HDP_PLAF7
ID HDP_PLAF7 Reviewed; 205 AA.
AC Q8IL04; A0A144A6G1;
DT 05-SEP-2012, integrated into UniProtKB/Swiss-Prot.
DT 01-MAR-2003, sequence version 1.
DT 03-AUG-2022, entry version 97.
DE RecName: Full=Heme ligase;
DE EC=4.99.1.8 {ECO:0000269|PubMed:18437218, ECO:0000269|PubMed:25138161, ECO:0000269|PubMed:28949547};
DE AltName: Full=Heme detoxification protein {ECO:0000303|PubMed:18437218};
DE Short=PfHDP {ECO:0000303|PubMed:28949547};
DE AltName: Full=Hemozoin synthase;
GN Name=HDP {ECO:0000303|PubMed:18437218}; ORFNames=PF14_0446, PF3D7_1446800;
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 FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, AND
RP SUBCELLULAR LOCATION.
RX PubMed=18437218; DOI=10.1371/journal.ppat.1000053;
RA Jani D., Nagarkatti R., Beatty W., Angel R., Slebodnick C., Andersen J.,
RA Kumar S., Rathore D.;
RT "HDP-a novel heme detoxification protein from the malaria parasite.";
RL PLoS Pathog. 4:E1000053-E1000053(2008).
RN [3]
RP FUNCTION, IDENTIFICATION IN THE HEMOZOIN FORMATION COMPLEX, INTERACTION
RP WITH FALCIPAIN 2, SUBCELLULAR LOCATION, DEVELOPMENTAL STAGE, AND
RP IDENTIFICATION BY MASS SPECTROMETRY.
RX PubMed=23471987; DOI=10.1073/pnas.1218412110;
RA Chugh M., Sundararaman V., Kumar S., Reddy V.S., Siddiqui W.A.,
RA Stuart K.D., Malhotra P.;
RT "Protein complex directs hemoglobin-to-hemozoin formation in Plasmodium
RT falciparum.";
RL Proc. Natl. Acad. Sci. U.S.A. 110:5392-5397(2013).
RN [4]
RP FUNCTION, CATALYTIC ACTIVITY, AND MUTAGENESIS OF HIS-44; HIS-58; HIS-70;
RP HIS-79; HIS-122; HIS-172; HIS-175; HIS-192 AND HIS-197.
RX PubMed=25138161; DOI=10.1038/srep06137;
RA Nakatani K., Ishikawa H., Aono S., Mizutani Y.;
RT "Identification of essential histidine residues involved in heme binding
RT and Hemozoin formation in heme detoxification protein from Plasmodium
RT falciparum.";
RL Sci. Rep. 4:6137-6137(2014).
RN [5]
RP FUNCTION, CATALYTIC ACTIVITY, INTERACTION WITH HOST HEMOGLOBIN, AND
RP MUTAGENESIS OF 1-MET--TYR-87; 120-LEU--PHE-205; 154-LEU--PHE-170;
RP 171-LYS--PHE-205 AND 191-CYS--PHE-205.
RX PubMed=28949547; DOI=10.1021/acs.jmedchem.7b00089;
RA Gupta P., Mehrotra S., Sharma A., Chugh M., Pandey R., Kaushik A.,
RA Khurana S., Srivastava N., Srivastava T., Deshmukh A., Panda A.,
RA Aggarwal P., Bhavesh N.S., Bhatnagar R.K., Mohmmed A., Gupta D.,
RA Malhotra P.;
RT "Exploring Heme and Hemoglobin Binding Regions of Plasmodium Heme
RT Detoxification Protein for New Antimalarial Discovery.";
RL J. Med. Chem. 60:8298-8308(2017).
CC -!- FUNCTION: Heme detoxifying enzyme that converts heme to crystalline
CC hemozoin (beta-hematin) to protect the organism from the toxic effects
CC of heme (PubMed:18437218, PubMed:23471987, PubMed:25138161,
CC PubMed:28949547). During its development, P.falciparum proteolyzes vast
CC amounts of host hemoglobin, leading to heme release (PubMed:18437218).
