Identification of human placental leucine aminopeptidase as oxytocinase

Tsujimoto, Masafumi; Mizutani, Shigehiko; Adachi, Hideki; Kimura, Masami; Nakazato, Hiroshi; Tsutsumi, Yutaka

doi:10.1016/0003-9861(92)90007-j

Cited by 130 publications

(96 citation statements)

References 15 publications

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“…In our previous work (24,38,39), we purified and characterized native membrane-bound and soluble forms as well as a recombinant soluble form of P-LAP/IRAP. When comparing the enzymatic properties toward synthetic and natural hormone substrates, little characteristic difference was observed between these enzymes tested so far.…”

Section: Discussionmentioning

confidence: 99%

Enzymatic Properties of Human Aminopeptidase A

Goto

Hattori

Ishii

et al. 2006

Journal of Biological Chemistry

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Aminopeptidase A (APA) is a type II membrane-bound protein implicated in the regulation of blood pressure in the brain renin-angiotensin system. In this study, a recombinant soluble form of APA was expressed in a baculovirus system, purified to homogeneity, and characterized. By using synthetic substrates, it was shown that although the enzyme has a rather broad substrate specificity in the absence of Ca 2؉ , the preferential release of acidic amino acid residues was observed in the presence of Ca 2؉ . Moreover, Ca 2؉ up-or down-regulated the enzymatic activity depending on the substrate. By searching for natural substrates of APA, we found that peptides having acidic amino acids at their N terminus (angiotensin II, neurokinin B, cholecystokinin-8, and chromogranin A) were cleaved by the enzyme efficiently in the presence but not in the absence of Ca 2؉ . Moreover kallidin (Lys-bradykinin) was converted to bradykinin effectively only in the absence of Ca 2؉ . These results suggest that Ca 2؉ increases the preference of the enzyme for the peptide substrates having N-terminal acidic amino acids. In addition, we found that angiotensin IV could bind to APA both in the presence and absence of Ca 2؉ and inhibited the enzymatic activity of APA competitively, suggesting that angiotensin IV acts as a negative regulator of the enzyme once generated from angiotensin II by the serial actions of aminopeptidases. Taken together, these results suggest that there exists a complex regulation of the enzymatic activity of APA, which may contribute to homeostasis such as regulation of blood pressure, maintenance of memory, and normal pregnancy by controlling the concentrations of peptide substrates.

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Section: Discussionmentioning

confidence: 99%

Enzymatic Properties of Human Aminopeptidase A

Goto

Hattori

Ishii

et al. 2006

Journal of Biological Chemistry

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“…4,26) In addition, P-LAP is able to hydrolyze AngIII. 4) Contrary to the previous belief that P-LAP is limited to placenta, northern blot analysis 27) and immunohistochemistry 28) have shown that P-LAP has a broad tissue distribution other than placenta. cDNA cloning of P-LAP has demonstrated that this enzyme is a homologue of rat insulin-regulated membrane aminopeptidase (IRAP), which is present in the glucose transporter isotype GLUT4 vesicles of rat adipocytes.…”

Section: Placental Leucine Aminopeptidase (P-lap)mentioning

confidence: 99%

Role of Aminopeptidases in the Blood Pressure Regulation

Mitsui

Nomura

Itakura

et al. 2004

Biological & Pharmaceutical Bulletin

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In addition to the neural and autoregulatory factors, blood pressure (BP) is regulated by humoral factors including vasoactive peptides. When evaluating the peptide actions, degradation by proteases should be also considered in addition to the generation of peptides and their receptors. This review describes the roles of aminopeptidase A, placental leucine aminopeptidase and kininase I, which are enzymes responsible for hydrolyzing angiotensin II (AngII), vasopressin (AVP) and bradykinin (BK), respectively, in BP regulation. Especially, we focus on the association of the proteases with preeclampsia, hypertensive disorder peculiar to pregnancy, since one of the representative organs that are rich in theses proteases is placenta. Although the physiological roles of the placental proteases have not been fully understood, several lines of evidence suggest that the proteases are involved in the maintenance of pregnancy homeostasis including fetal and maternal BP regulation through the metabolism of bioactive peptides at the interface between mother and fetus.

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“…Membrane-anchored M1 proteins, such as the insulin-responsive aminopeptidase (IRAP), have been shown to process signaling peptides (Tsujimoto et al, 1992;Herbst et al, 1997;Albiston et al, 2004). Like IRAP, APM1 is found in a unique light membrane fraction not characterized by other markers ( Figure 11).…”

Section: Apm1 Activity Is More Analogous To Mammalianmentioning

confidence: 99%

“…Like IRAP, APM1 is found in a unique light membrane fraction not characterized by other markers ( Figure 11). However, the lack of a transmembrane helix, extracellular enzymatic activity domain, and the unique N-terminal extension that mediates IRAP-GLUT4 interactions (Tsujimoto et al, 1992;Herbst et al, 1997;Albiston et al, 2004) indicates that APM1 does not process extracellular peptide hormones or mediate GLUT4-like trafficking. APN/CD13 functions in cell surface uptake of cholesterol and cell adhesion to the extracellular matrix (Kramer et al, 2005;Wulfaenger et al, 2008).…”

Section: Apm1 Activity Is More Analogous To Mammalianmentioning

confidence: 99%

Mutation of the Membrane-Associated M1 Protease APM1 Results in Distinct Embryonic and Seedling Developmental Defects inArabidopsis

et al. 2009

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Aminopeptidase M1 (APM1), a single copy gene in Arabidopsis thaliana, encodes a metallopeptidase originally identified via its affinity for, and hydrolysis of, the auxin transport inhibitor 1-naphthylphthalamic acid (NPA). Mutations in this gene result in haploinsufficiency. Loss-of-function mutants show irregular, uncoordinated cell divisions throughout embryogenesis, affecting the shape and number of cotyledons and the hypophysis, and is seedling lethal at 5 d after germination due to root growth arrest. Quiescent center and cell cycle markers show no signals in apm1-1 knockdown mutants, and the ground tissue specifiers SHORTROOT and SCARECROW are misexpressed or mislocalized. apm1 mutants have multiple, fused cotyledons and hypocotyls with enlarged epidermal cells with cell adhesion defects. apm1 alleles show defects in gravitropism and auxin transport. Gravistimulation decreases APM1 expression in auxin-accumulating root epidermal cells, and auxin treatment increases expression in the stele. On sucrose gradients, APM1 occurs in unique light membrane fractions. APM1 localizes at the margins of Golgi cisternae, plasma membrane, select multivesicular bodies, tonoplast, dense intravacuolar bodies, and maturing metaxylem cells. APM1 associates with brefeldin A-sensitive endomembrane structures and the plasma membrane in cortical and epidermal cells. The auxin-related phenotypes and mislocalization of auxin efflux proteins in apm1 are consistent with biochemical interactions between APM1 and NPA.

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Identification of human placental leucine aminopeptidase as oxytocinase

Cited by 130 publications

References 15 publications

Enzymatic Properties of Human Aminopeptidase A

Enzymatic Properties of Human Aminopeptidase A

Role of Aminopeptidases in the Blood Pressure Regulation

Mutation of the Membrane-Associated M1 Protease APM1 Results in Distinct Embryonic and Seedling Developmental Defects inArabidopsis

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