The Experts below are selected from a list of 318 Experts worldwide ranked by ideXlab platform
Atsushi Enomoto - One of the best experts on this subject based on the ideXlab platform.
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molecular identification of a renal urate Anion Exchanger that regulates blood urate levels
Nature, 2002Co-Authors: Promsuk Jutabha, Yasuhiro Shigeta, Arthit Chairoungdua, Atsushi Enomoto, Makoto Hosoyamada, Hiroaki Kimura, Michio TakedaAbstract:Urate, a naturally occurring product of purine metabolism, is a scavenger of biological oxidants implicated in numerous disease processes1,2,3, as demonstrated by its capacity of neuroprotection4,5. It is present at higher levels in human blood (200–500 µM) than in other mammals6, because humans have an effective renal urate reabsorption system, despite their evolutionary loss of hepatic uricase by mutational silencing6,7,8. The molecular basis for urate handling in the human kidney remains unclear because of difficulties in understanding diverse urate transport systems and species differences6,9,10. Here we identify the long-hypothesized9,10,11 urate transporter in the human kidney (URAT1, encoded by SLC22A12), a urate–Anion Exchanger regulating blood urate levels and targeted by uricosuric and antiuricosuric agents (which affect excretion of uric acid). Moreover, we provide evidence that patients with idiopathic renal hypouricaemia (lack of blood uric acid) have defects in SLC22A12. Identification of URAT1 should provide insights into the nature of urate homeostasis, as well as lead to the development of better agents against hyperuricaemia, a disadvantage concomitant with human evolution.
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Molecular identification of a renal urate–Anion Exchanger that regulates blood urate levels
Nature, 2002Co-Authors: Atsushi Enomoto, Promsuk Jutabha, Yasuhiro Shigeta, Michio Takeda, Arthit Chairoungdua, Takashi Sekine, Makoto Hosoyamada, Hiroaki Kimura, Takashi IgarashiAbstract:Urate, a naturally occurring product of purine metabolism, is a scavenger of biological oxidants implicated in numerous disease processes1,2,3, as demonstrated by its capacity of neuroprotection4,5. It is present at higher levels in human blood (200–500 µM) than in other mammals6, because humans have an effective renal urate reabsorption system, despite their evolutionary loss of hepatic uricase by mutational silencing6,7,8. The molecular basis for urate handling in the human kidney remains unclear because of difficulties in understanding diverse urate transport systems and species differences6,9,10. Here we identify the long-hypothesized9,10,11 urate transporter in the human kidney (URAT1, encoded by SLC22A12), a urate–Anion Exchanger regulating blood urate levels and targeted by uricosuric and antiuricosuric agents (which affect excretion of uric acid). Moreover, we provide evidence that patients with idiopathic renal hypouricaemia (lack of blood uric acid) have defects in SLC22A12. Identification of URAT1 should provide insights into the nature of urate homeostasis, as well as lead to the development of better agents against hyperuricaemia, a disadvantage concomitant with human evolution.
Helene Guizouarn - One of the best experts on this subject based on the ideXlab platform.
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structural model of the Anion Exchanger 1 slc4a1 and identification of transmembrane segments forming the transport site
Journal of Biological Chemistry, 2013Co-Authors: Helene Guizouarn, Catherine Etchebest, Damien BarneaudroccaAbstract:The Anion Exchanger 1 (AE1), a member of bicarbonate transporter family SLC4, mediates an electroneutral chloride/bicarbonate exchange in physiological conditions. However, some point mutations in AE1 membrane-spanning domain convert the electroneutral Anion Exchanger into a Na+ and K+ conductance or induce a cation leak in a still functional Anion Exchanger. The molecular determinants that govern ion movement through this transporter are still unknown. The present study was intended to identify the ion translocation pathway within AE1. In the absence of a resolutive three-dimensional structure of AE1 membrane-spanning domain, in silico modeling combined with site-directed mutagenesis experiments was done. A structural model of AE1 membrane-spanning domain is proposed, and this model is based on the structure of a uracil-proton symporter. This model was used to design cysteine-scanning mutagenesis on transmembrane (TM) segments 3 and 5. By measuring AE1 Anion exchange activity or cation leak, it is proposed that there is a unique transport site comprising TM3–5 and TM8 that should function as an Anion Exchanger and a cation leak. Background: There is still no high resolution three-dimensional structure available for the membrane-spanning domain of Anion Exchanger 1 (AE1). Results: A three-dimensional model of AE1 membrane-spanning domain has been generated in silico and experimentally assessed. Conclusion: Transmembrane segments forming AE1 transport site have been identified. Significance: This is the first three-dimensional model of AE1 membrane-spanning domain based on a cation symporter.
