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Decisive structural determinants for the interaction of proline derivatives with the intestinal H+/peptide symporter
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| Zeitschriftentitel: | European Journal of Biochemistry |
|---|---|
| Personen und Körperschaften: | , , , , , , , , |
| In: | European Journal of Biochemistry, 266, 1999, 2, S. 502-508 |
| Format: | E-Article |
| Sprache: | Englisch |
| veröffentlicht: |
Wiley
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| Schlagwörter: |
| author_facet |
Brandsch, Matthias Knütter, Ilka Thunecke, Frank Hartrodt, Bianka Born, Ilona Börner, Volker Hirche, Frank Fischer, Gunter Neubert, Klaus Brandsch, Matthias Knütter, Ilka Thunecke, Frank Hartrodt, Bianka Born, Ilona Börner, Volker Hirche, Frank Fischer, Gunter Neubert, Klaus |
|---|---|
| author |
Brandsch, Matthias Knütter, Ilka Thunecke, Frank Hartrodt, Bianka Born, Ilona Börner, Volker Hirche, Frank Fischer, Gunter Neubert, Klaus |
| spellingShingle |
Brandsch, Matthias Knütter, Ilka Thunecke, Frank Hartrodt, Bianka Born, Ilona Börner, Volker Hirche, Frank Fischer, Gunter Neubert, Klaus European Journal of Biochemistry Decisive structural determinants for the interaction of proline derivatives with the intestinal H+/peptide symporter Biochemistry |
| author_sort |
brandsch, matthias |
| spelling |
Brandsch, Matthias Knütter, Ilka Thunecke, Frank Hartrodt, Bianka Born, Ilona Börner, Volker Hirche, Frank Fischer, Gunter Neubert, Klaus 0014-2956 1432-1033 Wiley Biochemistry http://dx.doi.org/10.1046/j.1432-1327.1999.00885.x <jats:p>To elucidate the decisive structural factors relevant for dipeptide–carrier interaction, the affinity of short amide and imide derivatives for the intestinal H<jats:sup>+</jats:sup>/peptide symporter (PEPT1) was investigated by measuring their ability to inhibit Gly‐Sar transport in Caco‐2 cells. Dipeptides with proline or alanine in the C‐terminal position displayed affinity constants (<jats:italic>K</jats:italic><jats:sub>i</jats:sub>) of 0.15–1.2 m<jats:sc>m</jats:sc> and 0.08–9.5 m<jats:sc>m</jats:sc>, respectively. There was no clear relationship between hydrophobicity, size or ionization status of the N‐terminal amino acid and the affinity of the dipeptides. However, analyzing the individual peptide bond conformations of Xaa‐Pro dipeptides, a striking correlation between the <jats:italic>cis</jats:italic>/<jats:italic>trans</jats:italic> ratios (<jats:italic>trans</jats:italic> contents 24–70%) and the affinity constants was observed. After correcting the <jats:italic>K</jats:italic><jats:sub>i</jats:sub> values for the incompetent <jats:italic>cis</jats:italic> isomers, the <jats:italic>K</jats:italic><jats:sub>i corr</jats:sub> values of most dipeptides were in a small range of 0.1–0.16 m<jats:sc>m</jats:sc>. This result revealed the decisive role of peptide bond conformation even for a transport protein that is quite promiscuous in substrate translocation. When measuring affinity constants of Xaa‐Pro and Xaa‐Sar dipeptides, the <jats:italic>cis</jats:italic>/<jats:italic>trans</jats:italic> ratios cannot be ignored. Lower affinities of Lys‐Pro, Arg‐Pro and Pro‐Pro indicate that additional molecular factors affect their binding at PEPT1. The <jats:italic>K</jats:italic><jats:sub>i</jats:sub> values obtained for the corresponding Xaa‐Ala dipeptides support this conclusion.</jats:p><jats:p>Potential substrates or inhibitors of peptide transport were found among Xaa‐piperidides and Xaa‐thiazolidides. Dipeptides with N‐terminal proline displayed a very diverse affinity profile. However, in contrast to current knowledge, several Pro‐Xaa dipeptides such as Pro‐Leu, Pro‐Tyr and Pro‐Pro are recognized by PEPT1 with appreciable affinities. Binding seems mainly determined by the hydrophobicity of the C‐terminal amino acid and the rigidity of the structure.</jats:p> Decisive structural determinants for the interaction of proline derivatives with the intestinal H<sup>+</sup>/peptide symporter European Journal of Biochemistry |