CC {ECO:0000269|PubMed:18437218, ECO:0000269|PubMed:23471987,
CC ECO:0000269|PubMed:25138161, ECO:0000269|PubMed:28949547}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=2 Fe(III)-heme b = beta-hematin; Xref=Rhea:RHEA:53712,
CC ChEBI:CHEBI:55376, ChEBI:CHEBI:55377; EC=4.99.1.8;
CC Evidence={ECO:0000269|PubMed:18437218, ECO:0000269|PubMed:25138161,
CC ECO:0000269|PubMed:28949547};
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC pH dependence:
CC Optimum pH is 4.5-5.2. {ECO:0000269|PubMed:18437218};
CC -!- SUBUNIT: Component of the hemozoin formation complex (HFC) composed of
CC falcipain 2, plasmepsins PMII, PMIII/HAP and PMIV, heme detoxifying
CC protein HDP and falcilysin FLN (PubMed:23471987). The HFC complex is
CC involved in hemoglobin degradation and detoxification of heme in the
CC food vacuole during the asexual blood stage (PubMed:23471987).
CC Interacts with falcipain 2; the interaction is direct and enhances HDP
CC catalytic activity (PubMed:23471987). Interacts with host hemoglobin
CC (PubMed:28949547). {ECO:0000269|PubMed:23471987,
CC ECO:0000269|PubMed:28949547}.
CC -!- SUBCELLULAR LOCATION: Vacuole {ECO:0000269|PubMed:18437218,
CC ECO:0000269|PubMed:23471987}. Host cytoplasm, host cytosol
CC {ECO:0000269|PubMed:18437218}. Note=Delivered to the food vacuole, the
CC site of hemozoin formation, via a unique trafficking route
CC (PubMed:18437218, PubMed:23471987). Initially secreted into the cytosol
CC of infected red blood cells (PubMed:18437218). A subsequent endocytosis
CC of host cytosol delivers HDP to the food vacuole (PubMed:18437218).
CC {ECO:0000269|PubMed:18437218, ECO:0000269|PubMed:23471987}.
CC -!- DEVELOPMENTAL STAGE: Expressed during the asexual blood stage including
CC in trophozoites (at protein level). {ECO:0000269|PubMed:23471987}.
CC -!- MISCELLANEOUS: HDP is critical for survival, suggesting it could be a
CC potential malaria drug target. {ECO:0000269|PubMed:28949547,
CC ECO:0000305|PubMed:18437218}.
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DR EMBL; LN999946; CZU00163.1; -; Genomic_DNA.
DR RefSeq; XP_001348620.1; XM_001348584.1.
DR AlphaFoldDB; Q8IL04; -.
DR SMR; Q8IL04; -.
DR STRING; 5833.PF14_0446; -.
DR BindingDB; Q8IL04; -.
DR ChEMBL; CHEMBL4105720; -.
DR EnsemblProtists; CZU00163; CZU00163; PF3D7_1446800.
DR GeneID; 812028; -.
DR KEGG; pfa:PF3D7_1446800; -.
DR VEuPathDB; PlasmoDB:PF3D7_1446800; -.
DR HOGENOM; CLU_1258320_0_0_1; -.
DR InParanoid; Q8IL04; -.
DR OMA; PFTGFIP; -.
DR PhylomeDB; Q8IL04; -.
DR BioCyc; MetaCyc:MON-15023; -.
DR BRENDA; 4.99.1.8; 4889.
DR Proteomes; UP000001450; Chromosome 14.
DR GO; GO:0020020; C:food vacuole; IDA:GeneDB.
DR GO; GO:0030430; C:host cell cytoplasm; IDA:GeneDB.
DR GO; GO:0044164; C:host cell cytosol; IDA:UniProtKB.
DR GO; GO:0020037; F:heme binding; IDA:UniProtKB.
