H+/amino acid transporter 1 (PAT1) is the imino acid carrier: An intestinal nutrient/drug transporter in human and rat

Anderson, Catriona M.H.; Grenade, Danielle S.; Boll, Michael; Foltz, Martin; Wake, Katherine A.; Kennedy, David J.; Munck, Lars Kristian; Miyauchi, Seiji; Taylor, Peter M.; Campbell, Frederick; Munck, B. G.; Daniel, Hannelore; Ganapathy, Vadivel; Thwaites, David T.

doi:10.1053/j.gastro.2004.08.017

Cited by 119 publications

(189 citation statements)

References 46 publications

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“…A major feature distinguishing these transporters is their substrate affinity: SLC36A1 is a low-affinity transporter, whereas SLC36A2 is a high-affinity transporter. SLC36A1 has been characterized as the intestinal imino acid and glycine transporter and suggested as a candidate for IG (22,23). More recently, 2 groups including ours identified SLC6A20 (IMINO) as a specific imino acid transporter (24,25).…”

Section: Introductionmentioning

confidence: 85%

Iminoglycinuria and hyperglycinuria are discrete human phenotypes resulting from complex mutations in proline and glycine transporters

Bröer¹,

Bailey²,

Kowalczuk³

et al. 2008

J. Clin. Invest.

102

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Iminoglycinuria (IG)is an autosomal recessive abnormality of renal transport of glycine and the imino acids proline and hydroxyproline, but the specific genetic defect(s) have not been determined. Similarly, although the related disorder hyperglycinuria (HG) without iminoaciduria has been attributed to heterozygosity of a putative defective glycine, proline, and hydroxyproline transporter, confirming the underlying genetic defect(s) has been difficult. Here we applied a candidate gene sequencing approach in 7 families first identified through newborn IG screening programs. Both inheritance and functional studies identified the gene encoding the proton amino acid transporter SLC36A2 (PAT2) as the major gene responsible for IG in these families, and its inheritance was consistent with a classical semidominant pattern in which 2 inherited nonfunctional alleles conferred the IG phenotype, while 1 nonfunctional allele was sufficient to confer the HG phenotype. Mutations in SLC36A2 that retained residual transport activity resulted in the IG phenotype when combined with mutations in the gene encoding the imino acid transporter SLC6A20 (IMINO). Additional mutations were identified in the genes encoding the putative glycine transporter SLC6A18 (XT2) and the neutral amino acid transporter SLC6A19 (B 0 AT1) in families with either IG or HG, suggesting that mutations in the genes encoding these transporters may also contribute to these phenotypes. In summary, although recognized as apparently simple Mendelian disorders, IG and HG exhibit complex molecular explanations depending on a major gene and accompanying modifier genes.

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Section: Introductionmentioning

confidence: 85%

Iminoglycinuria and hyperglycinuria are discrete human phenotypes resulting from complex mutations in proline and glycine transporters

Bröer¹,

Bailey²,

Kowalczuk³

et al. 2008

J. Clin. Invest.

102

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“…Luminal transporters -with the exception of the low affinity small neutral amino/imino acid transporter 1 (PAT1) (Anderson et al 2004) -showed very low or negligible transcript expression values in the large intestine.…”

Section: Axial Distribution Of Intestinal Ace Ace2 Amino Acid and Pmentioning

confidence: 99%

Human intestine luminal ACE2 and amino acid transporter expression increased by ACE-inhibitors

