Fan H
Biosynthesis of Nature-Inspired Unnatural Cannabinoids
Natural products make up a large proportion of medicine available today. Cannabinoids from the plant Cannabis sativa is one unique class of meroterpenoids that have shown a wide range of bioactivities and recently seen significant developments in their status as therapeutic agents for various indications.
ReadAblation of H+/glucose Exporter SLC45A2 Enhances Melanosomal Glycolysis to Inhibit Melanin Biosynthesis and Promote Melanoma Metastasis
Solute carrier transporters are the second largest family of membrane proteins responsible for the transport of various substances such as saccharides, lipids, amino acids, and inorganic ions across cellular membranes (Zhang et al., 2019). One third of all solute carriers such as SLC2, SLC22, and SLC45 subfamily belong to the major facilitator superfamily clan (Chen et al., 2014; Perland et al., 2017). The majority of major facilitator superfamily proteins are generated from a single two-transmembrane segment hairpin structure that triplicated to give a six two-transmembrane segment unit and then duplicated to a 12-two-transmembrane segment protein (Reddy et al., 2012). The most widely accepted working model for transporters is the alternating access mechanism with alternated facilitated access to binding sites on either side of the membrane (Diallinas, 2014).
ReadSLC22A14 is a mitochondrial riboflavin transporter required for sperm oxidative phosphorylation and male fertility
Ablation of Slc22a14 causes male infertility in mice, but the underlying mechanisms remain unknown. Here, we show that SLC22A14 is a riboflavin transporter localized at the inner mitochondrial membrane of the spermatozoa mid-piece and show by genetic, biochemical, multi-omic, and nutritional evidence that riboflavin transport deficiency suppresses the oxidative phosphorylation and reprograms spermatozoa energy metabolism by disrupting flavoenzyme functions.
ReadUbiquitin Ligase SMURF2 Interacts with Filovirus VP40 and Promotes Egress of VP40 VLPs
Filoviruses Ebola (EBOV) and Marburg (MARV) are devastating high-priority pathogens capable of causing explosive outbreaks with high human mortality rates. The matrix proteins of EBOV and MARV, as well as eVP40 and mVP40, respectively, are the key viral proteins that drive virus assembly and egress and can bud independently from cells in the form of virus-like particles (VLPs).
ReadAngiomotin Counteracts the Negative Regulatory Effect of Host WWOX on Viral PPxY-Mediated Egress
Filoviruses (Ebola [EBOV] and Marburg [MARV]) and arenavirus (Lassa virus; LASV) are zoonotic, emerging pathogens that cause outbreaks of severe hemorrhagic fever in humans. A fundamental understanding of the virus-host interface is critical for understanding the biology of these viruses and for developing future strategies for therapeutic intervention. Here, we identified host WW-domain containing protein WWOX as a novel interactor with VP40 and Z, and showed that WWOX inhibited budding of VP40/Z virus-like particles (VLPs) and live virus in a PPxY/WW-domain dependent manner. Our findings are important to the field as they expand the repertoire of host interactors found to regulate PPxY-mediated budding of RNA viruses, and further highlight the competitive interplay and modular virus-host interactions that impact both the virus lifecycle and the host cell.
ReadMechanism-based Inactivation of Cytochrome P450 3A4 by Benzbromarone
Benzbromarone (BBR), a potent uricosuric agent for the management of gout, is known to cause fatal fulminant hepatitis. While the mechanism of BBR-induced idiosyncratic hepatotoxicity remains unelucidated, cytochrome P450 enzyme (CYP450)-mediated bioactivation of BBR to electrophilic reactive metabolites is commonly regarded as a key molecular-initiating event.
ReadSubmolecular probing of the complement C5a receptor–ligand binding reveals a cooperative two-site binding mechanism
A current challenge to produce effective therapeutics is to accurately determine the location of the ligand-biding site and to characterize its properties. So far, the mechanisms underlying the functional activation of cell surface receptors by ligands with a complex binding mechanism remain poorly understood due to a lack of suitable nanoscopic methods to study them in their native environment.
ReadIn-Silico Identified New Natural Sortase A Inhibitors Disrupt S. aureus Biofilm Formation
Sortase A (SrtA) is a membrane-associated enzyme that anchors surface-exposed proteins to the cell wall envelope of Gram-positive bacteria such as Staphylococcus aureus. As SrtA is essential for Gram-positive bacterial pathogenesis but dispensable for microbial growth or viability, SrtA is considered a favorable target for the enhancement of novel anti-infective drugs that aim to interfere with key bacterial virulence mechanisms, such as biofilm formation, without developing drug resistance.
Read