{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T11:43:09Z","timestamp":1791546189740,"version":"4.3.4"},"reference-count":56,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,2,3]],"date-time":"2021-02-03T00:00:00Z","timestamp":1612310400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,2,3]],"date-time":"2021-02-03T00:00:00Z","timestamp":1612310400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100000038","name":"Natural Sciences and Engineering Research Council of Canada","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000038","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000196","name":"Canada Foundation for Innovation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000196","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003150","name":"Fonds Qu\u00e9b\u00e9cois de la Recherche sur la Nature et les Technologies","doi-asserted-by":"publisher","award":["Doctoral research scholarship"],"award-info":[{"award-number":["Doctoral research scholarship"]}],"id":[{"id":"10.13039\/501100003150","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001602","name":"Science Foundation Ireland","doi-asserted-by":"publisher","award":["17\/RP\/5368"],"award-info":[{"award-number":["17\/RP\/5368"]}],"id":[{"id":"10.13039\/501100001602","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The <jats:italic>Plasmodium falciparum<\/jats:italic> M1 alanyl aminopeptidase and M17 leucyl aminopeptidase, <jats:italic>Pf<\/jats:italic>M1AAP and <jats:italic>Pf<\/jats:italic>M17LAP, are potential targets for novel anti-malarial drug development. Inhibitors of these aminopeptidases have been shown to kill malaria parasites in culture and reduce parasite growth in murine models. The two enzymes may function in the terminal stages of haemoglobin digestion, providing free amino acids for protein synthesis by the rapidly growing intra-erythrocytic parasites. Here we have performed a comparative cellular and biochemical characterisation of the two enzymes. Cell fractionation and immunolocalisation studies reveal that both enzymes are associated with the soluble cytosolic fraction of the parasite, with no evidence that they are present within other compartments, such as the digestive vacuole (DV). Enzyme kinetic studies show that the optimal pH of both enzymes is in the neutral range (pH 7.0\u20138.0), although <jats:italic>Pf<\/jats:italic>M1AAP also possesses some activity (&lt;\u200920%) at the lower pH range of 5.0\u20135.5. The data supports the proposal that <jats:italic>Pf<\/jats:italic>M1AAP and <jats:italic>Pf<\/jats:italic>M17LAP function in the cytoplasm of the parasite, likely in the degradation of haemoglobin-derived peptides generated in the DV and transported to the cytosol.<\/jats:p>","DOI":"10.1038\/s41598-021-82499-4","type":"journal-article","created":{"date-parts":[[2021,2,3]],"date-time":"2021-02-03T11:10:36Z","timestamp":1612350636000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["Biochemical and cellular characterisation of the Plasmodium falciparum M1 alanyl aminopeptidase (PfM1AAP) and M17 leucyl aminopeptidase (PfM17LAP)"],"prefix":"10.1038","volume":"11","author":[{"given":"Rency","family":"Mathew","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juliane","family":"Wunderlich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karine","family":"Thivierge","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krystyna","family":"Cwiklinski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claire","family":"Dumont","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leann","family":"Tilley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Petra","family":"Rohrbach","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John P.","family":"Dalton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,2,3]]},"reference":[{"key":"82499_CR1","unstructured":"World malaria report 2019. Licence: CC BY-NC-SA 3.0 IGO (World Health Organization, Geneva, 2019)."