Journal articles: 'Aminopeptidases Synthesis'

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Kohno, H., and T. Kanno. "Properties and activities of aminopeptidases in normal and mitogen-stimulated human lymphocytes." Biochemical Journal 226, no. 1 (February 15, 1985): 59–65. http://dx.doi.org/10.1042/bj2260059.

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Human peripheral lymphocytes were found to contain at least two distinct aminopeptidases, designated cytosol aminopeptidase and microsomal aminopeptidase, which differed from one another with respect to intracellular localization, substrate specificity, metal-ion activation, Km value and electrophoretic mobility. No change in these aminopeptidase activities was observed in cultured lymphocytes in the absence of mitogen throughout the cultivation period. The addition of phytohaemagglutinin or concanavalin A to the culture medium caused, in dose-dependent manner, a significant increase in cytosol aminopeptidase activity in lymphocytes. On the other hand, no increase in microsomal aminopeptidase activity was observed under the same conditions. The biochemical properties of aminopeptidases in stimulated cultured lymphocytes were identical with those of the enzymes in peripheral lymphocytes and unstimulated cultured lymphocyte. The phytohaemagglutinin dose-response curves for lymphocyte activation as measured by the DNA synthesis rate and for cytosol aminopeptidase activity were observed to be similar. However, when DNA synthesis was temporarily blocked by hydroxyurea, the rate of increase of aminopeptidase activity was unaffected. Pokeweed mitogen only slightly increased the cytosol aminopeptidase activity in cultured lymphocytes, although the lymphocytes were highly activated.

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Cunningham, Eithne, Marcin Drag, Pawel Kafarski, and Angus Bell. "Chemical Target Validation Studies of Aminopeptidase in Malaria Parasites Using α-Aminoalkylphosphonate and Phosphonopeptide Inhibitors." Antimicrobial Agents and Chemotherapy 52, no. 9 (May 5, 2008): 3221–28. http://dx.doi.org/10.1128/aac.01327-07.

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ABSTRACT During its intraerythrocytic phase, the most lethal human malarial parasite, Plasmodium falciparum, digests host cell hemoglobin as a source of some of the amino acids required for its own protein synthesis. A number of parasite endopeptidases (including plasmepsins and falcipains) process the globin into small peptides. These peptides appear to be further digested to free amino acids by aminopeptidases, enzymes that catalyze the sequential cleavage of N-terminal amino acids from peptides. Aminopeptidases are classified into different evolutionary families according to their sequence motifs and preferred substrates. The aminopeptidase inhibitor bestatin can disrupt parasite development, suggesting that this group of enzymes might be a chemotherapeutic target. Two bestatin-susceptible aminopeptidase activities, associated with gene products belonging to the M1 and M17 families, have been described in blood-stage P. falciparum parasites, but it is not known whether one or both are required for parasite development. To establish whether inhibition of the M17 aminopeptidase is sufficient to confer antimalarial activity, we evaluated 35 aminoalkylphosphonate and phosphonopeptide compounds designed to be specific inhibitors of M17 aminopeptidases. The compounds had a range of activities against cultured P. falciparum parasites with 50% inhibitory concentrations down to 14 μM. Some of the compounds were also potent inhibitors of parasite aminopeptidase activity, though it appeared that many were capable of inhibiting the M1 as well as the M17 enzyme. There was a strong correlation between the potencies of the compounds against whole parasites and against the enzyme, suggesting that M17 and/or M1 aminopeptidases may be valid antimalarial drug targets.

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Salomon, Emmanuel, Marjorie Schmitt, Anil Marapaka, Athanasios Stamogiannos, Germain Revelant, Céline Schmitt, Sarah Alavi, et al. "Aminobenzosuberone Scaffold as a Modular Chemical Tool for the Inhibition of Therapeutically Relevant M1 Aminopeptidases." Molecules 23, no. 10 (October 11, 2018): 2607. http://dx.doi.org/10.3390/molecules23102607.

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The synthesis of racemic substituted 7-amino-5,7,8,9-tetrahydrobenzocyclohepten-6-one hydrochlorides was optimized to enhance reproducibility and increase the overall yield. In order to investigate their specificity, series of enzyme inhibition assays were carried out against a diversity of proteases, covering representative members of aspartic, cysteine, metallo and serine endopeptidases and including eight members of the monometallic M1 family of aminopeptidases as well as two members of the bimetallic M17 and M28 aminopeptidase families. This aminobenzosuberone scaffold indeed demonstrated selective inhibition of M1 aminopeptidases to the exclusion of other tested protease families; it was particularly potent against mammalian APN and its bacterial/parasitic orthologues EcPepN and PfAM1.

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Bradshaw, Ralph A., and Elizabeth Yi. "Methionine aminopeptidases and angiogenesis." Essays in Biochemistry 38 (October 1, 2002): 65–78. http://dx.doi.org/10.1042/bse0380065.

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The initiator methionine residue of proteins is removed during synthesis by a specific and ubiquitous enzyme, methionine aminopeptidase (MetAP). Prokaryotes have a single gene, while eukaryotes have two isoforms. This family of metalloenzymes generally cleaves substrates in which the penultimate residue is one of the seven smaller amino acids (glycine, alanine, serine, threonine, proline, cysteine and valine). One of the eukaryotic isoforms (MetAP2) has an additional non-proteolytic function and is the principle target of a family of anti-angiogenic drugs that are related to fumagillin. The resulting covalent modification inhibits the protease activity of MetAP2 and blocks cell-cycle function in endothelial and some cancer cells. The role of MetAP2 in the mitogenic activity of these cells is unknown.

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Teague, Andrea S., Manik A. Amin, Kian-Huat Lim, Albert C. Lockhart, Ashiq Masood, Joel Picus, Preet Paul Singh, Rama Suresh, Benjamin R. Tan, and Andrea Wang-Gillam. "A phase I/II study combining tosedostat with capecitabine in patients with metastatic pancreatic adenocarcinoma." Journal of Clinical Oncology 34, no. 4_suppl (February 1, 2016): TPS471. http://dx.doi.org/10.1200/jco.2016.34.4_suppl.tps471.

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TPS471 Background: Metastatic pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis. Recent advances with fluorouracil in combination with oxaliplatin and irinotecan (FOLFIRINOX) and nab-paclitaxel combined with gemcitabine (AG) have improved survival in patients with PDAC. A fluorouracil-based regimen is recommended for patients who progress after a gemcitabine-based regimen. Tosedostat is an oral aminopeptidase inhibitor shown to have anti-proliferative effects in malignancies. Aminopeptidase inhibitors disrupt the cleavage of amino acids from peptides downstream of proteasomal degradation, preventing the recycling of amino acids needed for new protein synthesis. This leads to intracellular depletion of amino acids, resulting in a cellular stress response known as the amino acid deprivation response, which leads to apoptosis. Because pancreatic cancer cells frequently upregulate expression of these aminopeptidases, aminopeptidases inhibitors hold therapeutic promise. Methods: This is a single institution phase I/II open-label trial to evaluate the safety and tolerability of tosedostat plus capecitabine in patients with metastatic PDAC that have progressed after a gemcitabine-based regimen. The phase I part will be conducted in a dose de-escalation fashion, with two planned dose levels of tosedostat (120mg or 60mg) p.o. daily on days 1 to 21 with capecitabine 1000 mg/m2 p.o. BID on days 1 to 14 of a 21-day cycle. If more than one patient in the tosedostat (120 mg) cohort experiences a dose limiting toxicity (DLT), then 6 more patient will be enrolled to the tosedostat (60 mg) cohort. A total of 36 patients will be enrolled in the phase II portion. Primary objective of the phase I portion is to determine the maximum tolerated dose and DLTs of tosedostat and capecitabine combination therapy. Primary objective of the phase II portion is to determine the progression-free survival at 3 months. Secondary objectives are to determine the overall response rate, time-to-progression, overall survival and CA 19-9 response. Exploratory objectives are to explore the predictive molecular biomarkers for treatment response and to explore the prognostic biomarkers. Clinical trial: NCT02352831. Clinical trial information: NCT02352831.

