Inhibitory Effect of Arphamenine A on Intestinal Dipeptide Transport

Enjoh, Masashi; Hashimoto, Kei; Arai, Soichi; Shimizu, Makoto

doi:10.1271/bbb.60.1893

Cited by 22 publications

(12 citation statements)

References 2 publications

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“…Demonstration that -AFA with 4 -10 CH 2 units in the backbone bind to PEPT1 and are transported in an electrogenic fashion clearly establishes that the presence of a peptide bond in a substrate is not a structural requirement. Although previous studies using modified peptides (25,26) demonstrated that the replacement of the peptide bond by a ketomethylene or thioxo function still retains the affinity of these dipeptide mimetics for interaction with PEPT1, our studies establish that the complete removal of the peptide bond as well as of the side chains is tolerated without a significant loss in affinity. The apparent affinities as determined for selected -AFA in the competition assays as well as by the influx of radiolabeled 6-AHA and electrophysiology are very similar to those of representative dipeptides or tripeptides.…”

Section: Recordings Of Substrate-induced Inward Currents and I-v Recontrasting

confidence: 55%

Minimal Molecular Determinants of Substrates for Recognition by the Intestinal Peptide Transporter

Döring¹,

Will²,

Amasheh³

et al. 1998

Journal of Biological Chemistry

135

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Proton-dependent electrogenic transporters for diand tripeptides have been identified in bacteria, fungi, plants, and mammalian cells. They all show sequenceindependent transport of all possible di-and tripeptides as well as of a variety of peptidomimetics. We used the mammalian intestinal peptide transporter PEPT1 as a model to define the molecular basis for its multisubstrate specificity. By employing computational analysis of possible substrate conformations in combination with transport assays using transgenic yeast cells and Xenopus laevis oocytes expressing PEPT1, the minimal structural requirements for substrate binding and transport were determined. Based on a series of medium chain fatty acids bearing an amino group as a head group (-amino fatty acids, -AFA), we show that electrogenic transport by PEPT1 requires as a minimum the two ionized head groups separated by at least four methylene groups. Consequently, a > 500 pm < 630 pm distance between the two charged centers (carboxylic carbon and amino nitrogen) is sufficient for substrate recognition and transport. Removal of either the amino group or the carboxyl group in -AFA maintained the affinity of the compound for interaction with the transporter but abolished the capability for electrogenic transport. Additional groups in the -AFA backbone that provide more hydrogen bonding sites appear to increase substrate affinity but are not essential. The information provided here does (a) explain the capability of the peptide carrier for sequence-independent transport of thousands of different substrates and (b) set the molecular basis for a rational drug design to increase the absorption of peptide-based drugs mediated by PEPT1.

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Section: Recordings Of Substrate-induced Inward Currents and I-v Recontrasting

confidence: 55%

Minimal Molecular Determinants of Substrates for Recognition by the Intestinal Peptide Transporter

Döring¹,

Will²,

Amasheh³

et al. 1998

Journal of Biological Chemistry

135

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“…3). The presence of arphamenine A, which is also a substrate for the peptide transporter with a low Km value, 21) slightly reduced the basolateral concentration of ValPro-Pro, although the decrease in the ‰ux was not signiˆcant. These results suggest that the peptide transporter did not play a signiˆcant role in the transepithelial transport of Val-Pro-Pro in the Caco-2 cell monolayer.…”

Section: Contribution Of Transporter-mediated Transport To the Transementioning

confidence: 95%

“…Gly-Pro is a good substrate for the peptide transporter with a low Km value, 21) and is fairly resistant to brush border peptidases. Gly-Pro has therefore often been used to analyze the peptide transporter functions.…”

Section: Contribution Of Transporter-mediated Transport To the Transementioning

confidence: 99%

Transepithelial Transport of the Bioactive Tripeptide, Val-Pro-Pro, in Human Intestinal Caco-2 Cell Monolayers

Satake

Enjoh

Nakamura³

et al. 2002

Bioscience, Biotechnology, and Biochemistry

Self Cite

209

167

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Some of the food-derived tripeptides with angiotensin converting enzyme (ACE)-inhibitory activity have been reported to be hypotensive after being orally administered. The mechanism for the intestinal transport of these tripeptides was studied by using monolayer-cultured human intestinal Caco-2 cells which express many enterocyte-like functions including the peptide transporter (PepT1)-mediated transport system. Val-Pro-Pro, an ACE-inhibitory peptide from fermented milk, was used as a model tripeptide. A significant amount of intact Val-Pro-Pro was transported across the Caco-2 cell monolayer. This transport was hardly inhibited by a competitive substrate for PepT1. Since no intact Val-Pro-Pro was detected in the cells, Val-Pro-Pro apically taken by Caco-2 cells via PepT1 was likely to have been quickly hydrolyzed by intracellular peptidases, producing free Val and Pro. These findings suggest that PepT1-mediated transport was not involved in the transepithelial transport of intact Val-Pro-Pro. Paracellular diffusion is suggested to have been the main mechanism for the transport of intact Val-Pro-Pro across the Caco-2 cell monolayer.

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“…7 indicates the AP-to-BL flux of KVLPVP was not significantly influenced in the presence of Gly-Pro (10 mM). In addition, the presence of arphamenine A (10 mM), which is also a substrate for the peptide transporter, 29) had minimal effect on the BL concentration of KVLPVP (Fig. 7).…”

Section: Contribution Of the Peptide Transporter To The Transepithelimentioning

confidence: 97%

Transepithelial Transport Characteristics of the Antihypertensive Peptide, Lys-Val-Leu-Pro-Val-Pro, in Human Intestinal Caco-2 Cell Monolayers

Sun

Liu

et al. 2009

Bioscience, Biotechnology, and Biochemistry

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An antihypertensive peptide, Lys-Val-Leu-Pro-Val-Pro (KVLPVP), can reduce blood pressure in hypertensive rats after being orally administered. In this study, the transepithelial transport of intact KVLPVP was examined by Caco-2 monolayers. The results were as follows: (i) The flux was not saturable for apical (AP) to basolateral (BL) or BL-AP transport when the concentration of KVLPVP was 1-8 mM. (ii) Sodium deoxycholate loosened the tight junction in the Caco-2 cells and significantly improved the transport process. (iii) Phenylarsine oxide, a transcytotic process inhibitor, had little effect on the transport process. (iv) The influx and eflux of KVLPVP remained unchanged in the presence of the ATP inhibitor sodium azide. (v) This transport was not inhibited by the peptide transporter substrates Gly-Pro or arphanine A. All these data indicate that paracellular transport diffusion was the major flux mechanism for the intact KVLPVP.

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Inhibitory Effect of Arphamenine A on Intestinal Dipeptide Transport

Cited by 22 publications

References 2 publications

Minimal Molecular Determinants of Substrates for Recognition by the Intestinal Peptide Transporter

Minimal Molecular Determinants of Substrates for Recognition by the Intestinal Peptide Transporter

Transepithelial Transport of the Bioactive Tripeptide, Val-Pro-Pro, in Human Intestinal Caco-2 Cell Monolayers

Transepithelial Transport Characteristics of the Antihypertensive Peptide, Lys-Val-Leu-Pro-Val-Pro, in Human Intestinal Caco-2 Cell Monolayers

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