},{"key":"82499_CR2","doi-asserted-by":"publisher","first-page":"4","DOI":"10.4103\/jmms.jmms_43_18","volume":"21","author":"A Khera","year":"2019","unstructured":"Khera, A. & Mukherjee, R. Artemisinin resistance: Cause for worry?. J. Mar. Med. Soc. 21, 4 (2019).","journal-title":"J. Mar. Med. Soc."},{"key":"82499_CR3","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1016\/0166-6851(84)90017-3","volume":"10","author":"DL Vander Jagt","year":"1984","unstructured":"Vander Jagt, D. L., Baack, B. R. & Hunsaker, L. A. Purification and characterization of an aminopeptidase from Plasmodium falciparum. Mol. Biochem. Parasitol. 10, 45\u201354 (1984).","journal-title":"Mol. Biochem. Parasitol."},{"key":"82499_CR4","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1111\/j.1550-7408.1994.tb01483.x","volume":"41","author":"GP Curley","year":"1994","unstructured":"Curley, G. P. et al. Aminopeptidases from Plasmodium falciparum, Plasmodium chabaudi chabaudi and Plasmodium berghei. J. Eukaryot. Microbiol. 41, 119\u2013123 (1994).","journal-title":"J. Eukaryot. Microbiol."},{"key":"82499_CR5","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1016\/j.tibs.2009.08.004","volume":"35","author":"TS Skinner-Adams","year":"2010","unstructured":"Skinner-Adams, T. S. et al. Plasmodium falciparum neutral aminopeptidases: New targets for anti-malarials. Trends. Biochem. Sci. 35, 53\u201361 (2010).","journal-title":"Trends. Biochem. Sci."},{"key":"82499_CR6","doi-asserted-by":"publisher","first-page":"2069","DOI":"10.1074\/jbc.M609251200","volume":"282","author":"CM Stack","year":"2007","unstructured":"Stack, C. M. et al. Characterization of the Plasmodium falciparum M17 leucyl aminopeptidase A protease involved in amino acid regulation with potential for antimalarial drug development. J. Biol. Chem. 282, 2069\u20132080 (2007).","journal-title":"J. Biol. Chem."},{"key":"82499_CR7","doi-asserted-by":"publisher","first-page":"2537","DOI":"10.1073\/pnas.0807398106","volume":"106","author":"S McGowan","year":"2009","unstructured":"McGowan, S. et al. Structural basis for the inhibition of the essential Plasmodium falciparum M1 neutral aminopeptidase. PNAS 106, 2537\u20132542 (2009).","journal-title":"PNAS"},{"key":"82499_CR8","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1016\/S0166-6851(97)00062-5","volume":"87","author":"KA Kolakovich","year":"1997","unstructured":"Kolakovich, K. A., Gluzman, I. Y., Duffin, K. L. & Goldberg, D. E. Generation of hemoglobin peptides in the acidic digestive vacuole of Plasmodium falciparum implicates peptide transport in amino acid production. Mol. Biochem. Parasitol. 87, 123\u2013135 (1997).","journal-title":"Mol. Biochem. Parasitol."},{"key":"82499_CR9","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1016\/S0166-6851(01)00327-9","volume":"117","author":"CS Gavigan","year":"2001","unstructured":"Gavigan, C. S., Dalton, J. P. & Bell, A. The role of aminopeptidases in haemoglobin degradation in Plasmodium falciparum-infected erythrocytes. Mol. Biochem. Parasitol. 117, 37\u201348 (2001).","journal-title":"Mol. Biochem. Parasitol."