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Bertin, Patrícia B., Silene P. Lozzi, Jerrilyn K. Howell, Glória Restrepo-Cadavid, David Neves, Antonio R. L. Teixeira, Marcelo V. de Sousa, Steven J. Norris, and Jaime M. Santana. "The Thermophilic, Homohexameric Aminopeptidase of Borrelia burgdorferi Is a Member of the M29 Family of Metallopeptidases." Infection and Immunity 73, no. 4 (April 2005): 2253–61. http://dx.doi.org/10.1128/iai.73.4.2253-2261.2005.

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ABSTRACT Proteases are implicated in several aspects of the physiology of microorganisms, as well as in host-pathogen interactions. Aminopeptidases are also emerging as novel drug targets in infectious agents. In this study, we have characterized an aminopeptidase from the spirochete Borrelia burgdorferi, the causative agent of Lyme disease. The aminopeptidolytic activity was identified in cell extracts from B. burgdorferi by using the substrate leucine-7-amido-4-methylcoumarin. A protein displaying this activity was purified from B. burgdorferi by a two-step chromatographic procedure, yielding a ∼300-kDa homo-oligomeric enzyme formed by monomers of ∼50 kDa. Gel enzymography experiments showed that enzymatic activity depends on the oligomeric structure of the protease but does not involve interchain disulfide bonds. The enzyme was identified by peptide mass fingerprinting as the putative aminopeptidase II of B. burgdorferi, encoded by the gene BB0069. It shares significant identity to members of the M29/T family of metallopeptidase, is sensitive to bestatin, has a neutral pH optimum, and displays maximal activity at 60°C. Its activity is 1.75-fold higher at the temperature of the mammalian host than at that of the insect host of the pathogen. The activity of this thermophilic aminopeptidase of B. burgdorferi (TAPBb) depends on Zn2+, and temperatures over 70°C promoted its inactivation through a transition from the hexameric state to the monomeric state. Since B. burgdorferi is deficient in pathways for amino acid synthesis, TAPBb could play a role in supplying required amino acids. Alternatively, the enzyme could be involved in peptide and/or protein processing.

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Ocain, Timothy D., and Daniel H. Rich. "Synthesis of sulfur-containing analogs of bestatin. Inhibition of aminopeptidases by .alpha.-thiolbestatin analogs." Journal of Medicinal Chemistry 31, no. 11 (November 1988): 2193–99. http://dx.doi.org/10.1021/jm00119a022.

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Wanat, Weronika, Michał Talma, Błażej Dziuk, and Paweł Kafarski. "Synthesis and Inhibitory Studies of Phosphonic Acid Analogues of Homophenylalanine and Phenylalanine towards Alanyl Aminopeptidases." Biomolecules 10, no. 9 (September 14, 2020): 1319. http://dx.doi.org/10.3390/biom10091319.

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A library of novel phosphonic acid analogues of homophenylalanine and phenylalanine, containing fluorine and bromine atoms in the phenyl ring, have been synthesized. Their inhibitory properties against two important alanine aminopeptidases, of human (hAPN, CD13) and porcine (pAPN) origin, were evaluated. Enzymatic studies and comparison with literature data indicated the higher inhibitory potential of the homophenylalanine over phenylalanine derivatives towards both enzymes. Their inhibition constants were in the submicromolar range for hAPN and the micromolar range for pAPN, with 1-amino-3-(3-fluorophenyl) propylphosphonic acid (compound 15c) being one of the best low-molecular inhibitors of both enzymes. To the best of our knowledge, P1 homophenylalanine analogues are the most active inhibitors of the APN among phosphonic and phosphinic derivatives described in the literature. Therefore, they constitute interesting building blocks for the further design of chemically more complex inhibitors. Based on molecular modeling simulations and SAR (structure-activity relationship) analysis, the optimal architecture of enzyme-inhibitor complexes for hAPN and pAPN were determined.

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Węglarz-Tomczak, Ewelina, Katarzyna Staszewska, Michał Talma, and Artur Mucha. "Enantiomeric α,β-diaminoethylphosphonic acids as potent inhibitors of aminopeptidases—stereoselective synthesis and biological activity." Tetrahedron Letters 57, no. 43 (October 2016): 4812–14. http://dx.doi.org/10.1016/j.tetlet.2016.09.051.

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Hebert, Elvira M., Raul R. Raya, and Graciela S. De Giori. "Nutritional Requirements and Nitrogen-Dependent Regulation of Proteinase Activity of Lactobacillus helveticus CRL 1062." Applied and Environmental Microbiology 66, no. 12 (December 1, 2000): 5316–21. http://dx.doi.org/10.1128/aem.66.12.5316-5321.2000.

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ABSTRACT The nutritional requirements of Lactobacillus helveticus CRL 1062 were determined with a simplified chemically defined medium (SCDM) and compared with those of L. helveticus CRL 974 (ATCC 15009). Both strains were found to be prototrophic for alanine, glycine, asparagine, glutamine, and cysteine. In addition, CRL 1062 also showed prototrophy for lysine and serine. The microorganisms also required riboflavin, calcium pantothenate, pyridoxal, nicotinic acid, and uracil for growth in liquid SCDM. The growth rate and the synthesis of their cell membrane-bound serine proteinases, but not of their intracellular leucyl-aminopeptidases, were influenced by the peptide content of the medium. The highest proteinase levels were found during cell growth in basal SCDM, while the synthesis of this enzyme was inhibited in SCDM supplemented with Casitone, Casamino Acids, or β-casein. Low-molecular-mass peptides (<3,000 Da), extracted from Casitone, and the dipeptide leucylproline (final concentration, 5 mM) play important roles in the medium-dependent regulation of proteinase activity. The addition of the dipeptide leucylproline (5 mM) to SCDM reduced proteinase activity by 25%.

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Hooper, Nigel M. "Proteases: a primer." Essays in Biochemistry 38 (October 1, 2002): 1–8. http://dx.doi.org/10.1042/bse0380001.

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A protease can be defined as an enzyme that hydrolyses peptide bonds. Proteases can be divided into endopeptidases, which cleave internal peptide bonds in substrates, and exopeptidases, which cleave the terminal peptide bonds. Exopeptidases can be further subdivided into aminopeptidases and carboxypeptidases. The Schechter and Berger nomenclature provides a model for describing the interactions between the peptide substrate and the active site of a protease. Proteases can also be classified as aspartic proteases, cysteine proteases, metalloproteases, serine proteases and threonine proteases, depending on the nature of the active site. Different inhibitors can be used experimentally to distinguish between these classes of protease. The MEROPs database groups proteases into families on the basis of similarities in sequence and structure. Protease activity can be regulated in vivo by endogenous inhibitors, by the activation of zymogens and by altering the rate of their synthesis and degradation.

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Gordon, E. M., J. D. Godfrey, N. G. Delaney, M. M. Asaad, D. Von Langen, and D. W. Cushman. "Design of novel inhibitors of aminopeptidases. Synthesis of peptide-derived diamino thiols and sulfur replacement analogs of bestatin." Journal of Medicinal Chemistry 31, no. 11 (November 1988): 2199–211. http://dx.doi.org/10.1021/jm00119a023.

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MOON, B. J., and K. L. HUH. "ChemInform Abstract: Facile Synthesis of (2S,3R)-3-Amino-2-hydroxy-4(4′-hydroxyphenyl) butanoic Acid. Application to the Synthesis of Inhibitors of Aminopeptidases." ChemInform 22, no. 34 (August 22, 2010): no. http://dx.doi.org/10.1002/chin.199134226.

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Irfan, Iram, Asghar Ali, Bharati Reddi, Mohd Abrar Khan, Phool Hasan, Sarfraz Ahmed, Amad Uddin, et al. "Design, Synthesis and Mechanistic Studies of Novel Isatin-Pyrazole Hydrazone Conjugates as Selective and Potent Bacterial MetAP Inhibitors." Antibiotics 11, no. 8 (August 19, 2022): 1126. http://dx.doi.org/10.3390/antibiotics11081126.