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Structural model of the Anion Exchanger 1 (SLC4A1) and identification of transmembrane segments forming the transport site.
Journal of Biological Chemistry, 2013Co-Authors: Damien Barneaud-rocca, Catherine Etchebest, Helene GuizouarnAbstract:The Anion Exchanger 1 (AE1), member of bicarbonate transporter family SLC4, mediates an electroneutral chloride/bicarbonate exchange in physiological conditions. However, some point mutations in AE1 membrane spanning domain convert the electroneutral Anion Exchanger into a Na+ and K+ conductance or induce a cation leak in a still functional Anion Exchanger. The molecular determinants that govern ion movement through this transporter are still unknown. The present study was intended to identify the ion translocation pathway within AE1. In the absence of resolutive 3D structure of AE1 membrane spanning domain, in silico modeling combined with site directed mutagenesis experiments have been done. A structural model of AE1 membrane spanning domain is proposed and this model is based on the structure of Uracil-proton symporter. This model was used to design cysteine-scanning mutagenesis on transmembrane segments (TM) 3 and 5. By measuring AE1 Anion exchange activity or cation leak it is proposed that there is a unique transport site comprising TM3-5 and 8 that should function as an Anion Exchanger and a cation leak.
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dual transport properties of Anion Exchanger 1 the same transmembrane segment is involved in Anion exchange and in a cation leak
Journal of Biological Chemistry, 2011Co-Authors: Damien Barneaudrocca, Franck Borgese, Helene GuizouarnAbstract:Previous results suggested that specific point mutations in human Anion Exchanger 1 (AE1) convert the electroneutral Anion Exchanger into a monovalent cation conductance. In the present study, the transport site for Anion exchange and for the cation leak has been studied by cysteine scanning mutagenesis and sulfhydryl reagent chemistry. Moreover, the role of some highly conserved amino acids within members of the SLC4 family to which AE1 belongs has been assessed in AE1 transport properties. The results suggest that the same transport site within the AE1 spanning domain is involved in Anion exchange or in cation transport. A functioning mechanism for this transport site is proposed according to transport properties of the different studied point mutations of AE1.
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Dual transport properties of Anion Exchanger 1: the same transmembrane segment domain is involved in Anion exchange and in a cation leak.
Journal of Biological Chemistry, 2011Co-Authors: Damien Barneaud-rocca, Franck Borgese, Helene GuizouarnAbstract:Previous results suggested that specific point mutations in human Anion Exchanger 1 (AE1) convert the electroneutral Anion Exchanger into a monovalent cation conductance. In the present study, the transport site for Anion exchange and for the cation leak has been studied by cysteine scanning mutagenesis and sulfhydryl reagent chemistry. Moreover the role of some highly conserved amino acids within members of the SLC4 family to which AE1 belongs, has been assessed in AE1 transport properties. The results suggest that the same transport site within AE1 spanning domain is involved in Anion exchange or in cation leak. A functioning mechanism for this transport site is proposed according to transport properties of the different studied point mutations of AE1.
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point mutations involved in red cell stomatocytosis convert the electroneutral Anion Exchanger 1 to a nonselective cation conductance
Blood, 2007Co-Authors: Helene Guizouarn, Sonia Martial, Nicole Gabillat, Franck BorgeseAbstract:The Anion Exchanger 1 (AE1) is encoded by the SLC4A1 gene and catalyzes the electroneutral Anion exchange across cell plasma membrane. It is the most abundant transmembrane protein expressed in red cell where it is involved in CO2 transport. Recently, 4 new point mutations of SLC4A1 gene have been described leading to missense mutations in the protein sequence (L687P, D705Y, S731P, or H734R). These point mutations were associated with hemolytic anemia, and it was shown that they confer a cation transport feature to the human AE1. Facing this unexpected property for an electroneutral Anion Exchanger, we have studied the transport features of mutated hAE1 by expression in xenopus oocytes. Our results show that the point mutations of hAE1 convert the electroneutral Anion Exchanger to a cation conductance: the Exchangers are no longer able to exchange Cl− and HCO3−, whereas they transport Na+ and K+ through a conductive mechanism. These data shed new light on transport mechanisms showing the tiny difference, in terms of primary sequence, between an electroneutral exchange and a conductive pathway.