},{"key":"82499_CR10","doi-asserted-by":"publisher","first-page":"149","DOI":"10.1016\/S0166-6851(98)00143-1","volume":"97","author":"I Florent","year":"1998","unstructured":"Florent, I. et al. A Plasmodium falciparum aminopeptidase gene belonging to the M1 family of zinc-metallopeptidases is expressed in erythrocytic stages. Mol. Biochem. Parasitol. 97, 149\u2013160 (1998).","journal-title":"Mol. Biochem. Parasitol."},{"key":"82499_CR11","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1017\/S0031182002001828","volume":"125","author":"M Allary","year":"2002","unstructured":"Allary, M., Schrevel, J. & Florent, I. Properties, stage-dependent expression and localization of Plasmodium falciparum M1 family zinc-aminopeptidase. Parasitol. 125, 1\u201310 (2002).","journal-title":"Parasitol."},{"key":"82499_CR12","doi-asserted-by":"publisher","first-page":"330","DOI":"10.3998\/ark.5550190.0013.424","volume":"4","author":"K Thivierge","year":"2012","unstructured":"Thivierge, K. et al. Anti-malaria drug development targeting the M1 alanyl and M17 leucyl aminopeptidases. Arkivoc. 4, 330\u2013346 (2012).","journal-title":"Arkivoc."},{"key":"82499_CR13","doi-asserted-by":"publisher","first-page":"2449","DOI":"10.1073\/pnas.0911813107","volume":"107","author":"S McGowan","year":"2010","unstructured":"McGowan, S. et al. Structure of the Plasmodium falciparum M17 aminopeptidase and significance for the design of drugs targeting the neutral exopeptidases. PNAS 107, 2449 (2010).","journal-title":"PNAS"},{"key":"82499_CR14","doi-asserted-by":"publisher","first-page":"35978","DOI":"10.1074\/jbc.M703643200","volume":"282","author":"S Dalal","year":"2007","unstructured":"Dalal, S. & Klemba, M. Roles for two aminopeptidases in vacuolar hemoglobin catabolism in Plasmodium falciparum. J. Biol. Chem. 282, 35978\u201335987 (2007).","journal-title":"J. Biol. Chem."},{"key":"82499_CR15","doi-asserted-by":"publisher","first-page":"552","DOI":"10.1007\/s004360050447","volume":"84","author":"MF Nankya-Kitaka","year":"1998","unstructured":"Nankya-Kitaka, M. F., Curley, G. P., Gavigan, C. S., Bell, A. & Dalton, J. P. Plasmodium chabaudi chabaudi and P. falciparum: Inhibition of aminopeptidase and parasite growth by bestatin and nitrobestatin. Parasitol. Res. 84, 552\u2013558 (1998).","journal-title":"Parasitol. Res."},{"key":"82499_CR16","doi-asserted-by":"publisher","first-page":"6024","DOI":"10.1021\/jm070733v","volume":"50","author":"TS Skinner-Adams","year":"2007","unstructured":"Skinner-Adams, T. S. et al. Identification of phosphinate dipeptide analog inhibitors directed against the Plasmodium falciparum M17 leucine aminopeptidase as lead antimalarial compounds. J. Med. Chem. 50, 6024\u20136031 (2007).","journal-title":"J. Med. Chem."},{"key":"82499_CR17","doi-asserted-by":"publisher","first-page":"3244","DOI":"10.1128\/AAC.06245-11","volume":"56","author":"TS Skinner-Adams","year":"2012","unstructured":"Skinner-Adams, T. S. et al. The Aminopeptidase inhibitor CHR-2863 is an orally bioavailable inhibitor of murine malaria. Antimicrob. Agents. Chemother. 56, 3244\u20133249 (2012).","journal-title":"Antimicrob. Agents. Chemother."},{"key":"82499_CR18","doi-asserted-by":"publisher","first-page":"1473","DOI":"10.1111\/febs.14009","volume":"284","author":"N Drinkwater","year":"2017","unstructured":"Drinkwater, N., Lee, J., Yang, W., Malcolm, T. R. & McGowan, S. M1 aminopeptidases as drug targets: Broad applications or therapeutic niche?. FEBS J. 284, 1473\u20131488 (2017).","journal-title":"FEBS J."