Possible Effects of Placental Leucine Aminopeptidase on the Regulation of Brain-Gut Hormones in the Fetoplacental Unit

Mizutani, Shigehiko; Goto, Kazushige; Tsujimoto, Mariko; Nakazato, Hiroshi; Matsuzawa, K; Furuhashi, Yoshihito; Arii, Kenji; Tsutsumi, Yutaka

doi:10.1159/000244325

Cited by 12 publications

(4 citation statements)

References 13 publications

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“…IRAP/P-LAP cleaves vasopressin, oxytocin, lysbradykinin, angiotensins III and IV, and the neuropeptides met-enkephalin and dynorphin A(1-8) in vitro (36,62,63). Other peptide hormones, among these insulin, have been tested for cleavage by IRAP/P-LAP and found to be unlikely substrates for IRAP/P-LAP (63,64). The cleavage of the N-terminal amino acid from each angiotensin converts it from one active form to another active form (65).…”

Section: Peptide Hormones Cleaved By Irap/p-lapmentioning

confidence: 99%

The insulin-regulated aminopeptidase a companion and regulator of GLUT4

Keller¹

2003

Front Biosci

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The insulin-regulated membrane aminopeptidase (IRAP) was originally identified in fat and muscle cells as a major protein in intracellular vesicles that also harbor the insulin-responsive glucose transporter GLUT4. IRAP, like GLUT4, predominantly localizes to these intracellular vesicles under basal conditions. In response to insulin IRAP, like GLUT4, translocates to the plasma membrane. Purification and cloning of IRAP revealed that it was a novel member of the family of zinc-dependent membrane aminopeptidases. Upon the cloning of the human placental oxytocinase (P-LAP) it was discovered that IRAP and P-LAP were the rat and human homologues of the same protein. The expression of IRAP/P-LAP is not limited to fat and muscle cells, and the subcellular distribution of IRAP/P-LAP is regulated by different peptide hormones and exercise. IRAP/P-LAP cleaves several peptide hormones in vitro. In insulin- and oxytocin-treated cells, concomitant with the appearance of IRAP/P-LAP at the cell surface, aminopeptidase activity toward extracellular substrates increases. A physiological function for IRAP/P-LAP may thus be the processing of circulating peptide hormones. These extracellular substrates, however, would be processed efficiently only when IRAP/P-LAP gets access to them after translocation to the cell surface upon stimulation of cells with insulin or other factors. The in vivo substrates for IRAP/P-LAP remain to be determined. The initial characterization of mice in which IRAP/P-LAP was deleted (IRAP -/- mice) revealed that GLUT4 protein levels were dramatically decreased in all fat and muscle tissues. This finding suggests a function for IRAP/P-LAP in the regulation of GLUT4 levels. Further characterization of the IRAP -/- mice is required to elucidate the role IRAP/P-LAP may play in the control of peptide hormone metabolism.

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Section: Peptide Hormones Cleaved By Irap/p-lapmentioning

confidence: 99%

The insulin-regulated aminopeptidase a companion and regulator of GLUT4

Keller¹

2003

Front Biosci

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“…Because the enzyme cleaves oxytocin and vasopressin between the N-terminal halfcystine residue and the penultimate tyrosine, it is also referred to as cystine or cystyl-aminopeptidase (CAP; EC 3.4.11.3) (Tuppy, 1968;Roy and Karim, 1983). In addition, it was reported that human placental leucine aminopeptidase (P-LAP) is identical to CAP and degrades angiotensin III (Tsujimoto et al, 1992) and somatostatin (Mizutani et al, 1996) as well as oxytocin and vasopressin. Therefore, this enzyme is an αaminoacyl-peptide hydrolase with a broad specificity, hydrolyzing peptide bonds with aromatic neutral and basic N-terminal amino acid residues in the peptides (Ryden, 1966;Sakura et al, 1981;Roy et al, 1993).…”