Michio Takeda - One of the best experts on this subject based on the ideXlab platform.
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molecular identification of a renal urate Anion Exchanger that regulates blood urate levels
Nature, 2002Co-Authors: Promsuk Jutabha, Yasuhiro Shigeta, Arthit Chairoungdua, Atsushi Enomoto, Makoto Hosoyamada, Hiroaki Kimura, Michio TakedaAbstract:Urate, a naturally occurring product of purine metabolism, is a scavenger of biological oxidants implicated in numerous disease processes1,2,3, as demonstrated by its capacity of neuroprotection4,5. It is present at higher levels in human blood (200–500 µM) than in other mammals6, because humans have an effective renal urate reabsorption system, despite their evolutionary loss of hepatic uricase by mutational silencing6,7,8. The molecular basis for urate handling in the human kidney remains unclear because of difficulties in understanding diverse urate transport systems and species differences6,9,10. Here we identify the long-hypothesized9,10,11 urate transporter in the human kidney (URAT1, encoded by SLC22A12), a urate–Anion Exchanger regulating blood urate levels and targeted by uricosuric and antiuricosuric agents (which affect excretion of uric acid). Moreover, we provide evidence that patients with idiopathic renal hypouricaemia (lack of blood uric acid) have defects in SLC22A12. Identification of URAT1 should provide insights into the nature of urate homeostasis, as well as lead to the development of better agents against hyperuricaemia, a disadvantage concomitant with human evolution.
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Molecular identification of a renal urate–Anion Exchanger that regulates blood urate levels
Nature, 2002Co-Authors: Atsushi Enomoto, Promsuk Jutabha, Yasuhiro Shigeta, Michio Takeda, Arthit Chairoungdua, Takashi Sekine, Makoto Hosoyamada, Hiroaki Kimura, Takashi IgarashiAbstract:Urate, a naturally occurring product of purine metabolism, is a scavenger of biological oxidants implicated in numerous disease processes1,2,3, as demonstrated by its capacity of neuroprotection4,5. It is present at higher levels in human blood (200–500 µM) than in other mammals6, because humans have an effective renal urate reabsorption system, despite their evolutionary loss of hepatic uricase by mutational silencing6,7,8. The molecular basis for urate handling in the human kidney remains unclear because of difficulties in understanding diverse urate transport systems and species differences6,9,10. Here we identify the long-hypothesized9,10,11 urate transporter in the human kidney (URAT1, encoded by SLC22A12), a urate–Anion Exchanger regulating blood urate levels and targeted by uricosuric and antiuricosuric agents (which affect excretion of uric acid). Moreover, we provide evidence that patients with idiopathic renal hypouricaemia (lack of blood uric acid) have defects in SLC22A12. Identification of URAT1 should provide insights into the nature of urate homeostasis, as well as lead to the development of better agents against hyperuricaemia, a disadvantage concomitant with human evolution.
Hiroaki Kimura - One of the best experts on this subject based on the ideXlab platform.
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molecular identification of a renal urate Anion Exchanger that regulates blood urate levels
Nature, 2002Co-Authors: Promsuk Jutabha, Yasuhiro Shigeta, Arthit Chairoungdua, Atsushi Enomoto, Makoto Hosoyamada, Hiroaki Kimura, Michio TakedaAbstract:Urate, a naturally occurring product of purine metabolism, is a scavenger of biological oxidants implicated in numerous disease processes1,2,3, as demonstrated by its capacity of neuroprotection4,5. It is present at higher levels in human blood (200–500 µM) than in other mammals6, because humans have an effective renal urate reabsorption system, despite their evolutionary loss of hepatic uricase by mutational silencing6,7,8. The molecular basis for urate handling in the human kidney remains unclear because of difficulties in understanding diverse urate transport systems and species differences6,9,10. Here we identify the long-hypothesized9,10,11 urate transporter in the human kidney (URAT1, encoded by SLC22A12), a urate–Anion Exchanger regulating blood urate levels and targeted by uricosuric and antiuricosuric agents (which affect excretion of uric acid). Moreover, we provide evidence that patients with idiopathic renal hypouricaemia (lack of blood uric acid) have defects in SLC22A12. Identification of URAT1 should provide insights into the nature of urate homeostasis, as well as lead to the development of better agents against hyperuricaemia, a disadvantage concomitant with human evolution.