},{"key":"82499_CR19","doi-asserted-by":"publisher","first-page":"7185","DOI":"10.1021\/acs.jmedchem.9b00757","volume":"62","author":"J Lee","year":"2019","unstructured":"Lee, J. et al. Novel human aminopeptidase N inhibitors: Discovery and optimization of subsite binding interactions. J. Med. Chem. 62, 7185\u20137209 (2019).","journal-title":"J. Med. Chem."},{"key":"82499_CR20","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1016\/j.biochi.2019.01.007","volume":"166","author":"N Drinkwater","year":"2019","unstructured":"Drinkwater, N., Malcolm, T. R. & McGowan, S. M17 aminopeptidases diversify function by moderating their macromolecular assemblies and active site environment. Biochimie 166, 38\u201351 (2019).","journal-title":"Biochimie"},{"key":"82499_CR21","doi-asserted-by":"publisher","first-page":"9168","DOI":"10.1021\/jm501323a","volume":"57","author":"SN Mistry","year":"2014","unstructured":"Mistry, S. N. et al. Two-pronged attack: Dual inhibition of Plasmodium falciparum M1 and M17 metalloaminopeptidases by a novel series of hydroxamic acid-based inhibitors. J. Med. Chem. 57, 9168\u20139183 (2014).","journal-title":"J. Med. Chem."},{"key":"82499_CR22","doi-asserted-by":"publisher","first-page":"789","DOI":"10.1002\/prot.24771","volume":"83","author":"N Drinkwater","year":"2015","unstructured":"Drinkwater, N., Bamert, R. S., Sivaraman, K. K., Paiardini, A. & McGowan, S. X-ray crystal structures of an orally available aminopeptidase inhibitor, Tosedostat, bound to anti-malarial drug targets PfA-M1 and PfA-M17. Proteins. 83, 789\u2013795 (2015).","journal-title":"Proteins."},{"key":"82499_CR23","doi-asserted-by":"publisher","first-page":"622","DOI":"10.1021\/acs.jmedchem.8b01310","volume":"62","author":"NB Vinh","year":"2019","unstructured":"Vinh, N. B. et al. Hydroxamic acid inhibitors provide cross-species inhibition of Plasmodium M1 and M17 aminopeptidases. J. Med. Chem. 62, 622\u2013640 (2019).","journal-title":"J. Med. Chem."},{"key":"82499_CR24","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1016\/j.ejmech.2016.01.015","volume":"110","author":"N Drinkwater","year":"2016","unstructured":"Drinkwater, N. et al. Potent dual inhibitors of Plasmodium falciparum M1 and M17 aminopeptidases through optimization of S1 pocket interactions. Eur. J. Med. Chem. 110, 43\u201364 (2016).","journal-title":"Eur. J. Med. Chem."},{"key":"82499_CR25","doi-asserted-by":"publisher","first-page":"313","DOI":"10.1016\/S0006-2952(98)00140-3","volume":"56","author":"KJ Saliba","year":"1998","unstructured":"Saliba, K. J., Folb, P. I. & Smith, P. J. Role for the Plasmodium falciparum digestive vacuole in chloroquine resistance. Biochem. Pharmacol. 56, 313\u2013320 (1998).","journal-title":"Biochem. Pharmacol."},{"key":"82499_CR26","doi-asserted-by":"publisher","first-page":"157","DOI":"10.1016\/S0166-6851(03)00119-1","volume":"129","author":"R Banerjee","year":"2003","unstructured":"Banerjee, R., Francis, S. E. & Goldberg, D. E. Food vacuole plasmepsins are processed at a conserved site by an acidic convertase activity in Plasmodium falciparum. Mol. Biochem. Parasitol. 129, 157\u2013165 (2003).","journal-title":"Mol. Biochem. Parasitol."},{"key":"82499_CR27","doi-asserted-by":"publisher","first-page":"e31938","DOI":"10.1371\/journal.pone.0031938","volume":"7","author":"M Poreba","year":"2012","unstructured":"Poreba, M. et al. Fingerprinting the substrate specificity of M1 and M17 aminopeptidases of human malaria, Plasmodium falciparum. PLoS ONE 7, e31938 (2012).","journal-title":"PLoS ONE"},{"key":"82499_CR28","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1186\/1475-2875-9-189","volume":"9","author":"O Azimzadeh","year":"2010","unstructured":"Azimzadeh, O., Sow, C., G\u00e8ze, M., Nyalwidhe, J. & Florent, I. Plasmodium falciparum PfA-M1 aminopeptidase is trafficked via the parasitophorous vacuole and marginally delivered to the food vacuole. Malar. J. 9, 189 (2010).","journal-title":"Malar. J."