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Methionine aminopeptidases (MetAPs) are attractive drug targets due to their essential role in eukaryotes as well as prokaryotic cells. In this study, biochemical assays were performed on newly synthesized Isatin-pyrazole hydrazones (PS1–14) to identify potent and selective bacterial MetAPs inhibitors. Compound PS9 inhibited prokaryotic MetAPs, i.e., MtMetAP1c, EfMetAP1a and SpMetAP1a with Ki values of 0.31, 6.93 and 0.37 µM, respectively. Interestingly, PS9 inhibited the human analogue HsMetAP1b with Ki (631.7 µM) about ten thousand-fold higher than the bacterial MetAPs. The in vitro screening against Gram-positive (Enterococcus faecalis, Bacillus subtilis and Staphylococcus aureus) and Gram-negative (Pseudomonas aeruginosa, Klebsiella pneumonia and Escherichia coli) bacterial strains also exhibited their antibacterial potential supported by minimum bactericidal concentration (MBC), disk diffusion assay, growth curve and time-kill curve experiments. Additionally, PS6 and PS9 had synergistic effects when combined with ampicillin (AMP) and ciprofloxacin (CIP) against selective bacterial strains. PS9 showed no significant cytotoxic effect on human RBCs, HEK293 cells and Galleria mellonella larvae in vivo. PS9 inhibited the growth of multidrug-resistant environmental isolates as it showed the MIC lower than the standard drugs used against selective bacterial strains. Overall, the study suggested PS9 could be a useful candidate for the development of antibacterial alternatives.

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Kannan Sivaraman, Komagal, Alessandro Paiardini, Marcin Sieńczyk, Chiara Ruggeri, Christine A. Oellig, John P. Dalton, Peter J. Scammells, Marcin Drag, and Sheena McGowan. "Synthesis and Structure–Activity Relationships of Phosphonic Arginine Mimetics as Inhibitors of the M1 and M17 Aminopeptidases from Plasmodium falciparum." Journal of Medicinal Chemistry 56, no. 12 (June 13, 2013): 5213–17. http://dx.doi.org/10.1021/jm4005972.

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Heck, T., B. Geueke, D. Seebach, S. Osswald, M. K. J. Ter Wiel, and H. P. E. Kohler. "β-Aminopeptidases: enzymatic degradation and synthesis of β-amino acid containing peptides and kinetic resolution of β-amino acid amides." New Biotechnology 25 (September 2009): S62. http://dx.doi.org/10.1016/j.nbt.2009.06.291.

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Masood, Mir Mohammad, Mohammad Irfan, Shadab Alam, Phool Hasan, Aarfa Queen, Shifa Shahid, Muhammad Zahid, Amir Azam, and Mohammad Abid. "Synthesis, Antimicrobial Evaluation and In silico Studies of Novel 2,4- disubstituted-1,3-thiazole Derivatives." Letters in Drug Design & Discovery 16, no. 2 (November 29, 2018): 160–73. http://dx.doi.org/10.2174/1570180815666180502120042.

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Background: 2,4-disubstituted-1,3-thiazole derivatives (2a–j), (3a–f) and (4a–f) were synthesized, characterized and screened for their potential as antimicrobial agents. In the preliminary screening against a panel of bacterial strains, nine compounds showed moderate to potent antibacterial activity (IC50 = 13.7-90.8 μg/ml). </P><P> Methods: In the antifungal screening, compound (4c) displayed potent antifungal activity (IC50 = 26.5 µg/ml) against Candida tropicalis comparable to the standard drug, fluconazole (IC50 = 10.5 µg/ml). Based on in vitro antimicrobial results, compounds 2f, 4c and 4e were selected for further pharmacological investigations. Hemolytic activity using human red blood cells (hRBCs) and cytotoxicity by MTT assay on human embryonic kidney (HEK-293) cells revealed non-toxic nature of the selected compounds (2f, 4c and 4e). To ascertain their possible mode of action, docking studies with the lead inhibitors (2f, 4c and 4e) were performed using crystal structure coordinates of bacterial methionine aminopeptidases (MetAPs), an enzyme involved in bacterial protein synthesis and maturation. Results: The results of in vitro and in silico studies provide a rationale for selected compounds (2f, 4c and 4e) to be carried forward for further structural modifications and structure-activity relationship (SAR) studies against these bacterial infections. Conclusion: The study suggested binding with one or more key amino acid residues in the active site of Streptococcus pneumoniae MetAP (SpMetAP) and Escherichia coli MetAP (EcMetAP). In silico physicochemical properties using QikProp confirmed their drug likeliness.

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Bantysh, Olga, Marina Serebryakova, Inna Zukher, Alexey Kulikovsky, Darya Tsibulskaya, Svetlana Dubiley, and Konstantin Severinov. "Enzymatic Synthesis and Functional Characterization of Bioactive Microcin C-Like Compounds with Altered Peptide Sequence and Length." Journal of Bacteriology 197, no. 19 (July 20, 2015): 3133–41. http://dx.doi.org/10.1128/jb.00271-15.

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ABSTRACTEscherichia colimicrocin C (McC) consists of a ribosomally synthesized heptapeptide attached to a modified adenosine. McC is actively taken up by sensitiveEscherichia colistrains through the YejABEF transporter. Inside the cell, McC is processed by aminopeptidases, which release nonhydrolyzable aminoacyl adenylate, an inhibitor of aspartyl-tRNA synthetase. McC is synthesized by the MccB enzyme, which terminally adenylates the MccA heptapeptide precursor MRTGNAN. Earlier, McC analogs with shortened peptide lengths were prepared by total chemical synthesis and were shown to have strongly reduced biological activity due to decreased uptake. Variants with longer peptides were difficult to synthesize, however. Here, we used recombinant MccB to prepare and characterize McC-like molecules with altered peptide moieties, including extended peptide lengths. We find that N-terminal extensions ofE. coliMccA heptapeptide do not affect MccB-catalyzed adenylation and that some extended-peptide-length McC analogs show improved biological activity. When the peptide length reaches 20 amino acids, both YejABEF and SbmA can perform facilitated transport of toxic peptide adenylates inside the cell. A C-terminal fusion of the carrier maltose-binding protein (MBP) with the MccA peptide is also recognized by MccBin vivoandin vitro, allowing highly specific adenylation and/or radioactive labeling of cellular proteins.IMPORTANCEEnzymatic adenylation of chemically synthesized peptides allowed us to generate biologically active derivatives of the peptide-nucleotide antibiotic microcin C with improved bioactivity and altered entry routes into target cells, opening the way for development of various McC-based antibacterial compounds not found in nature.

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Ye, Min, Lei Xiong, Yi Dong, Chao Xie, Zhen Zhang, Lingling Shen, Zeyun Li, et al. "The Potential Role of the Methionine Aminopeptidase Gene PxMetAP1 in a Cosmopolitan Pest for Bacillus thuringiensis Toxin Tolerance." International Journal of Molecular Sciences 23, no. 21 (October 27, 2022): 13005. http://dx.doi.org/10.3390/ijms232113005.

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Methionine aminopeptidases (MetAPs) catalyze the cleavage of the N-terminal initiator methionine (iMet) in new peptide chains and arylamides, which is essential for protein and peptide synthesis. MetAP is differentially expressed in two diamondback moth (DBM; Plutella xylostella) strains: the G88 susceptible strain and the Cry1S1000 strain, which are resistant to the Bt toxin Cry1Ac, implicating that MetAP expression might be associated with Bt resistance. In this study, we identified and cloned a MetAP gene from DBMs, named PxMetAP1, which has a CDS of 1140 bp and encodes a 379 amino acid protein. The relative expression of PxMetAP1 was found to be ~2.2-fold lower in the Cry1S1000 strain compared to that in the G88 strain. PxMetAP1 presents a stage- and tissue-specific expression pattern, with higher levels in the eggs, adults, integument, and fatbody of DBMs. The linkage between PxMetAP1 and Cry1Ac resistance is verified by genetic linkage analysis. The knockout of PxMetAP1 in G88 by CRISPR/Cas9 leads to a ~5.6-fold decrease in sensitivity to the Cry1Ac toxin, further supporting the association between the PxMetAP1 gene and Bt tolerance. Our research sheds light on the role of MetAP genes in the development of Bt tolerance in P. xylostella and enriches the knowledge for the management of such a cosmopolitan pest.

