Loading…

Biosynthesis and Maturation of the Malaria Aspartic Hemoglobinases Plasmepsins I and II

During the intraerythrocytic stage of infection, the malaria parasite Plasmodium falciparum digests most of the host cell hemoglobin. Hemoglobin degradation occurs in the acidic digestive vacuole and is essential for the survival of the parasite. Two aspartic proteases, plasmepsins I and II, have be...

Full description

Saved in:
Bibliographic Details
Published in:The Journal of biological chemistry 1997-06, Vol.272 (23), p.14961-14968
Main Authors: Francis, S E, Banerjee, R, Goldberg, D E
Format: Article
Language:English
Subjects:
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
cited_by cdi_FETCH-LOGICAL-c431t-634c5be81b62fb0f6c6dec89708c84b0c1c06960bc53783fb55bc37e3291e8ab3
cites cdi_FETCH-LOGICAL-c431t-634c5be81b62fb0f6c6dec89708c84b0c1c06960bc53783fb55bc37e3291e8ab3
container_end_page 14968
container_issue 23
container_start_page 14961
container_title The Journal of biological chemistry
container_volume 272
creator Francis, S E
Banerjee, R
Goldberg, D E
description During the intraerythrocytic stage of infection, the malaria parasite Plasmodium falciparum digests most of the host cell hemoglobin. Hemoglobin degradation occurs in the acidic digestive vacuole and is essential for the survival of the parasite. Two aspartic proteases, plasmepsins I and II, have been isolated from the vacuole and shown to make the initial cleavages in the hemoglobin molecule. We have studied the biosynthesis of these two enzymes. Plasmepsin I is synthesized and processed to the mature form soon after the parasite invades the red blood cell, while plasmepsin II synthesis is delayed until later in development. Otherwise, biosynthesis of the plasmepsins is identical. The proplasmepsins are type II integral membrane proteins that are transported through the secretory pathway before cleavage to the soluble form. They are not glycosylated in vivo , despite the presence of several potential glycosylation sites. Proplasmepsin maturation appears to require acidic conditions and is reversibly inhibited by the tripeptide aldehydes N-acetyl - l - leucyl - l - leucyl -norleucinal and N-acetyl - l - leucyl - l - leucyl -methional. These compounds are known to inhibit cysteine proteases and the chymotryptic activity of proteasomes but not aspartic proteases. However, proplasmepsin processing is not blocked by other cysteine protease inhibitors, nor by the proteasome inhibitor lactacystin. Processing is also not blocked by aspartic protease inhibitors. This inhibitor profile suggests that unlike most other aspartic proteases, proplasmepsin maturation may not be autocatalytic in vivo , but instead could require the action of an unusual processing enzyme. Compounds that block processing are expected to be potent antimalarials.
doi_str_mv 10.1074/jbc.272.23.14961
format article
fullrecord <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_79045556</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>79045556</sourcerecordid><originalsourceid>FETCH-LOGICAL-c431t-634c5be81b62fb0f6c6dec89708c84b0c1c06960bc53783fb55bc37e3291e8ab3</originalsourceid><addsrcrecordid>eNpVkMFLwzAUh4Moc07vXoQexFtr0jRpc5xD3UDRg6K3kGTpmtE2M69F9t9btyH4Lg_e7_e-w4fQJcEJwXl2u9YmSfM0SWlCMsHJERoTXNCYMvJ5jMYYpyQWKStO0RnAGg-TCTJCI0G4yLgYo48752HbdpUFB5Fql9Gz6vqgOufbyJfREAyXWgWnoilsVOiciea28avaa9cqsBC91goauwHXQrTYMRaLc3RSqhrsxWFP0PvD_dtsHj-9PC5m06fYZJR0MaeZYdoWRPO01Ljkhi-tKUSOC1NkGhtiMBcca8NoXtBSM6YNzS1NBbGF0nSCbvbcTfBfvYVONg6MrWvVWt-DzAXOGGN8KOJ90QQPEGwpN8E1KmwlwfLXpRxcysGlTKncuRxerg7sXjd2-fdwkDfk1_u8cqvq2wUrtfOmss1_zA8BX3vZ</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>79045556</pqid></control><display><type>article</type><title>Biosynthesis and Maturation of the Malaria Aspartic Hemoglobinases Plasmepsins I and II</title><source>ScienceDirect</source><creator>Francis, S E ; Banerjee, R ; Goldberg, D E</creator><creatorcontrib>Francis, S E ; Banerjee, R ; Goldberg, D E</creatorcontrib><description>During the intraerythrocytic stage of infection, the malaria parasite Plasmodium falciparum digests most of the host cell hemoglobin. Hemoglobin degradation occurs in the acidic digestive vacuole and is essential for the survival of the parasite. Two aspartic