and 2q, which contain methylene adjacent to the ester oxygen atom, were clearly higher than those towards 2m and 2o, respectively. When fluorine-containing esters (2r and 2s) were compared with corresponding non-fluorine esters containing the same carbon number (2b and 2m), the hydrolytic activity of hCES1b was about 2-fold and 3-fold higher, respectively. Surprisingly, the hCES2 showed markedly higher hydrolytic activity towards 2r and 2s than towards 2b and 2m, by about 11-fold and 48-fold, respectively. However, the hydrolytic activity of hCES1c was lower at 2r than 2b, although at 2s was higher than 2m. The aromatic esters (2t–2y) showed different trends with hCES1 and hCES2. hCES1b and hCES1c showed the highest hydrolytic activity towards 2v among these esters. In other words, the hydrolytic activity increased from 2t to 2v, and decreased from 2w to 2y. Conversely, the hydrolytic activity of hCES2 tended to increase from 2t to 2x, though 2y showed a slight decrease. When comparing the thioester to the corresponding ester, hCES1 and hCES2 both showed slightly lower hydrolytic activity towards 5b than 2b. In contrast, 5m was hydrolyzed more rapidly than 2m by hCES1b and hCES1c, but less rapidly by hCES2. The amides (6a, 6b, and 6v) were barely hydrolyzed under these conditions.