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Cloos, Jacqueline, Godefridus J. Peters, Marjon Al, Yehuda G. Assaraf, Lixia Wang, Jack W. Singer, Jorge E. Cortes, Gert J. Ossenkoppele, and Gerrit Jansen. "Statins Potentiate Aminopeptidase Inhibitor (pro)Drug Activity in Acute Myeloid Leukemia Cells." Blood 132, Supplement 1 (November 29, 2018): 3945. http://dx.doi.org/10.1182/blood-2018-99-114447.

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Abstract Tosedostat represents a next generation oral aminopeptidase inhibitor prodrug that has recently demonstrated promising activity in elderly patients with relapsed and refractory acute myeloid leukemia (AML). This prodrug is bio-activated to its hydrophilic active metabolite by intracellular esterases including carboxylesterase 1 (CES1) hence enhancing its cellular retention and promoting targeting of multiple aminopeptidases. Aminopeptidase inhibition provokes an amino acid deprivation response, inhibition of mTOR activity and blockade of protein synthesis. The fact that CES1 also has an important physiological function in cholesterol metabolism (i.e. conversion of cholesteryl-esters to cholesterol), and the notion that AML cells display an aberrant cholesterol metabolism, prompted us to explore whether or not statins, as inhibitors of the mevalonate-cholesterol biosynthesis pathway, can potentiate the cytotoxic activity of aminopeptidase inhibitor prodrugs. Here, we discovered that the antitumor activity of CHR2863, a close structural analogue of Tosedostat, is markedly potentiated by non-toxic and clinically achievable concentrations of statins. These findings were supported by the following lines of experimental evidence; (i) A strong synergy in cell growth inhibition (combination indices < 0.1) of CHR2863 with various statins (simvastatin, fluvastatin, lovastatin and pravastatin) was demonstrated for U937 AML cells and U937 sublines displaying acquired resistance to CHR2863. (ii) This potent synergy between CHR2863 and simvastatin was also observed with a spectrum of human AML cell lines including THP1, MV4-11, and KG1, but not with acute lymphocytic leukemia (CCRF-CEM) or solid tumor cell lines (MCF7 breast cancer, KB nasopharyngeal carcinoma and SW1573 non-small cell lung cancer). (iii) The synergistic effects with non-toxic concentrations of statins were specific for aminopeptidase inhibitors, either prodrugs (CHR2863) or direct inhibitors (e.g. Bestatin), but not for other unrelated cytotoxic agents, including daunorubicin and an esterase-dependent prodrug of a histone deacetylase inhibitor. (iv) The synergy of CHR2863 with statins was also corroborated by enhanced apoptosis induction and cell cycle arrest which increased the sub-G1 fraction. (v) Statin potentiation of CHR2863 activity was abrogated by co-administration with mevalonate or farnesylpyrophosphate, and partly by geranylgeranylpyrophosphate, suggesting the involvement of protein prenylation. Consistenly, the farnesyltransferase inhibitor FTI-277 also synergized with CHR2863 activity. (vi) Mechanistically, non-toxic concentrations of simvastatin impaired Rheb prenylation which is required for lysosomal membrane association and activation of mTOR. Hence, we propose that the dual inhibitory effect of impaired Rheb prenylation by statins and CHR2863-induced mTOR inhibition achieves a potent synergistic inhibition on human AML cells. (viii) Finally, retrospective analysis in a clinical trial of relapsed and refractory elderly AML patients treated with combination chemotherapy including Tosedostat (Cortes et al, Lancet Oncol 2013), revealed a clinical benefit for patients who used a statin. AML patients on statins (n=8) and Tosedostat (switching from 240 to 120 mg/m2) had a 50% probability of 6 months survival as compared to 3 months survival for patients not on statins (n= 27). The two-year overall survival (20%) was not impacted by statin administration. Collectively, these novel findings uncover a potent therapeutic combination of statins and aminopeptidase inhibitors for the treatment of AML. This drug combination warrants further clinical evaluation, particularly in the context of elderly patients using statins for other comorbidities. Disclosures Cloos: Takeda: Research Funding; Merus: Research Funding; Novartis: Research Funding; Helsinn: Research Funding; Johnson&Johnson: Research Funding. Wang:CTI BioPharma: Employment, Equity Ownership. Singer:CTI BioPharma: Employment, Other: Stock options. Cortes:Novartis: Consultancy, Research Funding; Astellas Pharma: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Arog: Research Funding. Ossenkoppele:Pfizer: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Research Funding; Roche: Consultancy, Honoraria; Celgene: Honoraria, Research Funding; Johnson & Johnson: Consultancy, Honoraria, Research Funding; Genmab: Research Funding.

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Danielsen, E. M. "Tyrosine sulphation is not required for microvillar expression of intestinal aminopeptidase N." Biochemical Journal 254, no. 1 (August 15, 1988): 219–22. http://dx.doi.org/10.1042/bj2540219.

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The effect of 2,6-dichloro-4-nitrophenol (DCNP), an inhibitor of phenol sulphotransferases (EC 2.8.2.-), on the biosynthesis of aminopeptidase N (EC 3.4.11.2) was studied in organ-cultured pig intestinal mucosal explants. At 50 microM DCNP did not affect protein synthesis but it decreased incorporation of [35S]sulphate into aminopeptidase N and other major microvillar hydrolases by 70-85% compared with controls, indicating an inhibition of their post-translational tyrosine sulphation. In labelling experiments with [35S]methionine from 0.5 to 5 h, DCNP was tested for its possible influence on synthesis, processing and microvillar expression of aminopeptidase N, but no effect on any of these parameters could be detected. It can therefore be concluded that tyrosine sulphation is not required (for instance as a sorting signal) for the targeting of newly synthesized enzymes to the microvillar membrane.

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Gimenez-Dejoz, Joan, Kousuke Tsuchiya, Ayaka Tateishi, Yoko Motoda, Takanori Kigawa, Yasuhisa Asano, and Keiji Numata. "Computational study on the polymerization reaction of d-aminopeptidase for the synthesis of d-peptides." RSC Advances 10, no. 30 (2020): 17582–92. http://dx.doi.org/10.1039/d0ra01138j.

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Herranz, Rosario, Julia Castro-Pichel, M. Teresa García-López, Isabel Gómez-Monterrey, Concepción Pérez, and Soledad Vinuesa. "Ketomethylenebestatin: Synthesis and Aminopeptidase Inhibition." Archiv der Pharmazie 326, no. 7 (1993): 395–98. http://dx.doi.org/10.1002/ardp.19933260705.

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24

Danielsen, E. M., and G. M. Cowell. "Biosynthesis of intestinal microvillar proteins Processing of N-linked carbohydrate is not required for surface expression." Biochemical Journal 240, no. 3 (December 15, 1986): 777–82. http://dx.doi.org/10.1042/bj2400777.

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Castanospermine, an inhibitor of glucosidase I, the initial enzyme in the trimming of N-linked carbohydrate, was used to study the importance of carbohydrate processing in the biosynthesis of microvillar enzymes in organ-cultured pig intestinal explants. For aminopeptidase N (EC 3.4.11.2), aminopeptidase A (EC 3.4.11.7), sucrase-isomaltase (EC 3.2.1.48-10) and maltase-glucoamylase (EC 3.2.1.20), castanospermine caused the formation of novel transient forms of higher Mr than corresponding controls, indicating a blocked removal of glucose residues. For the first three enzymes, the ‘mature’ (Golgi-processed) forms were similar in size to or slightly smaller than corresponding controls and were, as shown for aminopeptidase N, endoglycosidase-H-sensitive, evidence of a blocked attachment of complex sugars. Maltase-glucoamylase did not undergo conversion into a ‘mature’ form, suggesting that, unlike other microvillar enzymes, it does not receive post-translational O-linked carbohydrate. Castanospermine suppressed the synthesis of the four enzymes, but did not block their transport to the microvillar membrane, showing that processing of N-linked carbohydrate is not required for microvillar expression. The proteinase inhibitor leupeptin partially restored the suppressed synthesis, indicating that the majority of the wrongly processed enzymes, probably because of conformational instability, become degraded soon after synthesis rather than being transported to the microvillar membrane.

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25

Dalton, John P., Patrick Skelly, and David W. Halton. "Role of the tegument and gut in nutrient uptake by parasitic platyhelminths." Canadian Journal of Zoology 82, no. 2 (February 1, 2004): 211–32. http://dx.doi.org/10.1139/z03-213.