proteases, plasmepsins I and II, have been isolated from the vacuole and shown to make the initial cleavages in the hemoglobin molecule. We have studied the biosynthesis of these two enzymes. Plasmepsin I is synthesized and processed to the mature form soon after the parasite invades the red blood cell, while plasmepsin II synthesis is delayed until later in development. Otherwise, biosynthesis of the plasmepsins is identical. The proplasmepsins are type II integral membrane proteins that are transported through the secretory pathway before cleavage to the soluble form. They are not glycosylated in vivo , despite the presence of several potential glycosylation sites. Proplasmepsin maturation appears to require acidic conditions and is reversibly inhibited by the tripeptide aldehydes N-acetyl - l - leucyl - l - leucyl -norleucinal and N-acetyl - l - leucyl - l - leucyl -methional. These compounds are known to inhibit cysteine proteases and the chymotryptic activity of proteasomes but not aspartic proteases. However, proplasmepsin processing is not blocked by other cysteine protease inhibitors, nor by the proteasome inhibitor lactacystin. Processing is also not blocked by aspartic protease inhibitors. This inhibitor profile suggests that unlike most other aspartic proteases, proplasmepsin maturation may not be autocatalytic in vivo , but instead could require the action of an unusual processing enzyme. Compounds that block processing are expected to be potent antimalarials.</description><identifier>ISSN: 0021-9258</identifier><identifier>EISSN: 1083-351X</identifier><identifier>DOI: 10.1074/jbc.272.23.14961</identifier><identifier>PMID: 9169469</identifier><language>eng</language><publisher>United States: American Society for Biochemistry and Molecular Biology</publisher><subject>Amino Acid Sequence ; Animals ; Antibodies ; Aspartic Acid Endopeptidases - biosynthesis ; Aspartic Acid Endopeptidases - metabolism ; Erythrocytes - parasitology ; Hemoglobins - metabolism ; Humans ; Immunoblotting ; Membrane Proteins - biosynthesis ; Membrane Proteins - metabolism ; Molecular Sequence Data ; Oligopeptides - pharmacology ; Peptide Fragments - chemistry ; Peptide Fragments - immunology ; Plasmodium falciparum - enzymology ; Plasmodium falciparum - pathogenicity ; Protease Inhibitors - pharmacology ; Protein Biosynthesis ; Protozoan Proteins ; Recombinant Proteins - biosynthesis ; Recombinant Proteins - metabolism ; Vacuoles - enzymology</subject><ispartof>The Journal of biological chemistry, 1997-06, Vol.272 (23), p.14961-14968</ispartof><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c431t-634c5be81b62fb0f6c6dec89708c84b0c1c06960bc53783fb55bc37e3291e8ab3</citedby><cites>FETCH-LOGICAL-c431t-634c5be81b62fb0f6c6dec89708c84b0c1c06960bc53783fb55bc37e3291e8ab3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,778,782,27911,27912</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/9169469$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Francis, S E</creatorcontrib><creatorcontrib>Banerjee, R</creatorcontrib><creatorcontrib>Goldberg, D E</creatorcontrib><title>Biosynthesis and Maturation of the Malaria Aspartic Hemoglobinases Plasmepsins I and II</title><title>The Journal of biological chemistry</title><addtitle>J Biol Chem</addtitle><description>During the intraerythrocytic stage of infection, the malaria parasite Plasmodium falciparum digests most of the host cell hemoglobin. Hemoglobin degradation occurs in the acidic digestive vacuole and is essential for the survival of the parasite. Two aspartic proteases, plasmepsins I and II, have been isolated from the vacuole and shown to make the initial cleavages in the hemoglobin molecule. We have studied the biosynthesis of these two enzymes. Plasmepsin I is synthesized and processed to the mature form soon after the parasite invades the red blood cell, while plasmepsin II synthesis is delayed until later in development. Otherwise, biosynthesis of the plasmepsins is identical. The proplasmepsins are type II integral membrane proteins that are transported through the secretory pathway before cleavage to the soluble form. They are not glycosylated in vivo , despite the presence of several potential glycosylation sites. Proplasmepsin maturation appears