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Biosynthetic Pathway of Artemisinin
Published in Tariq Aftab, M. Naeem, M. Masroor, A. Khan, Artemisia annua, 2017
The other pathway, the non-mevalonate pathway (MEP), to IPP begins with pyruvate and occurs in the plastid with no mevalonate intermediate. The first key, regulatory, step toward the synthesis of terpenes is the synthesis of 1-deoxy-D-xylulose-5-phosphate (DXP) via 1-deoxy-D-xylulose-5-phosphate synthase (DXS). DXP is then converted to 2-C-methyl-D-erythritol-4-phosphate via 1-deoxy-D-xylulose-5-phosphate reductoisomerase (DXR). Several subsequent steps synthesize the plastid pool of IPP (Rohmer et al., 1996).
Tanshinone Diterpenes
Published in Dilip Ghosh, Pulok K. Mukherjee, Natural Medicines, 2019
Mohamed-Elamir F. Hegazy, Tarik A. Mohamed, Abdelsamed I. Elshamy, Ahmed R. Hamed, Sara Abdelfatah, Soleiman E. Helaly, Nahla S. Abdel-Azim, Khaled A. Shams, Abdel-Razik H. Farrag, Abdessamad Debbab, Tahia K. Mohamed, El-Seedi Hesham R., Mohamed E.M. Saeed, Masaaki Noji, Akemi Umeyama, Paul W. Paré, Thomas Efferth
The biosynthesis of the terpenoids in higher plants occurs through two distinct pathways as outlined below. The mevalonic acid (MVA) pathway occurs in the cytosol (Seto et al. 1996) and is responsible for the synthesis of sterols, certain sesquiterpenes and the side chain of ubiquinone (Arigoni et al. 1997; Wang et al. 2010). The MVA pathway plays a role in tanshinone synthesis with extensive crosstalk between the two pathways.The 2-C-methyl-d-erythritol-4-phosphate (MEP) or non-MVA pathway occurs in plastids (Seto et al. 1996) and is responsible for tanshinone biosynthesis. In MEP pathways, 1-deoxy-d-xylulose-5-phosphate synthase (DXS) catalysed the coupling of pyruvate and glyceraldehyde-3-phosphate (GA-3P) into 1-deoxy-d-xylulose-5-phosphate (DXP), which is consecutively converted into MEP through the action of 1-deoxy-d-xylulose-5-phosphate reductoisomerase (DXR). Through a series of enzymatic conversions MEP is converted to the universal precursors isopentenyl-diphosphate (IPP) and dimethylallyl diphosphate (DMAPP) for terpene formation (Rohmer 1999). In the reacting of IPP or DMAPP with carbonium ion, IPP leads to the production of geranyl diphosphate (GPP). GPP, with an active allylic phosphate group reversely reacts with IPP to produce farnesyl pyrophosphate (FPP) (Cunningham et al. 1994). Then, geranylgeranyl diphosphate synthase (GGPPS) catalyses the consecutive condensation of three IPP molecules with DMAPP to give the C-20 compound, geranylgeranyl diphosphate (GGPP), an essential linear precursor for the biosynthesis of diterpenes (Wang and Ohnuma 1999). GGPP can be converted to miltirone and neocryptotanshinone intermediates by the installation of other groups on the pathway to tanshinone diterpenes (Figure 4.6).
Unmasking allosteric-binding sites: novel targets for GPCR drug discovery
Published in Expert Opinion on Drug Discovery, 2022
Verònica Casadó-Anguera, Vicent Casadó
A large amount of hidden allosteric sites have been found in many proteins based on several experimental methods, such as room-temperature X-ray crystallography, high-throughput screening, and cysteine trapping, but mostly on computational methods such as structure-based identification and structure-based statistical mechanical model of allostery, large-scale molecular dynamics (MD) simulations, accelerated MD simulations, MD-based Markov state analysis, mixed-solvent MD simulations-based methods, and normal mode analysis [27]. This has led to the discovery of new allosteric modulators. They include many enzymes such as phosphofructokinase, glyceraldehyde-3-phosphate dehydrogenase, pyruvate kinase, TEM1 β-lactamase, protein tyrosine phosphatase-1B, MAP p38 kinase, β-secretase-1 protease, cAMP-dependent protein kinase, 1-deoxy-D-xylulose-5-phosphate reductoisomerase, kynurenine/alpha-aminoadipate amino-transferase, etc. Also, different hidden allosteric sites have been detected in receptors mainly by MD simulations; these include angiotensin-II type-1 receptor, β2-adrenoceptor, adenosine A1 and A2A receptors, M2 muscarinic receptor, or epidermal growth factor receptor [13,26,27,36,42,165]. However, the still shortage paucity of marketed allosteric modulators most likely is due to different factors, including their frequently adverse structure–activity relationships, their relatively higher hydrophobicity and reduced binding affinity, compared to orthosteric ligands, and the reduced knowledge of allosteric interactions and their consequences for protein modulation. Thus, until 2019, only one FDA-approved (in 2017) allosteric drug has been discovered exclusively using in silico methods. This compound is named enasidenib (Idhifa®) and is an inhibitor of the digestive enzyme isocitrate dehydrogenase IDH2 used for acute myeloid leukemia [13].