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The ease of procuring nutrient is probably the main selection pressure that drives and maintains the host–parasite relationship. The feeding activities of the ectoparasitic monogeneans exhibit similarities with the predatory turbellarians, with certain monopisthocotylean members feeding by means of a protrusible pharynx. These parasites degrade fish skin by secreting enzymes extracorporeally, but most of the digestion is carried out intracellularly in cells lining a well-differentiated gut. Some polyopisthocotylean monogeneans, however, living within the vascularized gill chamber, took advantage of the availability of a more highly nutritious, consistent, and renewable diet in the form of blood, and this represented a major step in the evolution of endoparasitism. Blood provides a rich source of carbohydrates for the production of energy and amino acids and fatty acids for the synthesis of parasite molecules and for egg production. The external surfaces of all parasitic flatworms depart from turbellarian character and are composed of a multifunctional syncytial tegument that is permeable to a variety of small organic solutes. Glucose and amino acid transporter molecules situated in the tegumental surface and basal membranes of trematodes and cestodes function in the uptake of these molecules and their distribution to the parasite tissues. Cestodes are bereft of any vestige of a gut, but their tegument has become elaborated into a highly efficient digestive–absorptive layer that competes with the vertebrate mucosa for nutrients. The patterns of energy metabolism in adult flatworm parasites are generally anaerobic and based on glycogen, with abbreviated metabolic pathways and the loss of biosynthetic capacities. In contrast to the tegument, the role of the gut is to digest host macromolecules and subsequently absorb the soluble products. However, the switch to blood as the major source of nutrient necessitated development of a means of overcoming the problems of blood clotting, attack by immune effector mechanisms, and the intracellular accumulations of haematin pigment. Digenean trematode, in contrast to monogeneans, digest blood extracellularly and their secretions include molecules capable of lysing erythrocytes and preventing blood clotting. Digestion of the ingested proteins is generally rapid, involving a range of cathepsin-like cysteine and aspartic proteases, which reduce the blood meal to absorbable peptides that are most likely further catabolized to amino acids by intracellular aminopeptidases. The parasites dispose of accumulated haematin by simply emptying the contents of their blind-ended gut.

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Protheroe, A., A. Reid, G. Attard, A. Davies, J. Spicer, L. Vidal, E. Bone, L. Hooftman, A. Harris, and J. De-Bono. "First in-human phase 1 trial of a novel amino-peptidase inhibitor, CHR-2797." Journal of Clinical Oncology 25, no. 18_suppl (June 20, 2007): 3537. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.3537.

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3537 Background: CHR-2797 is a novel, orally bioavailable agent which displays potent, tumor cell-selective, anti-proliferative properties. It is an inhibitor of Zn++-dependent aminopeptidases and generates signs of amino acid deprivation in sensitive cells, decreased protein synthesis and an increase in the level of the pro-apoptotic protein, Noxa. CHR-79888 is an active metabolite of CHR-2797. Patients and Methods: This study was conducted according to an accelerated titration design to define the MTD, DLT, toxicity profile and PK of CHR-2797 when administered orally for 28 days or longer. Patients (ECOG PS = 2) with histologically confirmed advanced solid tumors resistant or refractory to standard therapy were eligible. Results: 37 pts (median age 61.5 years [range 22.4–80.1]; 30M/7F; median ECOG PS 1; median prior regimens 2, range 0–6) enrolled in 12 cohorts (doses between 10 and 320mg). The first four patients received a 10 mg dose for 7, 14, 21 or 28 days respectively. Subsequent cohorts received 28 days continuous dosing, with dose doubling in single patient cohorts until drug-related toxicity = Grade 2. Thereafter the study followed a 3+3 design with = 40% dose increments. Common (gr 1–2) toxicity included fatigue (47%), diarrhea (47%), dizziness (24%), constipation, vomiting, abdominal pain (all 21%), and thrombocytopenia (18%). Toxicities show dose dependency for thrombocytopenia and fatigue. MTD was declared at 320 mg after 2 DLT’s were reported: 2 patients were unable to complete 28 days of daily dosing due to syncope/anemia, and dizziness/visual disturbances/thrombocytopenia, respectively. Patients recovered fully after cessation of the drug. The dose level below (240 mg) was expanded to 13 patients. Plasma PK was determined for both CHR-2797 and -79888, on days 1 and 28, which showed dose proportional increases in AUC and Cmax. Intracellular and intratumoral levels of both the parent and metabolite were also measured. So far 4 patients continued therapy for 7–9 months: one patient (RCC [130 mg]) achieved a PR, and 3 patients (ovarian ca [40 mg], NSCLC [130 mg], and breast ca [180 mg] had confirmed SD (> 3 months). Conclusion: Once daily oral CHR-2797 can be administered safely for 28 days in doses up to 240 mg and exhibits favorable PK. No significant financial relationships to disclose.

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Arima, Jiro, Masazumi Morimoto, Hirokazu Usuki, Nobuhiro Mori, and Tadashi Hatanaka. "The Aminolysis Reaction of Streptomyces S9 Aminopeptidase Promotes the Synthesis of Diverse Prolyl Dipeptides." Applied and Environmental Microbiology 76, no. 12 (April 23, 2010): 4109–12. http://dx.doi.org/10.1128/aem.00577-10.

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ABSTRACT Prolyl dipeptide synthesis by S9 aminopeptidase from Streptomyces thermocyaneoviolaceus (S9AP-St) has been demonstrated. In the synthesis, S9AP-St preferentially used l-Pro-OBzl as the acyl donor, yielding synthesized dipeptides having an l-Pro-Xaa structure. In addition, S9AP-St showed broad specificity toward the acyl acceptor. Furthermore, S9AP-St produced cyclo (l-Pro-l-His) with a conversion ratio of substrate to cyclo (l-Pro-l-His) higher than 40%.

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Brock, Thomas G., Young-Jik Lee, Elana Maydanski, Tessa L. Marburger, Ming Luo, Robert Paine, and Marc Peters-Golden. "Nuclear localization of leukotriene A4 hydrolase in type II alveolar epithelial cells in normal and fibrotic lung." American Journal of Physiology-Lung Cellular and Molecular Physiology 289, no. 2 (August 2005): L224—L232. http://dx.doi.org/10.1152/ajplung.00423.2004.

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Leukotriene A4 (LTA4) hydrolase catalyzes the final step in leukotriene B4 (LTB4) synthesis. In addition to its role in LTB4 synthesis, the enzyme possesses aminopeptidase activity. In this study, we sought to define the subcellular distribution of LTA4 hydrolase in alveolar epithelial cells, which lack 5-lipoxygenase and do not synthesize LTA4. Immunohistochemical staining localized LTA4 hydrolase in the nucleus of type II but not type I alveolar epithelial cells of normal mouse, human, and rat lungs. Nuclear localization of LTA4 hydrolase was also demonstrated in proliferating type II-like A549 cells. The apparent redistribution of LTA4 hydrolase from the nucleus to the cytoplasm during type II-to-type I cell differentiation in vivo was recapitulated in vitro. Surprisingly, this change in localization of LTA4 hydrolase did not affect the capacity of isolated cells to convert LTA4 to LTB4. However, proliferation of A549 cells was inhibited by the aminopeptidase inhibitor bestatin. Nuclear accumulation of LTA4 hydrolase was also conspicuous in epithelial cells during alveolar repair following bleomycin-induced acute lung injury in mice, as well as in hyperplastic type II cells associated with fibrotic lung tissues from patients with idiopathic pulmonary fibrosis. These results show for the first time that LTA4 hydrolase can be accumulated in the nucleus of type II alveolar epithelial cells and that redistribution of the enzyme to the cytoplasm occurs with differentiation to the type I phenotype. Furthermore, the aminopeptidase activity of LTA4 hydrolase within the nucleus may play a role in promoting epithelial cell growth.

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Cesati, Richard R., Greg Dwyer, Reinaldo C. Jones, Megan P. Hayes, Padmaja Yalamanchili, and David S. Casebier. "Amino Acid Derived Enamides: Synthesis and Aminopeptidase Activity." Organic Letters 9, no. 26 (December 2007): 5617–20. http://dx.doi.org/10.1021/ol7025729.

