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000273914 0247_ $$2doi$$a10.1016/j.jbc.2024.107835
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000273914 037__ $$aDZNE-2024-01388
000273914 041__ $$aEnglish
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000273914 1001_ $$aWittern, Carla Isabel$$b0
000273914 245__ $$aComprehensive characterization of the OCT1 phenylalanine-244-alanine substitution reveals highly substrate-dependent effects on transporter function.
000273914 260__ $$aBethesda, Md.$$bSoc.$$c2024
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000273914 520__ $$aOrganic cation transporters (OCTs) can transport structurally highly diverse substrates. The molecular basis of this extensive polyspecificity has been further elucidated by cryo-EM. Apparently, in addition to negatively charged amino acids, aromatic residues may contribute to substrate binding and substrate selectivity. In this study, we provide a comprehensive characterization of phenylalanine 244 in OCT1 function. We analyzed the uptake of 144 OCT1 substrates for the phenylalanine 244 to alanine substitution compared to WTOCT1. This substitution had highly substrate-specific effects ranging from transport reduced to 10% of WT activity up to 8-fold increased transport rates. Four percent of substrates showed strongly increased uptake (>200% of WT) whereas 39% showed strongly reduced transport (<50% of WT). Particularly with larger, more hydrophobic, and more aromatic substrates, the Phe244Ala substitution resulted in higher transport rates and lower inhibition of the transporter. In contrast, substrates with a lower molecular weight and less aromatic rings showed generally decreased uptake rates. A comparison of our data to available transport kinetic data demonstrates that generally, high-affinity low-capacity substrates show increased uptake by the Phe244Ala substitution, whereas low-affinity high-capacity substrates are characterized by reduced transport rates. Altogether, our study provides the first comprehensive characterization of the functional role of an aromatic amino acid within the substrate translocation pathway of OCT1. The pleiotropic function further highlights that phenylalanine 244 interacts in a highly specific manner with OCT1 substrates and inhibitors.
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000273914 650_7 $$2Other$$aalanine mutagenesis
000273914 650_7 $$2Other$$abinding pocket
000273914 650_7 $$2Other$$ainhibition
000273914 650_7 $$2Other$$aorganic cation transporter 1
000273914 650_7 $$2Other$$apolyspecificity
000273914 650_7 $$2Other$$asite-directed mutagenesis
000273914 650_7 $$2Other$$atransport
000273914 650_7 $$047E5O17Y3R$$2NLM Chemicals$$aPhenylalanine
000273914 650_7 $$0OF5P57N2ZX$$2NLM Chemicals$$aAlanine
000273914 650_7 $$2NLM Chemicals$$aOrganic Cation Transporter 1
000273914 650_2 $$2MeSH$$aHumans
000273914 650_2 $$2MeSH$$aPhenylalanine: metabolism
000273914 650_2 $$2MeSH$$aPhenylalanine: chemistry
000273914 650_2 $$2MeSH$$aAmino Acid Substitution
000273914 650_2 $$2MeSH$$aSubstrate Specificity
000273914 650_2 $$2MeSH$$aHEK293 Cells
000273914 650_2 $$2MeSH$$aAlanine: metabolism
000273914 650_2 $$2MeSH$$aAlanine: chemistry
000273914 650_2 $$2MeSH$$aKinetics
000273914 650_2 $$2MeSH$$aBiological Transport
000273914 650_2 $$2MeSH$$aOrganic Cation Transporter 1: metabolism
000273914 650_2 $$2MeSH$$aOrganic Cation Transporter 1: genetics
000273914 650_2 $$2MeSH$$aOrganic Cation Transporter 1: chemistry
000273914 7001_ $$0P:(DE-2719)9001406$$aSchröder, Sophie$$b1$$udzne
000273914 7001_ $$aJensen, Ole$$b2
000273914 7001_ $$aBrockmöller, Jürgen$$b3
000273914 7001_ $$aGebauer, Lukas$$b4
000273914 773__ $$0PERI:(DE-600)1474604-9$$a10.1016/j.jbc.2024.107835$$gVol. 300, no. 11, p. 107835 -$$n11$$p107835$$tThe journal of biological chemistry$$v300$$x0021-9258$$y2024
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