et al. 2014

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Sodium-dependent neutral amino acid transporter B(0)AT1 (SLC6A19) and imino acid (proline) transporter SIT1 (SLC6A20) are expressed at the luminal membrane of small intestine enterocytes and proximal tubule kidney cells where they exert key functions for amino acid (re)absorption as documented by their role in Hartnup disorder and iminoglycinuria, respectively. Expression of B(0)AT1 was shown in rodent intestine to depend on the presence of the carboxypeptidase angiotensin-converting enzyme 2 (ACE2). This enzyme belongs to the renin-angiotensin system and its expression is induced by treatment with ACE-inhibitors (ACEIs) or angiotensin II AT1 receptor blockers (ARBs) in many rodent tissues. We show here in the Xenopus laevis oocyte expression system that human ACE2 also functionally interacts with SIT1. To investigate in human intestine the potential effect of ACEIs or ARBs on ACE2, we analysed intestinal biopsies taken during routine gastroduodenoscopy and ileocolonoscopy from 46 patients of which 9 were under ACEI and 13 ARB treatment. Analysis of transcript expression by real-time PCR and of proteins by immunofluorescence showed a co-localization of SIT1 and B(0)AT1 with ACE2 in the brush-border membrane of human small intestine enterocytes and a distinct axial expression pattern of the tested gene products along the intestine. Patients treated with ACEIs displayed in comparison with untreated controls increased intestinal mRNA levels of ACE2, peptide transporter PEPT1 (SLC15A1) and AA transporters B(0)AT1 and PAT1 (SLC36A1). This study unravels in human intestine the localization and distribution of intestinal transporters involved in amino acid absorption and suggests that ACEIs impact on their expression. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64

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“…The mechanistic properties of the B 0 -type transport activity in the intestine [12][13][14][16][17][18][19][20] fits well with properties of the cloned mouse B 0 AT1, as reported here. As a result, it appears likely that B 0 AT1 is the only transport activity for large neutral amino acids in the small intestine, whereas smaller amino acids are also transported by ASCT2 [13] and PAT1 [15].…”

Section: Physiological Significancementioning

confidence: 99%

“…Large neutral amino acids are transported by three different transport systems in the intestine, namely system B 0 , system B 0,+ (an Na + -dependent transporter for neutral and cationic amino acids) and system ASC (an Na + -dependent transporter for midsize neutral amino acids) [12][13][14]. Small neutral amino acids are, in addition, transported by PAT1 (proton-amino acid cotransporter 1) [15]. The activity of the intestinal system B 0 , typically studied in preparations from jejunum, is very similar to the activity observed in kidney cortex [16][17][18][19][20].…”

Section: Introductionmentioning

confidence: 99%

Characterization of mouse amino acid transporter B0AT1 (slc6a19)

Böhmer

Bröer

Munzinger

et al. 2005

Biochemical Journal

129

110

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The mechanism of the mouse (m)B 0 AT1 (slc6a19) transporter was studied in detail using two electrode voltage-clamp techniques and tracer studies in the Xenopus oocyte expression system. All neutral amino acids induced inward currents at physiological potentials, but large neutral non-aromatic amino acids were the preferred substrates of mB 0 AT1. Substrates were transported with K 0.5 values ranging from approx. 1 mM to approx. 10 mM. The transporter mediates Na + -amino acid co-transport with a stoichiometry of 1:1. No other ions were involved in the transport mechanism. An increase in the extracellular Na + concentration reduced the K 0.5 for leucine, and vice versa. Moreover, the K 0.5 values and V max values of both substrates varied with the membrane potential. As a result, K 0.5 and V max values are a complex function of the concentration of substrate and co-substrate and the membrane potential. A model is presented assuming random binding order and a positive charge associated with the ternary [Na + -substratetransporter] complex, which is consistent with the experimental data.

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H+/amino acid transporter 1 (PAT1) is the imino acid carrier: An intestinal nutrient/drug transporter in human and rat

Cited by 119 publications

References 46 publications

Iminoglycinuria and hyperglycinuria are discrete human phenotypes resulting from complex mutations in proline and glycine transporters

Iminoglycinuria and hyperglycinuria are discrete human phenotypes resulting from complex mutations in proline and glycine transporters

Human intestine luminal ACE2 and amino acid transporter expression increased by ACE-inhibitors

Characterization of mouse amino acid transporter B0AT1 (slc6a19)

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