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30

Arima, Jiro, Masazumi Morimoto, Hirokazu Usuki, Nobuhiro Mori, and Tadashi Hatanaka. "β-Alanyl peptide synthesis by Streptomyces S9 aminopeptidase." Journal of Biotechnology 147, no. 1 (May 3, 2010): 52–58. http://dx.doi.org/10.1016/j.jbiotec.2010.03.007.

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31

Haldar, Manas K., Michael D. Scott, Nitesh Sule, D. K. Srivastava, and Sanku Mallik. "Synthesis of barbiturate-based methionine aminopeptidase-1 inhibitors." Bioorganic & Medicinal Chemistry Letters 18, no. 7 (April 2008): 2373–76. http://dx.doi.org/10.1016/j.bmcl.2008.02.066.

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32

He, Xinyuan, Yiming Hu, Wen Shi, Xiaohua Li, and Huimin Ma. "Design, synthesis and application of a near-infrared fluorescent probe for in vivo imaging of aminopeptidase N." Chemical Communications 53, no. 68 (2017): 9438–41. http://dx.doi.org/10.1039/c7cc05142e.

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33

Arima, Jiro, Yoshiko Uesugi, Misugi Uraji, Masaki Iwabuchi, and Tadashi Hatanaka. "Dipeptide Synthesis by an Aminopeptidase from Streptomyces septatus TH-2 and Its Application to Synthesis of Biologically Active Peptides." Applied and Environmental Microbiology 72, no. 6 (June 2006): 4225–31. http://dx.doi.org/10.1128/aem.00150-06.

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ABSTRACT Dipeptide synthesis by aminopeptidase from Streptomyces septatus TH-2 (SSAP) was demonstrated using free amino acid as an acyl donor and aminoacyl methyl ester as an acyl acceptor in 98% methanol (MeOH). SSAP retained its activity after more than 100 h in 98% MeOH, and in the case of phenylalanyl-phenylalanine methyl ester synthesis, the enzyme reaction reached equilibrium when more than 50% of the free phenylalanine was converted to the product. In an investigation of the specificity of SSAP toward acyl donors and acyl acceptors, SSAP showed a broad specificity toward various free amino acids and aminoacyl methyl esters. Furthermore, we applied SSAP to the synthesis of several biologically active peptides, such as aspartyl-phenylalanine, alanyl-tyrosine, and valyl-tyrosine methyl esters.

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34

Herranz, Rosario, Soledad Vinuesa, Julia Castro-Pichel, Concepción Pérez, and M. Teresa García-López. "Aminodeoxybestatin and epi-aminodeoxybestatin: stereospecific synthesis and aminopeptidase inhibition." J. Chem. Soc., Perkin Trans. 1, no. 14 (1992): 1825–30. http://dx.doi.org/10.1039/p19920001825.

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35

Byrum, Robert S., Jennifer L. Goulet, John N. Snouwaert, Richard J. Griffiths, and Beverly H. Koller. "Determination of the Contribution of Cysteinyl Leukotrienes and Leukotriene B4 in Acute Inflammatory Responses Using 5-Lipoxygenase- and Leukotriene A4 Hydrolase-Deficient Mice." Journal of Immunology 163, no. 12 (December 15, 1999): 6810–19. http://dx.doi.org/10.4049/jimmunol.163.12.6810.

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Abstract Arachidonic acid metabolism by 5-lipoxygenase leads to production of the potent inflammatory mediators, leukotriene (LT) B4 and the cysteinyl LT. Relative synthesis of these subclasses of LT, each with different proinflammatory properties, depends on the expression and subsequent activity of LTA4 hydrolase and LTC4 synthase, respectively. LTA4 hydrolase differs from other proteins required for LT synthesis because it is expressed ubiquitously. Also, in vitro studies indicate that it possesses an aminopeptidase activity. Introduction of cysteinyl LT and LTB4 into animals has shown LTB4 is a potent chemoattractant, while the cysteinyl LT alter vascular permeability and smooth muscle tone. It has been impossible to determine the relative contributions of these two classes of LT to inflammatory responses in vivo or to define possible synergy resulting from the synthesis of both classes of mediators. To address this question, we have generated LTA4 hydrolase-deficient mice. These mice develop normally and are healthy. Using these animals, we show that LTA4 hydrolase is required for the production of LTB4 in an in vivo inflammatory response. We show that LTB4 is responsible for the characteristic influx of neutrophils accompanying topical arachidonic acid and that it contributes to the vascular changes seen in this model. In contrast, LTB4 influences only the cellular component of zymosan A-induced peritonitis. Furthermore, LTA4 hydrolase-deficient mice are resistant to platelet-activating factor, identifying LTB4 as one mediator of the physiological changes seen in systemic shock. We do not identify an in vivo role for the aminopeptidase activity of LTA4 hydrolase.

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36

Davies, Faith, Gert Ossenkoppele, Pierre Zachee, Richard Noppeney, Alan Burnett, Michel Delforge, Pieter Sonneveld, et al. "A Phase I Study of CHR-2797, an Orally Active Aminopeptidase Inhibitor in Elderly and/or Treatment Refractory Patients with Acute Myeloid Leukemia or Multiple Myeloma." Blood 110, no. 11 (November 16, 2007): 443. http://dx.doi.org/10.1182/blood.v110.11.443.443.

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Abstract Background. CHR-2797 is a novel, orally bioavailable agent which displays potent, tumor cell-selective, anti-proliferative properties. It is an inhibitor of Zn++-dependent aminopeptidases and generates signs of amino acid deprivation in sensitive cells, decreased protein synthesis and an increase in the level of the pro-apoptotic protein, NOXA. CHR-79888 is an active metabolite of CHR-2797. Methods. This was an open label, single agent, dose escalating phase I salvage study to assess tolerance, MTD/DLT, activity, and pharmacokinetics of CHR-2797 in patients with hematological malignancies. Elderly patients and/or relapsed patients with acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and multiple myeloma (MM) were eligible. Patients were treated with escalating once daily doses (60–180 mg) for up to 84 days or until progressive disease (PD). Clinical responses were assessed by monthly bone marrow aspirates in AML/MDS patients and by M-protein levels in MM patients. Results. Sixteen adults (4 women, 12 men) of median age 70 yrs, (range 45–84 yrs) were accrued between May 2006 and Jan 2007: 13 patients with AML, 1 with MDS, and 2 with MM. Thirteen patients finished the dose finding phase of 28 days and 6 patients continued for at least 84 days. CHR-2797 was well tolerated and, except for one patient with grade III ALT elevation, no grade III/IV drug related non-hematological toxicity was observed during the first 28 days of treatment. Two patients on 180 mg developed DLT that was considered drug related: >75 percent reduction in platelet count. CHR-2797 had no influence on hemoglobin or neutrophils in this trial. Overall the most frequently reported adverse events were thrombocytopenia (6.7%), diarrhea (4.5%), dizziness (3.9%), and fatigue (3.9%). Five AML patients died in the first 3 months of the trial or within 4 weeks of discontinuing CHR-2797: 3 due to disease progression and 2 following a MI (not related to drug). Bone marrow studies revealed complete responses (< 5% blasts in bone marrow) in 3/12 AML patients after 1–3 months of therapy (60 and 130mg), one of which was also a cytogenetic response. One of the 2 responding patients on 130 mg was evaluated as a CRp at 3 months; this patient was in remission for 3 months following platelet recovery after the drug was stopped. One further AML patient (60 mg) became completely transfusion independent and remained so for 6 weeks. Good exposure to CHR-2797, including levels of the active metabolite CHR-79888 has been observed on days 1 and 28 with a terminal half life (for 79888) of 8– 11 hours. Conclusions. Oral once daily CHR-2797 in AML/MDS/MM patients with adverse prognostic risk was well tolerated. MTD for maintenance therapy was reached at 180 mg. Single agent CHR-2797 therapy showed encouraging clinical activity (incl. 3/12 CRs) in these elderly and poor risk AML patients who were able to continue therapy for at least 28 days. Because of the favorable results a phase II study with CHR-2797 in advanced AML is currently in progress.