},{"key":"82499_CR29","doi-asserted-by":"publisher","first-page":"27255","DOI":"10.1074\/jbc.M111.225318","volume":"286","author":"D Ragheb","year":"2011","unstructured":"Ragheb, D., Dalal, S., Bompiani, K. M., Ray, W. K. & Klemba, M. Distribution and biochemical properties of an M1-family aminopeptidase in Plasmodium falciparum indicate a role in vacuolar hemoglobin catabolism. J. Biol. Chem. 286, 27255\u201327265 (2011).","journal-title":"J. Biol. Chem."},{"key":"82499_CR30","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1016\/j.molbiopara.2004.05.009","volume":"137","author":"CJ Tonkin","year":"2004","unstructured":"Tonkin, C. J. et al. Localization of organellar proteins in Plasmodium falciparum using a novel set of transfection vectors and a new immunofluorescence fixation method. Mol. Biochem. Parasitol. 137, 13\u201321 (2004).","journal-title":"Mol. Biochem. Parasitol."},{"key":"82499_CR31","doi-asserted-by":"publisher","first-page":"3993","DOI":"10.1529\/biophysj.103.038422","volume":"86","author":"SV Costes","year":"2004","unstructured":"Costes, S. V. et al. Automatic and quantitative measurement of protein-protein colocalization in live cells. Biophys. J. 86, 3993\u20134003 (2004).","journal-title":"Biophys. J."},{"key":"82499_CR32","doi-asserted-by":"publisher","first-page":"152","DOI":"10.1038\/nmeth.1855","volume":"9","author":"U Schnell","year":"2012","unstructured":"Schnell, U., Dijk, F., Sjollema, K. A. & Giepmans, B. N. G. Immunolabeling artifacts and the need for live-cell imaging. Nat. Methods. 9, 152\u2013158 (2012).","journal-title":"Nat. Methods."},{"key":"82499_CR33","doi-asserted-by":"publisher","first-page":"1004","DOI":"10.1111\/j.1462-5822.2006.00847.x","volume":"9","author":"Y Kuhn","year":"2007","unstructured":"Kuhn, Y., Rohrbach, P. & Lanzer, M. Quantitative pH measurements in Plasmodium falciparum-infected erythrocytes using pHluorin. Cell. Microbiol. 9, 1004\u20131013 (2007).","journal-title":"Cell. Microbiol."},{"key":"82499_CR34","doi-asserted-by":"publisher","first-page":"343","DOI":"10.1042\/BJ20070934","volume":"407","author":"N Klonis","year":"2007","unstructured":"Klonis, N. et al. Evaluation of pH during cytostomal endocytosis and vacuolar catabolism of haemoglobin in Plasmodium falciparum. Biochem. J. 407, 343\u2013354 (2007).","journal-title":"Biochem. J."},{"key":"82499_CR35","doi-asserted-by":"publisher","first-page":"140","DOI":"10.1097\/00062752-200203000-00010","volume":"9","author":"PJ Rosenthal","year":"2002","unstructured":"Rosenthal, P. J. Hydrolysis of erythrocyte proteins by proteases of malaria parasites. Curr. Opin. Hematol. 9, 140\u2013145 (2002).","journal-title":"Curr. Opin. Hematol."},{"key":"82499_CR36","doi-asserted-by":"publisher","first-page":"1489","DOI":"10.1016\/j.ijpara.2004.10.003","volume":"34","author":"PJ Rosenthal","year":"2004","unstructured":"Rosenthal, P. J. Cysteine proteases of malaria parasites. Int. J. Parasitol. 34, 1489\u20131499 (2004).","journal-title":"Int. J. Parasitol."},{"key":"82499_CR37","doi-asserted-by":"publisher","first-page":"43000","DOI":"10.1074\/jbc.M408123200","volume":"279","author":"M Klemba","year":"2004","unstructured":"Klemba, M., Gluzman, I. & Goldberg, D. E. A Plasmodium falciparum dipeptidyl aminopeptidase I participates in vacuolar hemoglobin degradation. J. Biol. Chem. 279, 43000\u201343007 (2004).","journal-title":"J. Biol. Chem."