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10.1046/j.1432-1327.1999.00885.x |
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Online Free |
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Chemie und Pharmazie |
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Wiley, 1999 |
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Wiley, 1999 |
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brandsch1999decisivestructuraldeterminantsfortheinteractionofprolinederivativeswiththeintestinalhpeptidesymporter |
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1999 |
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European Journal of Biochemistry |
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49 |
| title |
Decisive structural determinants for the interaction of proline derivatives with the intestinal H+/peptide symporter |
| title_unstemmed |
Decisive structural determinants for the interaction of proline derivatives with the intestinal H+/peptide symporter |
| title_full |
Decisive structural determinants for the interaction of proline derivatives with the intestinal H+/peptide symporter |
| title_fullStr |
Decisive structural determinants for the interaction of proline derivatives with the intestinal H+/peptide symporter |
| title_full_unstemmed |
Decisive structural determinants for the interaction of proline derivatives with the intestinal H+/peptide symporter |
| title_short |
Decisive structural determinants for the interaction of proline derivatives with the intestinal H+/peptide symporter |
| title_sort |
decisive structural determinants for the interaction of proline derivatives with the intestinal h<sup>+</sup>/peptide symporter |
| topic |
Biochemistry |
| url |
http://dx.doi.org/10.1046/j.1432-1327.1999.00885.x |
| publishDate |
1999 |
| physical |
502-508 |
| description |
<jats:p>To elucidate the decisive structural factors relevant for dipeptide–carrier interaction, the affinity of short amide and imide derivatives for the intestinal H<jats:sup>+</jats:sup>/peptide symporter (PEPT1) was investigated by measuring their ability to inhibit Gly‐Sar transport in Caco‐2 cells. Dipeptides with proline or alanine in the C‐terminal position displayed affinity constants (<jats:italic>K</jats:italic><jats:sub>i</jats:sub>) of 0.15–1.2 m<jats:sc>m</jats:sc> and 0.08–9.5 m<jats:sc>m</jats:sc>, respectively. There was no clear relationship between hydrophobicity, size or ionization status of the N‐terminal amino acid and the affinity of the dipeptides. However, analyzing the individual peptide bond conformations of Xaa‐Pro dipeptides, a striking correlation between the <jats:italic>cis</jats:italic>/<jats:italic>trans</jats:italic> ratios (<jats:italic>trans</jats:italic> contents 24–70%) and the affinity constants was observed. After correcting the <jats:italic>K</jats:italic><jats:sub>i</jats:sub> values for the incompetent <jats:italic>cis</jats:italic> isomers, the <jats:italic>K</jats:italic><jats:sub>i corr</jats:sub> values of most dipeptides were in a small range of 0.1–0.16 m<jats:sc>m</jats:sc>. This result revealed the decisive role of peptide bond conformation even for a transport protein that is quite promiscuous in substrate translocation. When measuring affinity constants of Xaa‐Pro and Xaa‐Sar dipeptides, the <jats:italic>cis</jats:italic>/<jats:italic>trans</jats:italic> ratios cannot be ignored. Lower affinities of Lys‐Pro, Arg‐Pro and Pro‐Pro indicate that additional molecular factors affect their binding at PEPT1. The <jats:italic>K</jats:italic><jats:sub>i</jats:sub> values obtained for the corresponding Xaa‐Ala dipeptides support this conclusion.