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LENDECKEL, Uwe, Th WEX, D. REINHOLD, Th KÄHNE, K. FRANK, J. FAUST, K. NEUBERT, and S. ANSORGE. "Induction of the membrane alanyl aminopeptidase gene and surface expression in human T-cells by mitogenic activation." Biochemical Journal 319, no. 3 (November 1, 1996): 817–21. http://dx.doi.org/10.1042/bj3190817.

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The metal-dependent membrane alanyl aminopeptidase (aminopeptidase N, APN, CD13; EC 3.4.11.2) is a well-established marker of normal and malignant cells of the myelo-monocytic lineage. It is also expressed by leukaemic blasts of a small group of patients suffering from acute or chronic lymphoid leukaemia. CD13-specific monoclonal antibodies do not bind to the surface of normal B lymphocytes, and APN mRNA was not detectable by Northern analysis in normal lymphocytes or in T-cell lines. Recently the expression of the APN gene in T-cell lines as well as the ability of these cells to cleave chromogenic substrates preferred by APN have been demonstrated [Lendeckel, Wex, Kähne, Frank, Reinhold and Ansorge (1994) Cell. Immunol. 153, 214–226]. Here, by means of dot-blot hybridization and RNase protection assay, evidence is provided that human peripheral T-cells as well as derived cell lines contain significant amounts of APN mRNA, comparable to that in the promyeloic cell line U937, and that mitogenic activation of peripheral human T-cells leads to a more than 4-fold increase in their APN mRNA content. In the course of activation, T-cells increase their total alanine p-nitroanilide-hydrolysing activity to approx. 7-fold that of resting cells. Furthermore these cells become immunoreactive towards CD13 to a significant extent (up to 51%) as shown by surface staining and confirmed by activity staining and immunostaining after isoelectric focusing (pI of T-cell APN = 4.6). In addition it is demonstrated by fluorescence microscopy that viable, activated T-cells effectively cleave the fluorogenic aminopeptidase substrate bis-glycyl-rhodamine 110 and that the corresponding aminopeptidase activity is associated with the cell surface. We show that specific inhibitors of APN, probestin and actinonin, strongly decrease DNA synthesis in phytohaemagglutinin (PHA)-stimulated T-cells. In summary, evidence is presented that in the course of mitogenic activation human peripheral T-cells increase the expression of APN both at the transcriptional level and at the cell surface. This has been demonstrated both at the APN mRNA level and at the protein level with respect to aminopeptidase enzymic activity and CD13 immunoreactivity.

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Mangaleswaran, Sivaprakasam, and Narshinha P. Argade. "A Facile Synthesis of Naturally Occurring Aminopeptidase Inhibitor Tyromycin A†." Journal of Organic Chemistry 66, no. 15 (July 2001): 5259–61. http://dx.doi.org/10.1021/jo010260e.

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39

Asano, Yasuhisa, Katsuhiko Kishino, Akiko Yamada, Sawako Hanamoto, and Kiyosi Kondo. "Plasmid-based, D-aminopeptidase-catalysed synthesis of (R)-amino acids." Recueil des Travaux Chimiques des Pays-Bas 110, no. 5 (September 2, 2010): 206–8. http://dx.doi.org/10.1002/recl.19911100513.

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40

SUDO, Tatsuhiko, Kiwako SHINOHARA, Naoshi DOHMAE, Koji TAKIO, Ron USAMI, Koki HORIKOSHI, and Hiroyuki OSADA. "Isolation and characterization of the gene encoding an aminopeptidase involved in the selective toxicity of ascamycin toward Xanthomonas campestris pv. citri." Biochemical Journal 319, no. 1 (October 1, 1996): 99–102. http://dx.doi.org/10.1042/bj3190099.

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An aminopeptidase gene named XAP has been isolated from Xanthomonas campestris pv. citri, a plant pathogenic bacterium. The bacterium is one of the rare micro-organisms susceptible to ascamycin, an aminoacyl nucleoside antibiotic that inhibits protein synthesis. Sequence analysis reveals that the gene encodes a 311 amino acid protein with a calculated molecular mass of 35134 Da and approx. 50% identity for amino acids to the proline iminopeptidase from Neisseria gonorrhoeae. The XAP gene product, Xap, expressed in Escherichia coli has proline iminopeptidase activity as well as ascamycin dealanylating activity in vitro.

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41

Torp, N., M. Rossi, J. T. Troelsen, J. Olsen, and E. M. Danielsen. "Lactase-phlorizin hydrolase and aminopeptidase N are differentially regulated in the small intestine of the pig." Biochemical Journal 295, no. 1 (October 1, 1993): 177–82. http://dx.doi.org/10.1042/bj2950177.

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The longitudinal expression of two brush-border enzymes, lactase-phlorizin hydrolase (EC 3.2.1.23/62) and aminopeptidase N (EC 3.4.11.2), was studied in the small intestine of the post-weaned pig. Whereas the level of mRNA, encoding aminopeptidase N (relative to that of beta-actin), only varied moderately from the duodenum to the terminal ileum, the amount of lactase-phlorizin hydrolase mRNA exhibited a sharp maximum in the proximal jejunum. For both enzymes, the level of protein synthesis, studied in cultured mucosal explants, correlated well with the level of mRNA, and no major variation in post-translational processing or intracellular transport was observed along the intestine. The mRNA/specific-activity ratio for both enzymes was markedly (3-5-fold) higher in the duodenum and proximal jejunum, compared with the ileum. This indicates an increased proximal turnover rate, most likely caused by the presence in the gut lumen of pancreatic proteases. In neonatal animals, the level of mRNA for lactase-phlorizin hydrolase in both proximal and distal regions of the intestine was of the same magnitude as in the proximal jejunum of the post-weaned pigs. Our results point to two mechanisms that affect the expression of lactase-phlorizin hydrolase in the pig during development: (1) a primary regulation at the level of mRNA (predominantly in the ileum); (2) an increased rate of turnover of the enzyme, mainly in the duodenum and proximal jejunum, and most likely due to an increased secretion into the gut lumen of pancreatic proteases (a mechanism also affecting aminopeptidase N and probably other brush-border enzymes as well).

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Stsiapanava, Alena, Bengt Samuelsson, and Jesper Z. Haeggström. "Capturing LTA4 hydrolase in action: Insights to the chemistry and dynamics of chemotactic LTB4 synthesis." Proceedings of the National Academy of Sciences 114, no. 36 (August 21, 2017): 9689–94. http://dx.doi.org/10.1073/pnas.1710850114.

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Human leukotriene (LT) A4 hydrolase/aminopeptidase (LTA4H) is a bifunctional enzyme that converts the highly unstable epoxide intermediate LTA4 into LTB4, a potent leukocyte activating agent, while the aminopeptidase activity cleaves and inactivates the chemotactic tripeptide Pro-Gly-Pro. Here, we describe high-resolution crystal structures of LTA4H complexed with LTA4, providing the structural underpinnings of the enzyme’s unique epoxide hydrolase (EH) activity, involving Zn2+, Y383, E271, D375, and two catalytic waters. The structures reveal that a single catalytic water is involved in both catalytic activities of LTA4H, alternating between epoxide ring opening and peptide bond hydrolysis, assisted by E271 and E296, respectively. Moreover, we have found two conformations of LTA4H, uncovering significant domain movements. The resulting structural alterations indicate that LTA4 entrance into the active site is a dynamic process that includes rearrangement of three moving domains to provide fast and efficient alignment and processing of the substrate. Thus, the movement of one dynamic domain widens the active site entrance, while another domain acts like a lid, opening and closing access to the hydrophobic tunnel, which accommodates the aliphatic tale of LTA4 during EH reaction. The enzyme–LTA4 complex structures and dynamic domain movements provide critical insights for development of drugs targeting LTA4H.

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Nishiyama, Shigeru, Yoshikazu Suzuki, and Shosuke Yamamura. "Total synthesis of OF4949-III, a novel inhibitor of aminopeptidase B." Tetrahedron Letters 29, no. 5 (1988): 559–62. http://dx.doi.org/10.1016/s0040-4039(00)80149-5.

