Transport of Small Aliphatic Amines by Polyspecific Solute Carriers: Deciphering Structure-Function Relationships.

Area of Science:

• Membrane transport
• Drug metabolism
• Pharmacokinetics

Background:

• Solute carrier (SLC) 22A and 47A family transporters are crucial for drug and metabolite transport.
• Understanding their substrate specificity is vital for drug development and predicting interactions.

Purpose of the Study:

• To elucidate the structure-function relationships governing the transport of small aliphatic amines by organic cation transporters (OCT) and multidrug and toxin extrusion transporters (MATE).
• To investigate the enantioselectivity of OCT and MATE transporter activity for these compounds.

Main Methods:

• Utilized HEK293 cells overexpressing OCT1, OCT2, OCT3, MATE1, or MATE2-K.
• Quantified substrate transport using liquid chromatography-tandem mass spectrometry.
• Employed 6-aminoquinolyl-N-hydroxysuccinimidyl carbamate derivatization where necessary.

Main Results:

• OCT2 uniquely transported small aliphatic amines and alkanolamines (60-145 Da) with modest (S)-enantioselectivity, unlike OCT1, OCT3, and MATEs.
• Transport was influenced by structural factors like chain length and amino group position; compounds with >2 positive charges were not transported.
• Identified OCT2 as an efficient efflux transporter for ethanolamine.

Conclusions:

• Small aliphatic amines are specific substrates for OCT2, with transport influenced by molecular weight and structure.
• Findings clarify OCT and MATE substrate preferences, aiding prediction of transporter interactions and drug design optimization.