Section: Introductionmentioning

confidence: 99%

Changes in Cystine Aminopeptidase (Oxytocinase) Activity in Mouse Serum, Placenta, Uterus and Liver during Pregnancy or after Steroid Hormone Treatments

Matsumoto

Mori

1998

Zoological Science

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Changes in cystine aminopeptidase (CAP) activity in serum, placenta, uterus and liver in mice under various physiological conditions were examined by enzymatic analysis using S-benzyl-L-cysteine-4-methylcoumaryl-7-amide as a substrate. Changes in serum CAP activity during pregnancy were less remarkable than those reported in humans; the activity was highest at day 13 of pregnancy and lowest at day 17. During the estrous cycle, the serum CAP level was high at diestrus, as high as that at day 13 of pregnancy. The activity in the male serum was significantly low compared to that in the diestrous serum. Although the CAP level was especially high in the maternal placenta, levels were also high in the fetal placenta, uterus and liver as compared with the serum, suggesting CAP synthesis in these tissues. The CAP activity in the uterine tissue was lower in pregnant than normal cycling mice. Furthermore, the serum CAP activity was modulated by estrogen and progesterone both in females and males, and by androgen in males. The relevance of these findings to the physiological role of CAP was discussed.

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“…LF-A1, LF-B1, LF-B2 and LF-C (Olsen et al 1991(Olsen et al , 1995Shapiro et al 1991). An enhancer region of about 300 bp that is localized 2.7 kb upstream of the epithelial promoter seems to enhance the activity ofboth promoters (Olsen et al 1997) APN is supposed to be involved in the degradation of neuropeptides (Ahmad et al 1992;Furuhashi et al 1988;Giros et al 1986;Miller et al 1994aMiller et al , 1994bMizutani et al 1993;Shibanoki et al 1991;Shimamura et al 1988Shimamura et al , 1991Ward et al 1990), cytokines and immunomodulatory peptides (Hoffmann et al 1993;Kanayama et al 1995;Mathe 1987), and angiotensins (Chansel et al 1998;Palmieri et al 1989;Palmieri et al 1985). Furthermore, APN may contribute in extracellular matrix degradation (Fujii et al 1995;Saiki et al 1993) and antigen processing (Hansen et al 1993;Larsen et al 1996).…”

Section: Characteristics and Functionsmentioning

confidence: 99%

Alanyl-Aminopeptidases in Human T Cells

Lendeckel

Bukowska

Lättig

et al. 2004

Aminopeptidases in Biology and Disease

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Inhibition of the enzymatic activity of alanyl-aminopeptidase leads to strong immunosuppression both in vitro and in vivo. Mechanisms involved include growth arrest, induction of immunosuppressive cytokines (TGF-13I), reduced expression of inflammatory or T cell stimulating cytokines (IL-2, IL-12) , and modulation of T cell signalling pathways. Thus, T cells appear to represent a major cellular target for the pharmacological treatment of T cell mediated diseases by virtue of aminopeptidase inhibitor administration. Membrane (APN) and cytosol alanyl-aminopeptidase (ApPS), both implicated in a variety of cellular functions, show similar substrate specifity and inhibitor sensitivity. Furthermore, both enzymes are expressed in practically all T cell subsets, including the population of natural regulatory T cells that was shown recently to control the immunological tolerance to self-antigens. While the involvement of APN and ApPS in the pathological immune response is evident, the precise molecular mechanisms remain to be identified. The development of inhibitors specific for APN and ApPS is an attractive field of study and would allow determination of the individual contribution of either enzyme in the immune response.

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Possible Effects of Placental Leucine Aminopeptidase on the Regulation of Brain-Gut Hormones in the Fetoplacental Unit

Cited by 12 publications

References 13 publications

The insulin-regulated aminopeptidase a companion and regulator of GLUT4

The insulin-regulated aminopeptidase a companion and regulator of GLUT4

Changes in Cystine Aminopeptidase (Oxytocinase) Activity in Mouse Serum, Placenta, Uterus and Liver during Pregnancy or after Steroid Hormone Treatments

Alanyl-Aminopeptidases in Human T Cells

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