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Zaytsev, Andrey V., Rosaleen J. Anderson, Alexandre Bedernjak, Paul W. Groundwater, Yongxue Huang, John D. Perry, Sylvain Orenga, Celine Roger-Dalbert, and Arthur James. "Synthesis and testing of chromogenic phenoxazinone substrates for β-alanyl aminopeptidase." Organic & Biomolecular Chemistry 6, no. 4 (2008): 682. http://dx.doi.org/10.1039/b716978g.

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HERRANZ, R., S. VINUESA, J. CASTRO-PICHEL, C. PEREZ, and M. T. GARCIA-LOPEZ. "ChemInform Abstract: Aminodeoxybestatin and epi-Aminodeoxybestatin: Stereospecific Synthesis and Aminopeptidase Inhibition." ChemInform 23, no. 46 (August 21, 2010): no. http://dx.doi.org/10.1002/chin.199246235.

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DEAN, Michael F., and Paul SANSOM. "Link peptide cartilage growth factor is degraded by membrane proteinases." Biochemical Journal 349, no. 2 (July 10, 2000): 473–79. http://dx.doi.org/10.1042/bj3490473.

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The peptide DHLSDNYTLDHDRAIH (Link N), cleaved from the N-terminus of the link protein component of cartilage proteoglycan aggregates by the action of stromelysin, can act as a growth factor and stimulate synthesis of proteoglycans and collagen in articular cartilage [McKenna, Liu, Sansom and Dean (1998) Arthritis Rheum. 41, 157-161]. The mechanism by which this biologically active peptide is degraded and inactivated was investigated using U937 monocytes as a model cell. Time-course experiments showed that two major proteases, an initial serine proteinase followed by a metalloproteinase, acted in sequence. Analysis of the resulting fragments showed that the serine endopeptidase cleavage was at the Leu3-Ser4 bond to produce the peptide SDNYTLDHDRAIH. The terminal serine could then be removed from the resulting peptide by an aminopeptidase. A second metallopeptidase liberated the peptides SDNYTL or DNYTL from DHDRAIH by cleavage at the Leu9-Asp10 bond. The DNYTL peptide intermediate was degraded too rapidly to allow sequencing and sequential aminopeptidase cleavages removed further amino acids from the N-terminus of the remaining DHDRAIH peptide. The identical patterns of breakdown that occurred when either whole cells or purified plasma membranes were used indicated that proteolysis and inactivation of Link N was carried out entirely by membrane-associated enzymes.

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FÆRGEMAN, Nils J., Søren FEDDERSEN, Janne K. CHRISTIANSEN, Morten K. LARSEN, Roger SCHNEITER, Christian UNGERMANN, Kudzai MUTENDA, Peter ROEPSTORFF, and Jens KNUDSEN. "Acyl-CoA-binding protein, Acb1p, is required for normal vacuole function and ceramide synthesis in Saccharomyces cerevisiae." Biochemical Journal 380, no. 3 (June 15, 2004): 907–18. http://dx.doi.org/10.1042/bj20031949.

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In the present study, we show that depletion of acyl-CoA-binding protein, Acb1p, in yeast affects ceramide levels, protein trafficking, vacuole fusion and structure. Vacuoles in Acb1p-depleted cells are multi-lobed, contain significantly less of the SNAREs (soluble N-ethylmaleimide-sensitive fusion protein attachment protein receptors) Nyv1p, Vam3p and Vti1p, and are unable to fuse in vitro. Mass spectrometric analysis revealed a dramatic reduction in the content of ceramides in whole-cell lipids and in vacuoles isolated from Acb1p-depleted cells. Maturation of yeast aminopeptidase I and carboxypeptidase Y is slightly delayed in Acb1p-depleted cells, whereas the maturation of alkaline phosphatase and Gas1p is unaffected. The fact that Gas1p maturation is unaffected by Acb1p depletion, despite the lowered ceramide content in these cells, indicates that ceramide synthesis in yeast could be compartmentalized. We suggest that the reduced ceramide synthesis in Acb1p-depleted cells leads to severely altered vacuole morphology, perturbed vacuole assembly and strong inhibition of homotypic vacuole fusion.

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48

Farsa, Oldřich, Milan Dockal, Jana Kováciková, and Mária Benesová. "Synthesis of 2-{[2-(2-oxo-1-azacycloalkyl)acetamido]phenoxy}acetic acids and their activity as aminopeptidase M inhibitors." Journal of the Serbian Chemical Society 73, no. 8-9 (2008): 771–80. http://dx.doi.org/10.2298/jsc0809771f.

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A series of 9 phenoxyacetic acids substituted in the o-, m-, and p-position of benzene ring with 2-(2-oxo-1-azacycloalkyl)acetamidic moiety containing 5-7-membered ?-lactam ring was prepared by a 4-step synthetic procedure. Five selected substances of this series were tested in vitro for inhibition of porcine kidney aminopeptidase M. 2-{4-[2-(2-Oxoperhydroazepin-1-yl)acetamido]phenoxy}acetic acid exhibited the highest activity with Ki = 243.6 ?M.

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49

Goldspink, D. F., V. M. Cox, S. K. Smith, L. A. Eaves, N. J. Osbaldeston, D. M. Lee, and D. Mantle. "Muscle growth in response to mechanical stimuli." American Journal of Physiology-Endocrinology and Metabolism 268, no. 2 (February 1, 1995): E288—E297. http://dx.doi.org/10.1152/ajpendo.1995.268.2.e288.

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The relative merits of the separate and combined uses of stretch and electrical stimulation at 10 Hz in influencing the rates of protein synthesis in vivo, proteolysis, and the growth of the extensor digitorum longus muscle have been investigated after 3 days in the rabbit. Continuous electrical stimulation failed to change muscle protein turnover or growth. Static stretch caused significant adaptive growth, with increases in c-fos, c-jun, and insulin-like growth factor I (IGF-I; 12-fold) mRNA levels, and protein (19%), RNA (128%), and DNA (45%) contents. Both the fractional (138%) and total (191%) rates of protein synthesis increased with stretch, correlating with increased ribosomal capacities. Combining stretch and electrical stimulation increased the mRNA concentration of IGF-I (40-fold). The adaptive growth was greater (35%), with massive increases in the nucleic acids (185 and 300%), ribosomal capacities (230%), and the rates of protein synthesis (345 and 450%). Large increases (i.e., 200-400%) in cathepsins B and L and dipeptidyl aminopeptidase I activities during stretch, with or without stimulation, suggest a role for these enzymes in tissue remodeling during muscle hypertrophy.

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50

Yamamoto, Yukihiro, Hirokazu Usuki, Masaki Iwabuchi, and Tadashi Hatanaka. "Prolyl Aminopeptidase from Streptomyces thermoluteus subsp. fuscus Strain NBRC14270 and Synthesis of Proline-Containing Peptides by Its S144C Variant." Applied and Environmental Microbiology 76, no. 18 (July 30, 2010): 6180–85. http://dx.doi.org/10.1128/aem.01242-10.

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ABSTRACT We specifically examined an exopeptidase, prolyl aminopeptidase (PAP), as a target for synthesis of proline-containing peptides. A PAP from Streptomyces thermoluteus subsp. fuscus NBRC14270 (PAP14270) was obtained using sequence-based screening. From PAP14270, 144Ser was replaced by Cys (scPAP14270) to give aminolysis activity. In contrast to wild-type PAP14270, scPAP14270 produced a polymer of proline benzyl ester and cyclo[Pro-Pro]. The product mass was confirmed using liquid chromatography-mass spectrometry (LC/MS). Several factors affecting the reaction, such as the pH, concentration of the substrate, and reaction time, were measured to determine their effects. Furthermore, a correlation was found between substrate specificity in proline peptide synthesis and the log D value of acyl acceptors in aminolysis catalyzed by scPAP14270. Results showed that dipeptide synthesis proceeded in a weakly acidic environment and that cyclization and polymerization occurred under alkaline conditions. Furthermore, results suggest that almost all amino acid esters whose log D value is greater than 0, except hydroxyproline benzyl ester (Hyp-OBzl), can be recognized as acyl acceptors. These findings support the use of PAPs as a tool for production of physiologically active proline peptides.

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Journal articles on the topic 'Aminopeptidases Synthesis'

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