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Herbal Therapies
Published in Anil K. Sharma, Raj K. Keservani, Surya Prakash Gautam, Herbal Product Development, 2020
H. Shahrul, M. L. Tan, A. H. Auni, S. R. Nur, S. M. N. Nurul
Ginseng is a well-known traditional herbal medicine due to its numerous benefits. Although ginseng exhibits a variety of physiological and pharmacological activities, ginseng saponin (or ginsenoside) has no specific receptor. Therefore, ginseng saponin alone may not explain all of ginseng’s actions (Nah et al., 2007). Recent studies found presence of unique form of LPAs, designated gintonin. It was co-isolated with ginseng proteins such as ginseng major latex-like protein 151 and ginseng major storage protein. The complex of LPAs and ginseng proteins could be involved in the physiological and pharmacological actions of LPAs as the free form of LPAs are labile to hydrolysis by lipid phosphate phosphatase (Salous et al., 2013). The protein component might protect LPAs from hydrolysis. They may also play roles in storage and transportion of LPAs to receptors at target organs. The most abundant LPA species in gintonin are LPA C18:2 > LPA C16:0 > LPA C18:1. The study also indicated that ginseng contained high LPAs content, where it was 10-fold than the amount present in corydalis tuber and other foodstuff.
Endotoxin Effects on Synthesis of Phosphatidic Acid and Phosphatidic Acid–Derived Diacylglyceride Species
Published in Helmut Brade, Steven M. Opal, Stefanie N. Vogel, David C. Morrison, Endotoxin in Health and Disease, 2020
The PA peak isolated from GMC whole-cell membranes was collected and analyzed by fast-atom bombardment-mass spectrometry (FAB-MS). FAB-MS negative ion spectrometry (FAB-NI) verified that this peak was PA. The peak was subsequently shown to have two separable components. The first, which appeared within 5 seconds of lipid A stimulation of GMC and oscillated in concentration during the first 5 minutes after stimulation with a period of 45 seconds to 1 minute, was derived from the activity of LPAAT, as suggested from the cis-PnA data. This PA was characterized by masses (FAB NI [M-H]-/z) in the 695–701 range. These LPAAT-derived PA species were shown by radioactive labeling, linked scan (tandem mass spectrometry: MS/MS), and gas-liquid chromatographic (GLC) analysis of acyl chains to be highly enriched in the fatty acid linoleate (C18:2;ω-6) in both the sn-1 and sn-2 positions (20–23), a somewhat unusual finding. Further verification for the provenance of this PA species was provided by fatty acyl competition experiments, in which incubation with a variety of unsaturated fatty acids, particularly linoleate and linolenate (C18:3;γ-3), inhibited both fluorescence uptake and formation of this specific PA species, strongly supporting the observation that this PA resulted from the activity of LPAAT [order of inhibitory strength: C18:2 ω-6 ≃ C18:3 ω-3 > C20:3 aω-3 = C20:5 ω-3 >> C20: 4 (arachidonate) > C18:1 (oleate) >>>> palmitate (C16: 0) or stearate (C18:0) (20–23)]. In analyzing the acyl content of membrane species, evidence was provided that the DG species appearing rapidly after the formation of linoleoyl PA species was synthesized directly from the LPAAT-dependent PA (i.e., was equally enriched in linoleate and linolenate) rather than from PI species (which are enriched in C20:4, arachidonate, and C20:3, eicosatrienoate). Mass spectrometric studies confirmed fluorescence and labeling data by showing a predominance of predicted dilinoleoyl, 1-oleoyl 2-linoleoyl, and dioleoyl DG generated in whole GMC and GMC plasma membrane-enriched microsomes (21). This indicated that lipid A also could be activating the enzyme phosphatidate phosphohydrolase (PAP) (recently considered to be a lipid phosphate phosphatase, addressing sphingosine 1-phosphate as well as PA), which was subsequently demonstrated by kinetic studies in GMC microsomes. It remains unclear as to whether PAP activation by lipid A occurs (1) due to direct interaction with the membrane, resulting in G-protein-mediated stimulation of the PAP, (2) due to direct interaction with PAP by lipid A, or (3) due to the increased synthesis of PA providing increased substrate for PAP.
Pyrrolidine-based 3-deoxysphingosylphosphorylcholine analogs as possible candidates against neglected tropical diseases (NTDs): identification of hit compounds towards development of potential treatment of Leishmania donovani
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2021
Ahmed H. E. Hassan, Trong-Nhat Phan, Seolmin Yoon, Cheol Jung Lee, Hye Rim Jeon, Seung-Hwan Kim, Joo Hwan No, Yong Sup Lee
As no resolved crystal structure is available yet for L. donovani IPCS, building a 3D homology model (uniport sequence ID: E9BT22) was conducted. It is a fact that IPCS shares with other members of lipid phosphate phosphatase (LPP) family of proteins a homologous phosphatase domain characterised with conserved residues. Especially, a conserved common catalytic triad (His211/His264/Asp268 of L. donovani IPCS homologous, for example, to His163/His207/Asp211 of Phosphatase phosphatidylglycerophosphate phosphatase B (PgpB); PDB IDs: 5jwy and 4px7, exists in TM3 (His211 or His163) and TM6 (His264/Asp268 or His207/Asp211) nearby the periplasm29,30. In addition to the six transmembrane helices of PgpB, the 3D structure involves four extracellular helices (EH1–4) connecting TM3 and TM4 as well as a cytoplasmic helix (CH1) after TM6.
Enzymatic kinetics regarding reversible metabolism of CS-0777, a sphingosine 1-phosphate receptor modulator, via phosphorylation and dephosphorylation in humans
Published in Xenobiotica, 2018
Shin-Ichi Inaba, Maki Yamaguchi-Goto, Kaoru Tanaka-Takanaka, Kiyoaki Yonesu, Hidetaka Sakurai, Kazuishi Kubota, Takashi Izumi
It is well known that the antiviral compounds in which an acyclic nucleoside structure is included, such as acyclovir, are good examples of prodrugs via phosphorylation activation (Freeman & Gardiner, 1996); meanwhile, there is little information about prodrugs aimed at modulation of S1P via phosphorylation, other than that reported about Gilenya (FTY720, fingolimod) and CS-0777. Gilenya, which is used for the treatment of relapsing-remitting multiple sclerosis, is the first approved S1P modulator in the USA and Europe, and its active form is also a phosphorylated metabolite in the body (Brinkmann et al., 2002). Sphingosine kinase and lipid phosphate phosphatase are considered to be the enzymes responsible for the phosphorylation of Gilenya, and dephosphorylation of phosphorylated Gilenya, respectively (Mechtcheriakova et al., 2007; Paugh et al., 2003). Physiological functions of these enzymes were believed to be associated with sphingosine metabolism.