</jats:p><jats:p>Potential substrates or inhibitors of peptide transport were found among Xaa‐piperidides and Xaa‐thiazolidides. Dipeptides with N‐terminal proline displayed a very diverse affinity profile. However, in contrast to current knowledge, several Pro‐Xaa dipeptides such as Pro‐Leu, Pro‐Tyr and Pro‐Pro are recognized by PEPT1 with appreciable affinities. Binding seems mainly determined by the hydrophobicity of the C‐terminal amino acid and the rigidity of the structure.</jats:p> |
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| description | <jats:p>To elucidate the decisive structural factors relevant for dipeptide–carrier interaction, the affinity of short amide and imide derivatives for the intestinal H<jats:sup>+</jats:sup>/peptide symporter (PEPT1) was investigated by measuring their ability to inhibit Gly‐Sar transport in Caco‐2 cells. Dipeptides with proline or alanine in the C‐terminal position displayed affinity constants (<jats:italic>K</jats:italic><jats:sub>i</jats:sub>) of 0.15–1.2 m<jats:sc>m</jats:sc> and 0.08–9.5 m<jats:sc>m</jats:sc>, respectively. There was no clear relationship between hydrophobicity, size or ionization status of the N‐terminal amino acid and the affinity of the dipeptides. However, analyzing the individual peptide bond conformations of Xaa‐Pro dipeptides, a striking correlation between the <jats:italic>cis</jats:italic>/<jats:italic>trans</jats:italic> ratios (<jats:italic>trans</jats:italic> contents 24–70%) and the affinity constants was observed. After correcting the <jats:italic>K</jats:italic><jats:sub>i</jats:sub> values for the incompetent <jats:italic>cis</jats:italic> isomers, the <jats:italic>K</jats:italic><jats:sub>i corr</jats:sub> values of most dipeptides were in a small range of 0.1–0.16 m<jats:sc>m</jats:sc>. This result revealed the decisive role of peptide bond conformation even for a transport protein that is quite promiscuous in substrate translocation. When measuring affinity constants of Xaa‐Pro and Xaa‐Sar dipeptides, the <jats:italic>cis</jats:italic>/<jats:italic>trans</jats:italic> ratios cannot be ignored. Lower affinities of Lys‐Pro, Arg‐Pro and Pro‐Pro indicate that additional molecular factors affect their binding at PEPT1. The <jats:italic>K</jats:italic><jats:sub>i</jats:sub> values obtained for the corresponding Xaa‐Ala dipeptides support this conclusion.</jats:p><jats:p>Potential substrates or inhibitors of peptide transport were found among Xaa‐piperidides and Xaa‐thiazolidides. Dipeptides with N‐terminal proline displayed a very diverse affinity profile. However, in contrast to current knowledge, several Pro‐Xaa dipeptides such as Pro‐Leu, Pro‐Tyr and Pro‐Pro are recognized by PEPT1 with appreciable affinities. Binding seems mainly determined by the hydrophobicity of the C‐terminal amino acid and the rigidity of the structure.</jats:p> |
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| imprint | Wiley, 1999 |
| imprint_str_mv | Wiley, 1999 |
| institution | DE-D275, DE-Bn3, DE-Brt1, DE-Zwi2, DE-D161, DE-Gla1, DE-Zi4, DE-15, DE-Rs1, DE-Pl11, DE-105, DE-14, DE-Ch1, DE-L229 |
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| physical | 502-508 |
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| series | European Journal of Biochemistry |
