Abstract
Covering: up to the end of 2019Diverse natural product small molecules have allowed critical insights into processes that govern eukaryotic cells' ability to secrete cytosolically synthesized secretory proteins into their surroundings or to insert newly synthesized integral membrane proteins into the lipid bilayer of the endoplasmic reticulum. In addition, many components of the endoplasmic reticulum, required for protein homeostasis or other processes such as lipid metabolism or maintenance of calcium homeostasis, are being investigated for their potential in modulating human disease conditions such as cancer, neurodegenerative conditions and diabetes. In this review, we cover recent findings up to the end of 2019 on natural products that influence protein secretion or impact ER protein homeostasis, and serve as powerful chemical tools to understand protein flux through the mammalian secretory pathway and as leads for the discovery of new therapeutics.
Highlights
There is no selectivity among the UPR branches as the compound induced GRP78, CHOP and ATF4 levels as well as XBP1 mRNA splicing and eIF2a phosphorylation at the same concentrations and time points in a given cell line.[139]
We focus on the upstream endoplasmic reticulum (ER) events
Since protein secretion is an essential pathway for mammalian cell physiology, selective modulation of pathway components is required for ultimate translational success and for development of selective pharmacological tools to further understand the biology which is by no means fully illuminated yet
Summary
Inhibitors of XBP1 mRNA splicing: trierixins and toyocamycin Activators of PERK pathway: cephalostatin and ritterostatin GN1N PERK and XBP1 mRNA splicing inducer with pleiotropic activities: withaferin A Kinase inhibitors of IRE1a and PERK: ATP mimics ERAD Mannosidase I inhibitors: kifunensine and 1deoxymannojirimycin Eeyarestatin I Therapeutic potential and opportunities for protein secretion modulation Con icts of interest Acknowledgements References. A fungal natural product HUN-7293 (Fig. 3) was discovered as a potent suppressor of expression of the human vascular endothelial cell adhesion molecule I (VCAM-1)[11] and a total synthesis of HUN-7293 was established enabling detailed SAR studies.[12,13,14] Later, two independent studies revealed that HUN-7293 (later named cotransin) inhibits cell surface receptor expression by preventing ER translocation or membrane insertion of newly synthesized secreted or membrane proteins.[15,16] Intriguingly, cotransin only inhibits biogenesis of a subset of the thousands of Sec[61] substrate proteins in a manner dependent on the Nterminal ER targeting signal peptide or transmembrane segment.[15,16] Photocrosslinking experiments with a photoactivatable analog of cotransin demonstrated that cotransin inhibits ER translocation by directly binding to the central poreforming Sec61a subunit of the Sec[61] translocon.[17] Later, an unbiased screen to identify speci c resistance-conferring point mutations, suggested that cotransin allosterically blocks Sec[61] gating facilitated by nascent secretory polypeptides.[18] Intriguingly, synthesis and testing of new cotransin analogs indicated that changes in the cotransin structure can alter the range of Sec[61] substrate proteins it inhibits.[19] A consensus sequence for cotransin-sensitive signal peptides or N-terminal transmembrane segments has not been identi ed, speci c point mutations that do not interfere with protein ER targeting or insertion, Hendrik Luesch received his Diplom in Chemistry at the University of Siegen (Germany) in 1997. In support of this notion, modi cations to the natural structures of apratoxin A and coibamide A have already yielded new inhibitors with reduced general cytotoxic effects while retaining their original antitumor efficacy in tumor xenogra models.[30,32,67]
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