Life sciences · 2023
Molecular characteristic analysis of single-nucleotide polymorphisms in SLC16A9/hMCT9.
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Yamaguchi Atsushi, Mukai Yuto, Sakuma Tomoya, Suganuma Yudai, Furugen Ayako, Narumi Katsuya, Kobayashi Masaki
Аннотация
AIMS: Human monocarboxylate transporter 9 (hMCT9), encoded by SLC16A9, is a transporter that mediates creatine transport across the transmembrane. Previously, we reported that hMCT9 is an extracellular pH- and Na+-sensitive creatine transporter with two kinetic components. Recently, some variants of hMCT9 have been found to be associated with serum uric acid levels, hyperuricemia, and gout. Among these, two single-nucleotide polymorphisms (SNPs) have also been reported: rs550527563 (L93M) and rs2242206 (T258K). However, the effect of these SNPs on hMCT9 transport activity remains unclear. This study aimed to determine the influence of hMCT9 L93M and T258K on transport characteristics.
MAIN METHODS: hMCT9 L93M and T258K were constructed by site-directed mutagenesis and expressed in Xenopus laevis oocyte. Transport activity of uric acid and creatine via hMCT9 were measured by using a Xenopus laevis oocyte heterologous expression system.
KEY FINDINGS: We assessed the transport activity of uric acid and creatine, and observed that hMCT9-expressing oocytes transported uric acid approximately 3- to 4-fold more than water-injected oocytes. hMCT9 L93M slightly reduced the transport activity of creatine, whereas hMCT9 T258K did not affect the transport activity. Interestingly, hMCT9 T258K abolished Na+ sensitivity and altered the substrate affinity from two components to one.
SIGNIFICANCE: In conclusion, hMCT9 SNPs affect transport activity and characteristics. hMCT9 L93M and T258K may induce dysfunction and contribute to pathologies such as hyperuricemia and gout. This is a first study to evaluate molecular characteristics of hMCT9 SNPs.
MAIN METHODS: hMCT9 L93M and T258K were constructed by site-directed mutagenesis and expressed in Xenopus laevis oocyte. Transport activity of uric acid and creatine via hMCT9 were measured by using a Xenopus laevis oocyte heterologous expression system.
KEY FINDINGS: We assessed the transport activity of uric acid and creatine, and observed that hMCT9-expressing oocytes transported uric acid approximately 3- to 4-fold more than water-injected oocytes. hMCT9 L93M slightly reduced the transport activity of creatine, whereas hMCT9 T258K did not affect the transport activity. Interestingly, hMCT9 T258K abolished Na+ sensitivity and altered the substrate affinity from two components to one.
SIGNIFICANCE: In conclusion, hMCT9 SNPs affect transport activity and characteristics. hMCT9 L93M and T258K may induce dysfunction and contribute to pathologies such as hyperuricemia and gout. This is a first study to evaluate molecular characteristics of hMCT9 SNPs.