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| spelling | Brandsch, Matthias Knütter, Ilka Thunecke, Frank Hartrodt, Bianka Born, Ilona Börner, Volker Hirche, Frank Fischer, Gunter Neubert, Klaus 0014-2956 1432-1033 Wiley Biochemistry http://dx.doi.org/10.1046/j.1432-1327.1999.00885.x <jats:p>To elucidate the decisive structural factors relevant for dipeptide–carrier interaction, the affinity of short amide and imide derivatives for the intestinal H<jats:sup>+</jats:sup>/peptide symporter (PEPT1) was investigated by measuring their ability to inhibit Gly‐Sar transport in Caco‐2 cells. Dipeptides with proline or alanine in the C‐terminal position displayed affinity constants (<jats:italic>K</jats:italic><jats:sub>i</jats:sub>) of 0.15–1.2 m<jats:sc>m</jats:sc> and 0.08–9.5 m<jats:sc>m</jats:sc>, respectively. There was no clear relationship between hydrophobicity, size or ionization status of the N‐terminal amino acid and the affinity of the dipeptides. However, analyzing the individual peptide bond conformations of Xaa‐Pro dipeptides, a striking correlation between the <jats:italic>cis</jats:italic>/<jats:italic>trans</jats:italic> ratios (<jats:italic>trans</jats:italic> contents 24–70%) and the affinity constants was observed. After correcting the <jats:italic>K</jats:italic><jats:sub>i</jats:sub> values for the incompetent <jats:italic>cis</jats:italic> isomers, the <jats:italic>K</jats:italic><jats:sub>i corr</jats:sub> values of most dipeptides were in a small range of 0.1–0.16 m<jats:sc>m</jats:sc>. This result revealed the decisive role of peptide bond conformation even for a transport protein that is quite promiscuous in substrate translocation. When measuring affinity constants of Xaa‐Pro and Xaa‐Sar dipeptides, the <jats:italic>cis</jats:italic>/<jats:italic>trans</jats:italic> ratios cannot be ignored. Lower affinities of Lys‐Pro, Arg‐Pro and Pro‐Pro indicate that additional molecular factors affect their binding at PEPT1. The <jats:italic>K</jats:italic><jats:sub>i</jats:sub> values obtained for the corresponding Xaa‐Ala dipeptides support this conclusion.</jats:p><jats:p>Potential substrates or inhibitors of peptide transport were found among Xaa‐piperidides and Xaa‐thiazolidides. Dipeptides with N‐terminal proline displayed a very diverse affinity profile. However, in contrast to current knowledge, several Pro‐Xaa dipeptides such as Pro‐Leu, Pro‐Tyr and Pro‐Pro are recognized by PEPT1 with appreciable affinities. Binding seems mainly determined by the hydrophobicity of the C‐terminal amino acid and the rigidity of the structure.</jats:p> Decisive structural determinants for the interaction of proline derivatives with the intestinal H<sup>+</sup>/peptide symporter European Journal of Biochemistry |
| spellingShingle | Brandsch, Matthias, Knütter, Ilka, Thunecke, Frank, Hartrodt, Bianka, Born, Ilona, Börner, Volker, Hirche, Frank, Fischer, Gunter, Neubert, Klaus, European Journal of Biochemistry, Decisive structural determinants for the interaction of proline derivatives with the intestinal H+/peptide symporter, Biochemistry |
| title | Decisive structural determinants for the interaction of proline derivatives with the intestinal H+/peptide symporter |
| title_full | Decisive structural determinants for the interaction of proline derivatives with the intestinal H+/peptide symporter |
| title_fullStr | Decisive structural determinants for the interaction of proline derivatives with the intestinal H+/peptide symporter |
| title_full_unstemmed | Decisive structural determinants for the interaction of proline derivatives with the intestinal H+/peptide symporter |
| title_short | Decisive structural determinants for the interaction of proline derivatives with the intestinal H+/peptide symporter |
| title_sort | decisive structural determinants for the interaction of proline derivatives with the intestinal h<sup>+</sup>/peptide symporter |
| title_unstemmed | Decisive structural determinants for the interaction of proline derivatives with the intestinal H+/peptide symporter |
| topic | Biochemistry |
| url | http://dx.doi.org/10.1046/j.1432-1327.1999.00885.x |