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Ene-Reductases in Pharmaceutical Chemistry
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
In the 1960s, fosfomycin (originally phosphonomycin, trade names Monurol and Monuril) was isolated by screening fermentation broths of Streptomyces fradiae within a collaborative project between Merck and the Spanish “Compañía Española de Penicilina y Antibióticos” (CEPA) (Hendlin et al., 1969). The compound exhibited broad antibacterial activity against Gram-positive as well as Gram-negative pathogens, and for more than 20 years, it has been used as an oral treatment for urinary tract infections (Silver, 2017). Due to its unique mode of action—inhibition of murein biosynthesis through irreversible interaction with enzyme MurA—fosfomycin makes cross-resistance uncommon and allows for synergies with other antibiotics (Falagas et al., 2016). In an era of antibiotic resistance and limited new treatment options, fosfomycin is of interest against multidrug-resistant (MDR) and extensively drug-resistant (XDR) nosocomial (hospital-acquired) infections, for which limited treatment options are available. Fosmidomycin, on the other hand, inhibits DXP reductoisomerase, a key enzyme in the non-mevalonate pathway of isoprenoid biosynthesis, and thus is considered for treatment of malaria in combination with for example clindamycin (Ruangweerayut et al., 2008).
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).
A bispecific nanobody approach to leverage the potent and widely applicable tumor cytolytic capacity of Vγ9Vδ2-T cells
Published in OncoImmunology, 2018
Renée C. G. de Bruin, John P. Veluchamy, Sinéad M. Lougheed, Famke L. Schneiders, Silvia Lopez-Lastra, Roeland Lameris, Anita G. Stam, Zsolt Sebestyen, Jürgen Kuball, Carla F. M. Molthoff, Erik Hooijberg, Rob C. Roovers, James P. Di Santo, Paul M. P. van Bergen en Henegouwen, Henk M. W. Verheul, Tanja D. de Gruijl, Hans J. van der Vliet
Vγ9Vδ2-T cells become activated by the recognition of non-peptidic phosphoantigens (pAg).13-15 These are upregulated by stressed cells, including malignant cells, as a consequence of an enhanced activity of the mevalonate pathway16 or through the non-mevalonate pathway upon bacterial infection.14,17,18 Furthermore, therapeutic agents such as aminobisphosphonates (NBP) can inhibit the mevalonate pathway and thus lead to intracellular pAg accumulation. Upon elevated intracellular levels of pAg in target cells, the GTPase RhoB translocates from the nucleus to the cytoplasm where it presumably binds to the membrane protein butyrophilin 3A1 (BTN3A1, also known as CD277). This binding might induce a conformational change of BTN3A1 that in turn is sensed by the Vγ9Vδ2-TCR and results in Vγ9Vδ2-T cell activation.19-23 Activation of Vγ9Vδ2-T cells can be enhanced by interactions between the NKG2D receptor expressed on most Vγ9Vδ2-T cells and by stress-related MICA, MICB and ULBP molecules that are upregulated in infected or transformed cells.3,24 This, in combination with enhanced pAg levels, allows Vγ9Vδ2-T cells to distinguish “normal” cells from ”altered-self” or tumor cells.25 Activated Vγ9Vδ2-T cells produce pro-inflammatory cytokines (e.g. IFN-γ, TNF-α, TRAIL and the chemokines MIP-1 and RANTES) in addition to cytolytic mediators (perforin, granzyme B) to induce the specific lysis of target cells, which is regulated through the perforin pathway or through Fas- and TRAIL-induced apoptosis.25,26