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Molecular identification of a renal urate–Anion Exchanger that regulates blood urate levels
Nature, 2002Co-Authors: Atsushi Enomoto, Promsuk Jutabha, Yasuhiro Shigeta, Michio Takeda, Arthit Chairoungdua, Takashi Sekine, Makoto Hosoyamada, Hiroaki Kimura, Takashi IgarashiAbstract:Urate, a naturally occurring product of purine metabolism, is a scavenger of biological oxidants implicated in numerous disease processes1,2,3, as demonstrated by its capacity of neuroprotection4,5. It is present at higher levels in human blood (200–500 µM) than in other mammals6, because humans have an effective renal urate reabsorption system, despite their evolutionary loss of hepatic uricase by mutational silencing6,7,8. The molecular basis for urate handling in the human kidney remains unclear because of difficulties in understanding diverse urate transport systems and species differences6,9,10. Here we identify the long-hypothesized9,10,11 urate transporter in the human kidney (URAT1, encoded by SLC22A12), a urate–Anion Exchanger regulating blood urate levels and targeted by uricosuric and antiuricosuric agents (which affect excretion of uric acid). Moreover, we provide evidence that patients with idiopathic renal hypouricaemia (lack of blood uric acid) have defects in SLC22A12. Identification of URAT1 should provide insights into the nature of urate homeostasis, as well as lead to the development of better agents against hyperuricaemia, a disadvantage concomitant with human evolution.
Yasuhiro Shigeta - One of the best experts on this subject based on the ideXlab platform.
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molecular identification of a renal urate Anion Exchanger that regulates blood urate levels
Nature, 2002Co-Authors: Promsuk Jutabha, Yasuhiro Shigeta, Arthit Chairoungdua, Atsushi Enomoto, Makoto Hosoyamada, Hiroaki Kimura, Michio TakedaAbstract:Urate, a naturally occurring product of purine metabolism, is a scavenger of biological oxidants implicated in numerous disease processes1,2,3, as demonstrated by its capacity of neuroprotection4,5. It is present at higher levels in human blood (200–500 µM) than in other mammals6, because humans have an effective renal urate reabsorption system, despite their evolutionary loss of hepatic uricase by mutational silencing6,7,8. The molecular basis for urate handling in the human kidney remains unclear because of difficulties in understanding diverse urate transport systems and species differences6,9,10. Here we identify the long-hypothesized9,10,11 urate transporter in the human kidney (URAT1, encoded by SLC22A12), a urate–Anion Exchanger regulating blood urate levels and targeted by uricosuric and antiuricosuric agents (which affect excretion of uric acid). Moreover, we provide evidence that patients with idiopathic renal hypouricaemia (lack of blood uric acid) have defects in SLC22A12. Identification of URAT1 should provide insights into the nature of urate homeostasis, as well as lead to the development of better agents against hyperuricaemia, a disadvantage concomitant with human evolution.
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Molecular identification of a renal urate–Anion Exchanger that regulates blood urate levels
Nature, 2002Co-Authors: Atsushi Enomoto, Promsuk Jutabha, Yasuhiro Shigeta, Michio Takeda, Arthit Chairoungdua, Takashi Sekine, Makoto Hosoyamada, Hiroaki Kimura, Takashi IgarashiAbstract:Urate, a naturally occurring product of purine metabolism, is a scavenger of biological oxidants implicated in numerous disease processes1,2,3, as demonstrated by its capacity of neuroprotection4,5. It is present at higher levels in human blood (200–500 µM) than in other mammals6, because humans have an effective renal urate reabsorption system, despite their evolutionary loss of hepatic uricase by mutational silencing6,7,8. The molecular basis for urate handling in the human kidney remains unclear because of difficulties in understanding diverse urate transport systems and species differences6,9,10. Here we identify the long-hypothesized9,10,11 urate transporter in the human kidney (URAT1, encoded by SLC22A12), a urate–Anion Exchanger regulating blood urate levels and targeted by uricosuric and antiuricosuric agents (which affect excretion of uric acid). Moreover, we provide evidence that patients with idiopathic renal hypouricaemia (lack of blood uric acid) have defects in SLC22A12. Identification of URAT1 should provide insights into the nature of urate homeostasis, as well as lead to the development of better agents against hyperuricaemia, a disadvantage concomitant with human evolution.