PLM1_PLAF7
ID PLM1_PLAF7 Reviewed; 452 AA.
AC Q7KQM4; A0A144A171;
DT 02-MAY-2006, integrated into UniProtKB/Swiss-Prot.
DT 05-JUL-2004, sequence version 1.
DT 03-AUG-2022, entry version 109.
DE RecName: Full=Plasmepsin I {ECO:0000303|PubMed:14709539};
DE EC=3.4.23.38 {ECO:0000269|PubMed:29943906};
DE AltName: Full=Aspartic hemoglobinase I {ECO:0000250|UniProtKB:P39898};
DE AltName: Full=Plasmepsin 1 {ECO:0000305};
DE Flags: Precursor;
GN Name=PMI {ECO:0000303|PubMed:14709539};
GN ORFNames=PF14_0076, PF3D7_1407900 {ECO:0000312|EMBL:CZT99786.1};
OS Plasmodium falciparum (isolate 3D7).
OC Eukaryota; Sar; Alveolata; Apicomplexa; Aconoidasida; Haemosporida;
OC Plasmodiidae; Plasmodium; Plasmodium (Laverania).
OX NCBI_TaxID=36329;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=3D7;
RX PubMed=12368864; DOI=10.1038/nature01097;
RA Gardner M.J., Hall N., Fung E., White O., Berriman M., Hyman R.W.,
RA Carlton J.M., Pain A., Nelson K.E., Bowman S., Paulsen I.T., James K.D.,
RA Eisen J.A., Rutherford K.M., Salzberg S.L., Craig A., Kyes S., Chan M.-S.,
RA Nene V., Shallom S.J., Suh B., Peterson J., Angiuoli S., Pertea M.,
RA Allen J., Selengut J., Haft D., Mather M.W., Vaidya A.B., Martin D.M.A.,
RA Fairlamb A.H., Fraunholz M.J., Roos D.S., Ralph S.A., McFadden G.I.,
RA Cummings L.M., Subramanian G.M., Mungall C., Venter J.C., Carucci D.J.,
RA Hoffman S.L., Newbold C., Davis R.W., Fraser C.M., Barrell B.G.;
RT "Genome sequence of the human malaria parasite Plasmodium falciparum.";
RL Nature 419:498-511(2002).
RN [2]
RP DEVELOPMENTAL STAGE, AND PROTEOLYTIC CLEAVAGE.
RX PubMed=14709539; DOI=10.1083/jcb200307147;
RA Klemba M., Beatty W., Gluzman I., Goldberg D.E.;
RT "Trafficking of plasmepsin II to the food vacuole of the malaria parasite
RT Plasmodium falciparum.";
RL J. Cell Biol. 164:47-56(2004).
RN [3]
RP DISRUPTION PHENOTYPE.
RX PubMed=15513918; DOI=10.1074/jbc.m409740200;
RA Liu J., Gluzman I.Y., Drew M.E., Goldberg D.E.;
RT "The role of Plasmodium falciparum food vacuole plasmepsins.";
RL J. Biol. Chem. 280:1432-1437(2005).
RN [4]
RP CATALYTIC ACTIVITY, AND ACTIVITY REGULATION.
RX PubMed=29943906; DOI=10.1111/febs.14598;
RA Mishra V., Rathore I., Arekar A., Sthanam L.K., Xiao H., Kiso Y., Sen S.,
RA Patankar S., Gustchina A., Hidaka K., Wlodawer A., Yada R.Y., Bhaumik P.;
RT "Deciphering the mechanism of potent peptidomimetic inhibitors targeting
RT plasmepsins - biochemical and structural insights.";
RL FEBS J. 285:3077-3096(2018).
CC -!- FUNCTION: During the asexual blood stage, catalyzes the initial
CC cleavage of native host hemoglobin (Hb) resulting in Hb denaturation;
CC specifically cleaves between Phe-33 and Leu-34 of Hb alpha-chain.
CC Digestion of host Hb is an essential step which provides the parasite
CC with amino acids for protein synthesis, and regulates osmolarity.
CC {ECO:0000250|UniProtKB:P39898}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=Hydrolysis of the 33-Phe-|-Leu-34 bond in the alpha-chain of
CC hemoglobin, leading to denaturation of molecule.; EC=3.4.23.38;
CC Evidence={ECO:0000269|PubMed:29943906};
CC -!- ACTIVITY REGULATION: Inhibited by KNI derived compounds KNI-10333 and
CC to a lesser extent KNI-10743. {ECO:0000269|PubMed:29943906}.
CC -!- SUBCELLULAR LOCATION: Membrane {ECO:0000250|UniProtKB:P39898}; Single-
CC pass type II membrane protein {ECO:0000250|UniProtKB:P39898}. Vacuole
CC lumen {ECO:0000250|UniProtKB:P39898}. Vacuole membrane
CC {ECO:0000250|UniProtKB:P39898}. Note=At the beginning of the asexual
CC blood stage, the transmembrane zymogen is transported to the cytostome,
CC an endocytic structure spanning the parasite cell membrane and the
CC parasitophorous vacuole membrane where host proteins such as hemoglobin
CC are endocytosed. Following endocytosis, localizes to the cytostome
CC vacuole membrane to be then delivered to the digestive (or food)
CC vacuole where it is cleaved into the soluble and active enzyme. In
CC trophozoites, localizes to the digestive vacuole, an acidic vacuole
CC where host hemoglobin is digested. {ECO:0000250|UniProtKB:P39898}.
CC -!- DEVELOPMENTAL STAGE: Expressed during the asexual blood stage including
CC in trophozoites (at protein level). {ECO:0000269|PubMed:14709539}.
