Abstract:
:The antipsychotic drug olanzapine is widely prescribed to treat schizophrenia and other psychotic disorders. However, it often causes unwanted side effects, including diabetes, due to disruption of insulin-dependant glucose metabolism through a mechanism yet to be elucidated. To determine if olanzapine can affect the first step in glucose metabolism - glucose transport inside cells - we investigated the effect of this drug on the transport activity of a model glucose transporter. The glucose transporter from Staphylococcus epidermidis (GlcPSe) is specific for glucose, inhibited by various human glucose transporter (GLUT) inhibitors, has high sequence and structure homology to GLUTs, and is readily amenable to transport assay, mutagenesis, and computational modeling. We found that olanzapine inhibits glucose transport of GlcPSe with an IC50 0.9 ± 0.1 mM. Computational docking of olanzapine to the GlcPSe structure revealed potential binding sites that were further examined through mutagenesis and transport assay to identify residues important for olanzapine inhibition. These investigations suggest that olanzapine binds in a polar region of the cytosolic part of the transporter, and interacts with residues R129, strictly conserved in all GLUTs, and N136, conserved in only a few GLUTs, including the insulin-responsive GLUT4. We propose that olanzapine inhibits GlcPSe by impeding the alternating opening and closing of the substrate cavity necessary for glucose transport. It accomplishes this by disrupting a key salt bridge formed by conserved residues R129 and E362, that stabilizes the outward-facing conformation of the transporter.
journal_name
FEBS Open Biojournal_title
FEBS open bioauthors
Babkin P,George Thompson AM,Iancu CV,Walters DE,Choe JYdoi
10.1016/j.fob.2015.04.006subject
Has Abstractpub_date
2015-04-15 00:00:00pages
335-40issn
2211-5463pii
S2211-5463(15)00036-4journal_volume
5pub_type
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