to require acidic conditions and is reversibly inhibited by the tripeptide aldehydes N-acetyl - l - leucyl - l - leucyl -norleucinal and N-acetyl - l - leucyl - l - leucyl -methional. These compounds are known to inhibit cysteine proteases and the chymotryptic activity of proteasomes but not aspartic proteases. However, proplasmepsin processing is not blocked by other cysteine protease inhibitors, nor by the proteasome inhibitor lactacystin. Processing is also not blocked by aspartic protease inhibitors. This inhibitor profile suggests that unlike most other aspartic proteases, proplasmepsin maturation may not be autocatalytic in vivo , but instead could require the action of an unusual processing enzyme. Compounds that block processing are expected to be potent antimalarials.</description><subject>Amino Acid Sequence</subject><subject>Animals</subject><subject>Antibodies</subject><subject>Aspartic Acid Endopeptidases - biosynthesis</subject><subject>Aspartic Acid Endopeptidases - metabolism</subject><subject>Erythrocytes - parasitology</subject><subject>Hemoglobins - metabolism</subject><subject>Humans</subject><subject>Immunoblotting</subject><subject>Membrane Proteins - biosynthesis</subject><subject>Membrane Proteins - metabolism</subject><subject>Molecular Sequence Data</subject><subject>Oligopeptides - pharmacology</subject><subject>Peptide Fragments - chemistry</subject><subject>Peptide Fragments - immunology</subject><subject>Plasmodium falciparum - enzymology</subject><subject>Plasmodium falciparum - pathogenicity</subject><subject>Protease Inhibitors - pharmacology</subject><subject>Protein Biosynthesis</subject><subject>Protozoan Proteins</subject><subject>Recombinant Proteins - biosynthesis</subject><subject>Recombinant Proteins - metabolism</subject><subject>Vacuoles - enzymology</subject><issn>0021-9258</issn><issn>1083-351X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1997</creationdate><recordtype>article</recordtype><recordid>eNpVkMFLwzAUh4Moc07vXoQexFtr0jRpc5xD3UDRg6K3kGTpmtE2M69F9t9btyH4Lg_e7_e-w4fQJcEJwXl2u9YmSfM0SWlCMsHJERoTXNCYMvJ5jMYYpyQWKStO0RnAGg-TCTJCI0G4yLgYo48752HbdpUFB5Fql9Gz6vqgOufbyJfREAyXWgWnoilsVOiciea28avaa9cqsBC91goauwHXQrTYMRaLc3RSqhrsxWFP0PvD_dtsHj-9PC5m06fYZJR0MaeZYdoWRPO01Ljkhi-tKUSOC1NkGhtiMBcca8NoXtBSM6YNzS1NBbGF0nSCbvbcTfBfvYVONg6MrWvVWt-DzAXOGGN8KOJ90QQPEGwpN8E1KmwlwfLXpRxcysGlTKncuRxerg7sXjd2-fdwkDfk1_u8cqvq2wUrtfOmss1_zA8BX3vZ</recordid><startdate>19970606</startdate><enddate>19970606</enddate><creator>Francis, S E</creator><creator>Banerjee, R</creator><creator>Goldberg, D E</creator><general>American Society for Biochemistry and Molecular Biology</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>19970606</creationdate><title>Biosynthesis and Maturation of the Malaria Aspartic Hemoglobinases Plasmepsins I and II</title><author>Francis, S E ; Banerjee, R ; Goldberg, D E</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c431t-634c5be81b62fb0f6c6dec89708c84b0c1c06960bc53783fb55bc37e3291e8ab3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1997</creationdate><topic>Amino Acid Sequence</topic><topic>Animals</topic><topic>Antibodies</topic><topic>Aspartic Acid Endopeptidases - biosynthesis</topic><topic>Aspartic Acid Endopeptidases - metabolism</topic><topic>Erythrocytes - parasitology</topic><topic>Hemoglobins - metabolism</topic><topic>Humans</topic><topic>Immunoblotting</topic><topic>Membrane Proteins - biosynthesis</topic><topic>Membrane Proteins - metabolism</topic><topic>Molecular Sequence Data</topic><topic>Oligopeptides - pharmacology</topic><topic>Peptide Fragments - chemistry</topic><topic>Peptide Fragments - immunology</topic><topic>Plasmodium falciparum - enzymology</topic><topic>Plasmodium falciparum - pathogenicity</topic><topic>Protease Inhibitors - pharmacology</topic><topic>Protein Biosynthesis</topic><topic>Protozoan Proteins</topic><topic>Recombinant Proteins - biosynthesis</topic><topic>Recombinant Proteins - metabolism</topic><topic>Vacuoles - enzymology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Francis, S E</creatorcontrib><creatorcontrib>Banerjee, R</creatorcontrib><creatorcontrib>Goldberg, D E</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>The Journal of biological chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Francis, S E</au><au>Banerjee, R</au><au>Goldberg, D E</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Biosynthesis and Maturation of the Malaria Aspartic Hemoglobinases Plasmepsins I and II</atitle><jtitle>The Journal of biological chemistry</jtitle><addtitle>J Biol Chem</addtitle><date>1997-06-06</date><risdate>1997</risdate><volume>272</volume><issue>23</issue><spage>14961</spage><epage>14968</epage><pages>14961-14968</pages><issn>0021-9258</issn><eissn>1083-351X</eissn><abstract>During the intraerythrocytic stage of infection, the malaria parasite Plasmodium falciparum digests most of the host cell hemoglobin. Hemoglobin degradation occurs in the acidic digestive vacuole and is essential for the survival of the parasite. Two aspartic proteases, plasmepsins I and II, have been isolated from the vacuole and shown to make the initial cleavages in the hemoglobin molecule. We have studied the biosynthesis of these two enzymes. Plasmepsin I is synthesized and processed to the mature form soon after the parasite invades the red blood cell, while plasmepsin II synthesis is delayed until later in development. Otherwise, biosynthesis of the plasmepsins is identical. The proplasmepsins are type II integral membrane proteins that are transported through the secretory pathway before cleavage to the soluble form. They are not glycosylated in vivo , despite the presence of several potential glycosylation sites. Proplasmepsin maturation appears to require acidic conditions and is reversibly inhibited by the tripeptide aldehydes N-acetyl - l - leucyl - l - leucyl -norleucinal and N-acetyl - l - leucyl - l - leucyl -methional. These compounds are known to inhibit cysteine proteases and the chymotryptic activity of proteasomes but not aspartic proteases. However, proplasmepsin processing is not blocked by other cysteine protease inhibitors, nor by the proteasome inhibitor lactacystin. Processing is also not blocked by aspartic protease inhibitors. This inhibitor profile suggests that unlike most other aspartic proteases, proplasmepsin maturation may not be autocatalytic in vivo , but instead could require the action of an unusual processing enzyme. Compounds that block processing are expected to be potent antimalarials.</abstract><cop>United States</cop><pub>American Society for Biochemistry and Molecular Biology</pub><pmid>9169469</pmid><doi>10.1074/jbc.272.23.14961</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record>
fulltext fulltext
identifier ISSN: 0021-9258
ispartof The Journal of biological chemistry, 1997-06, Vol.272 (23), p.14961-14968
issn 0021-9258
1083-351X
language eng
recordid cdi_proquest_miscellaneous_79045556
source ScienceDirect
subjects Amino Acid Sequence
Animals
Antibodies
Aspartic Acid Endopeptidases - biosynthesis
Aspartic Acid Endopeptidases - metabolism
Erythrocytes - parasitology
Hemoglobins - metabolism
Humans
Immunoblotting
Membrane Proteins - biosynthesis
Membrane Proteins - metabolism
Molecular Sequence Data
Oligopeptides - pharmacology
Peptide Fragments - chemistry
Peptide Fragments - immunology
Plasmodium falciparum - enzymology
Plasmodium falciparum - pathogenicity
Protease Inhibitors - pharmacology
Protein Biosynthesis
Protozoan Proteins
Recombinant Proteins - biosynthesis
Recombinant Proteins - metabolism
Vacuoles - enzymology
title Biosynthesis and Maturation of the Malaria Aspartic Hemoglobinases Plasmepsins I and II
url http://sfxeu10.hosted.exlibrisgroup.com/loughborough?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-15T17%3A11%3A59IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Biosynthesis%20and%20Maturation%20of%20the%20Malaria%20Aspartic%20Hemoglobinases%20Plasmepsins%20I%20and%20II&rft.jtitle=The%20Journal%20of%20biological%20chemistry&rft.au=Francis,%20S%20E&rft.date=1997-06-06&rft.volume=272&rft.issue=23&rft.spage=14961&rft.epage=14968&rft.pages=14961-14968&rft.issn=0021-9258&rft.eissn=1083-351X&rft_id=info:doi/10.1074/jbc.272.23.14961&rft_dat=%3Cproquest_cross%3E79045556%3C/proquest_cross%3E%3Cgrp_id%3Ecdi_FETCH-LOGICAL-c431t-634c5be81b62fb0f6c6dec89708c84b0c1c06960bc53783fb55bc37e3291e8ab3%3C/grp_id%3E%3Coa%3E%3C/oa%3E%3Curl%3E%3C/url%3E&rft_id=info:oai/&rft_pqid=79045556&rft_id=info:pmid/9169469&rfr_iscdi=true