},{"key":"82499_CR38","doi-asserted-by":"publisher","first-page":"8840","DOI":"10.1073\/pnas.0601876103","volume":"103","author":"J Liu","year":"2006","unstructured":"Liu, J., Istvan, E. S., Gluzman, I. Y., Gross, J. & Goldberg, D. E. Plasmodium falciparum ensures its amino acid supply with multiple acquisition pathways and redundant proteolytic enzyme systems. PNAS 103, 8840 (2006).","journal-title":"PNAS"},{"key":"82499_CR39","doi-asserted-by":"publisher","first-page":"E526","DOI":"10.1073\/pnas.1105601108","volume":"108","author":"MB Harbut","year":"2011","unstructured":"Harbut, M. B. et al. Bestatin-based chemical biology strategy reveals distinct roles for malaria M1- and M17-family aminopeptidases. PNAS 108, E526 (2011).","journal-title":"PNAS"},{"key":"82499_CR40","doi-asserted-by":"publisher","first-page":"5157","DOI":"10.1073\/pnas.1217452110","volume":"110","author":"N Klonis","year":"2013","unstructured":"Klonis, N. et al. Altered temporal response of malaria parasites determines differential sensitivity to artemisinin. PNAS 110, 5157\u20135162 (2013).","journal-title":"PNAS"},{"key":"82499_CR41","first-page":"406","volume":"129","author":"SC Xie","year":"2016","unstructured":"Xie, S. C. et al. Haemoglobin degradation underpins the sensitivity of early ring stage Plasmodium falciparum to artemisinins. J. Cell Sci. 129, 406\u2013416 (2016).","journal-title":"J. Cell Sci."},{"key":"82499_CR42","doi-asserted-by":"publisher","first-page":"533","DOI":"10.1016\/j.pt.2020.03.006","volume":"36","author":"SC Xie","year":"2020","unstructured":"Xie, S. C., Ralph, S. A. & Tilley, L. K13, the cytostome, and artemisinin resistance. Trends. Parasitol. 36, 533\u2013544 (2020).","journal-title":"Trends. Parasitol."},{"key":"82499_CR43","first-page":"1424","volume":"4","author":"J Wunderlich","year":"2012","unstructured":"Wunderlich, J., Rohrbach, P. & Dalton, J. P. The malaria digestive vacuole. Front. Biosci. 4, 1424\u20131448 (2012).","journal-title":"Front. Biosci."},{"key":"82499_CR44","doi-asserted-by":"publisher","first-page":"e1006525","DOI":"10.1371\/journal.pcbi.1006525","volume":"14","author":"DS Moore","year":"2018","unstructured":"Moore, D. S., Brines, C., Jewhurst, H., Dalton, J. P. & Tikhonova, I. G. Steered molecular dynamics simulations reveal critical residues for (un) binding of substrates, inhibitors and a product to the malarial M1 aminopeptidase. PLoS Comput. Biol. 14, e1006525 (2018).","journal-title":"PLoS Comput. Biol."},{"key":"82499_CR45","doi-asserted-by":"publisher","first-page":"e849","DOI":"10.1371\/journal.pntd.0000849","volume":"4","author":"B-K Na","year":"2010","unstructured":"Na, B.-K. et al. Biochemical properties of a novel cysteine protease of Plasmodium vivax, vivapain-4. PLoS Negl. Trop. Dis. 4, e849 (2010).","journal-title":"PLoS Negl. Trop. Dis."},{"key":"82499_CR46","unstructured":"Kong, Y., Na, B.-K., Kim, S.-H. & Bae, Y.-A. Use of a cysteine protease of Plasmodium vivax. (2011). Patent US9677063B2."},{"key":"82499_CR47","doi-asserted-by":"publisher","first-page":"38022","DOI":"10.1074\/jbc.M306842200","volume":"278","author":"CE Murata","year":"2003","unstructured":"Murata, C. E. & Goldberg, D. E. Plasmodium falciparum falcilysin A metalloprotease with dual specificity. J. Biol. Chem. 278, 38022\u201338028 (2003).","journal-title":"J. Biol. Chem."},{"key":"82499_CR48","doi-asserted-by":"publisher","first-page":"376","DOI":"10.1111\/j.1550-7408.1983.tb02934.x","volume":"30","author":"C Slomianny","year":"1983","unstructured":"Slomianny, C., Charet, P. & Prensier, G. Ultrastructural localization of enzymes involved in the feeding process in Plasmodium chabaudi and Babesia hylomysci. J. Protozool. 