The making of a potent L-lactate transport inhibitor.
Patrick D BosshartDavid KalbermatterSara BonettiDimitrios FotiadisPublished in: Communications chemistry (2021)
L-lactate is an important metabolite, energy source, and signaling molecule in health and disease. In mammals, its transport across biological membranes is mediated by monocarboxylate transporters (MCTs) of the solute carrier 16 (SLC16) family. Malfunction, overexpression or absence of transporters of this family are associated with diseases such as cancer and type 2 diabetes. Moreover, lactate acts as a signaling molecule and virulence factor in certain bacterial infections. Here, we report the rational, structure-guided identification of potent, nanomolar affinity inhibitors acting on an L-lactate-specific SLC16 homologue from the bacterium Syntrophobacter fumaroxidans (SfMCT). High-resolution crystal structures of SfMCT with bound inhibitors uncovered their interaction mechanism on an atomic level and the role of water molecules in inhibitor binding. The presented systematic approach is a valuable procedure for the identification of L-lactate transport inhibitors. Furthermore, identified inhibitors represent potential tool compounds to interfere with monocarboxylate transport across biological membranes mediated by MCTs.
Keyphrases
- type diabetes
- high resolution
- healthcare
- public health
- escherichia coli
- pseudomonas aeruginosa
- staphylococcus aureus
- mental health
- cardiovascular disease
- cell proliferation
- squamous cell carcinoma
- risk assessment
- minimally invasive
- health information
- papillary thyroid
- climate change
- biofilm formation
- squamous cell
- weight loss
- human health
- liquid chromatography