CC -!- PTM: Not N-glycosylated. {ECO:0000250|UniProtKB:P39898}.
CC -!- PTM: Proteolytically cleaved into the soluble active mature form in the
CC digestive vacuole by cysteine protease falcipains; the process begins
CC at the early ring stage (PubMed:14709539). Proteolysis requires an
CC acidic environment (By similarity). {ECO:0000250|UniProtKB:P39898,
CC ECO:0000269|PubMed:14709539}.
CC -!- DISRUPTION PHENOTYPE: No growth defect (PubMed:15513918). However,
CC slight decrease in proliferation and slight increase in doubling time
CC during the asexual blood stage in an amino acid-limited medium
CC (PubMed:15513918). {ECO:0000269|PubMed:15513918}.
CC -!- SIMILARITY: Belongs to the peptidase A1 family. {ECO:0000305}.
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DR EMBL; LN999946; CZT99786.1; -; Genomic_DNA.
DR RefSeq; XP_001348249.1; XM_001348213.1.
DR AlphaFoldDB; Q7KQM4; -.
DR SMR; Q7KQM4; -.
DR STRING; 5833.PF14_0076; -.
DR DrugBank; DB11638; Artenimol.
DR MEROPS; A01.022; -.
DR SwissPalm; Q7KQM4; -.
DR PRIDE; Q7KQM4; -.
DR EnsemblProtists; CZT99786; CZT99786; PF3D7_1407900.
DR GeneID; 811658; -.
DR KEGG; pfa:PF3D7_1407900; -.
DR VEuPathDB; PlasmoDB:PF3D7_1407900; -.
DR HOGENOM; CLU_013253_3_2_1; -.
DR InParanoid; Q7KQM4; -.
DR OMA; GVECANL; -.
DR PhylomeDB; Q7KQM4; -.
DR Proteomes; UP000001450; Chromosome 14.
DR GO; GO:0020020; C:food vacuole; TAS:GeneDB.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0005775; C:vacuolar lumen; IEA:UniProtKB-SubCell.
DR GO; GO:0005774; C:vacuolar membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0004190; F:aspartic-type endopeptidase activity; IDA:UniProtKB.
DR GO; GO:0042540; P:hemoglobin catabolic process; TAS:GeneDB.
DR GO; GO:0006508; P:proteolysis; IBA:GO_Central.
DR CDD; cd05471; pepsin_like; 1.
DR Gene3D; 2.40.70.10; -; 2.
DR InterPro; IPR001461; Aspartic_peptidase_A1.
DR InterPro; IPR001969; Aspartic_peptidase_AS.
DR InterPro; IPR034164; Pepsin-like_dom.
DR InterPro; IPR033121; PEPTIDASE_A1.
DR InterPro; IPR021109; Peptidase_aspartic_dom_sf.
DR PANTHER; PTHR47966; PTHR47966; 1.
DR Pfam; PF00026; Asp; 1.
DR PRINTS; PR00792; PEPSIN.
DR SUPFAM; SSF50630; SSF50630; 1.
DR PROSITE; PS00141; ASP_PROTEASE; 2.
DR PROSITE; PS51767; PEPTIDASE_A1; 1.
PE 1: Evidence at protein level;
KW Aspartyl protease; Disulfide bond; Hydrolase; Membrane; Protease;
KW Reference proteome; Signal-anchor; Transmembrane; Transmembrane helix;
KW Vacuole; Zymogen.
FT PROPEP 1..123
FT /evidence="ECO:0000250|UniProtKB:P39898"
FT /id="PRO_0000233400"
FT CHAIN 124..452
FT /note="Plasmepsin I"
FT /id="PRO_0000233401"
FT TOPO_DOM 1..37
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305"
FT TRANSMEM 38..58
FT /note="Helical; Signal-anchor for type II membrane protein"
FT /evidence="ECO:0000255"
FT TOPO_DOM 59..452
FT /note="Lumenal"
FT /evidence="ECO:0000305"
FT DOMAIN 139..446
FT /note="Peptidase A1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01103"
FT ACT_SITE 157
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01103"
FT ACT_SITE 337
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01103"
FT DISULFID 170..175
FT /evidence="ECO:0000250|UniProtKB:P39898"
FT DISULFID 372..408
FT /evidence="ECO:0000250|UniProtKB:P39898"
SQ SEQUENCE 452 AA; 51461 MW; 8F8F8478F2F7D931 CRC64;
MALSIKEDFS SAFAKNESAV NSSTFNNNMK TWKIQKRFQI LYVFFFLLIT GALFYYLIDN
VLFPKNKKIN EIMNTSKHVI IGFSIENSHD RIMKTVKQHR LKNYIKESLK FFKTGLTQKP
HLGNAGDSVT LNDVANVMYY GEAQIGDNKQ KFAFIFDTGS ANLWVPSAQC NTIGCKTKNL
YDSNKSKTYE KDGTKVEMNY VSGTVSGFFS KDIVTIANLS FPYKFIEVTD TNGFEPAYTL
GQFDGIVGLG WKDLSIGSVD PVVVELKNQN KIEQAVFTFY LPFDDKHKGY LTIGGIEDRF
YEGQLTYEKL NHDLYWQVDL DLHFGNLTVE KATAIVDSGT SSITAPTEFL NKFFEGLDVV
KIPFLPLYIT TCNNPKLPTL EFRSATNVYT LEPEYYLQQI FDFGISLCMV SIIPVDLNKN
TFILGDPFMR KYFTVFDYDN HTVGFALAKK KL