30, 376\u2013382 (1983).","journal-title":"J. Protozool."},{"key":"82499_CR49","doi-asserted-by":"publisher","first-page":"945","DOI":"10.1017\/S0031182009006398","volume":"136","author":"H Jia","year":"2009","unstructured":"Jia, H. et al. Characterization of a leucine aminopeptidase of Babesia gibsoni. Parasitol. 136, 945\u2013952 (2009).","journal-title":"Parasitol."},{"key":"82499_CR50","doi-asserted-by":"publisher","first-page":"884","DOI":"10.1128\/EC.00062-14","volume":"13","author":"S Gras","year":"2014","unstructured":"Gras, S. et al. Aminopeptidase N1 (EtAPN1), an M1 metalloprotease of the apicomplexan parasite Eimeria tenella, participates in parasite development. Eukaryot. Cell. 13, 884\u2013895 (2014).","journal-title":"Eukaryot. Cell."},{"key":"82499_CR51","doi-asserted-by":"publisher","first-page":"1404","DOI":"10.1292\/jvms.17-0119","volume":"79","author":"Q Li","year":"2017","unstructured":"Li, Q. et al. Biochemical characterization of aminopeptidase N2 from Toxoplasma gondii. J. Vet. Med. Sci. 79, 1404\u20131411 (2017).","journal-title":"J. Vet. Med. Sci."},{"key":"82499_CR52","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.molbiopara.2009.11.005","volume":"170","author":"H Jia","year":"2010","unstructured":"Jia, H. et al. Characterization of a leucine aminopeptidase from Toxoplasma gondii. Mol. Biochem. Parasitol. 170, 1\u20136 (2010).","journal-title":"Mol. Biochem. Parasitol."},{"key":"82499_CR53","doi-asserted-by":"publisher","first-page":"673","DOI":"10.1126\/science.781840","volume":"193","author":"W Trager","year":"1976","unstructured":"Trager, W. & Jensen, J. B. Human malaria parasites in continuous culture. Science 193, 673\u2013675 (1976).","journal-title":"Science"},{"key":"82499_CR54","doi-asserted-by":"publisher","first-page":"215","DOI":"10.1016\/j.ijpara.2012.01.001","volume":"42","author":"JP Dalton","year":"2012","unstructured":"Dalton, J. P. et al. Large-scale growth of the Plasmodium falciparum malaria parasite in a wave bioreactor. Int. J. Parasitol. 42, 215\u2013220 (2012).","journal-title":"Int. J. Parasitol."},{"key":"82499_CR55","doi-asserted-by":"publisher","first-page":"418","DOI":"10.2307\/3280287","volume":"65","author":"C Lambros","year":"1979","unstructured":"Lambros, C. & Vanderberg, J. P. Synchronization of Plasmodium falciparum erythrocytic stages in culture. J. Parasitol. 65, 418\u2013420 (1979).","journal-title":"J. Parasitol."},{"key":"82499_CR56","volume-title":"A Guide to Protein Isolation","author":"C Dennison","year":"2013","unstructured":"Dennison, C. A Guide to Protein Isolation Vol. 3 (Springer Science & Business Media, New York, 2013)."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-82499-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-82499-4","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-82499-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,28]],"date-time":"2023-01-28T17:07:27Z","timestamp":1674925647000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-82499-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,2,3]]},"references-count":56,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["82499"],"URL":"https:\/\/doi.org\/10.1038\/s41598-021-82499-4","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,2,3]]},"assertion":[{"value":"25 June 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 January 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 February 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"2854"}}