DR GO; GO:0004392; F:heme oxygenase (decyclizing) activity; IDA:GeneDB.
DR GO; GO:0016829; F:lyase activity; IDA:UniProtKB.
DR GO; GO:0042167; P:heme catabolic process; IDA:UniProtKB.
DR Gene3D; 2.30.180.10; -; 1.
DR InterPro; IPR036378; FAS1_dom_sf.
DR InterPro; IPR000782; FAS1_domain.
DR Pfam; PF02469; Fasciclin; 1.
DR SMART; SM00554; FAS1; 1.
DR SUPFAM; SSF82153; SSF82153; 1.
DR PROSITE; PS50213; FAS1; 1.
PE 1: Evidence at protein level;
KW Host cytoplasm; Lyase; Reference proteome; Vacuole.
FT CHAIN 1..205
FT /note="Heme ligase"
FT /id="PRO_0000418492"
FT DOMAIN 48..203
FT /note="FAS1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00082"
FT REGION 154..172
FT /note="Required for binding to host hemoglobin"
FT /evidence="ECO:0000269|PubMed:28949547"
FT REGION 171..181
FT /note="Heme binding domain"
FT /evidence="ECO:0000269|PubMed:28949547"
FT REGION 191..200
FT /note="Heme binding domain"
FT /evidence="ECO:0000269|PubMed:28949547"
FT SITE 122
FT /note="Heme binding"
FT /evidence="ECO:0000269|PubMed:25138161"
FT SITE 172
FT /note="Required to bring heme into proper alignment for the
FT reaction"
FT /evidence="ECO:0000269|PubMed:25138161"
FT SITE 175
FT /note="Heme binding"
FT /evidence="ECO:0000269|PubMed:25138161"
FT SITE 197
FT /note="Required to bring heme into proper alignment for the
FT reaction"
FT /evidence="ECO:0000269|PubMed:25138161"
FT MUTAGEN 1..87
FT /note="Missing: 71% reduction in catalytic activity."
FT /evidence="ECO:0000269|PubMed:28949547"
FT MUTAGEN 44
FT /note="H->A: No effect on catalytic activity. 50% reduction
FT in catalytic activity; when associated with A-58, A-70, A-
FT 79, A-122, A-172, A-175, A-192 and A-197."
FT /evidence="ECO:0000269|PubMed:25138161"
FT MUTAGEN 58
FT /note="H->A: No effect on catalytic activity. 50% reduction
FT in catalytic activity; when associated with A-44, A-70, A-
FT 79, A-122, A-172, A-175, A-192 and A-197."
FT /evidence="ECO:0000269|PubMed:25138161"
FT MUTAGEN 70
FT /note="H->A: No effect on catalytic activity. 50% reduction
FT in catalytic activity; when associated with A-44, A-58, A-
FT 79, A-122, A-172, A-175, A-192 and A-197."
FT /evidence="ECO:0000269|PubMed:25138161"
FT MUTAGEN 79
FT /note="H->A: No effect on catalytic activity. 50% reduction
FT in catalytic activity; when associated with A-44, A-58, A-
FT 70, A-122, A-172, A-175, A-192 and A-197."
FT /evidence="ECO:0000269|PubMed:25138161"
FT MUTAGEN 120..205
FT /note="Missing: 75% reduction in catalytic activity."
FT /evidence="ECO:0000269|PubMed:28949547"
FT MUTAGEN 122
FT /note="H->A: 50% reduction in catalytic activity. 50%
FT reduction in catalytic activity; when associated with A-44,
FT A-58, A-70, A-79, A-172, A-175, A-192 and A-197."
FT /evidence="ECO:0000269|PubMed:25138161"
FT MUTAGEN 154..170
FT /note="Missing: 4% reduction in catalytic activity."
FT /evidence="ECO:0000269|PubMed:28949547"
FT MUTAGEN 171..205
FT /note="Missing: 30% reduction in catalytic activity. Slight
FT decrease in heme binding."
FT /evidence="ECO:0000269|PubMed:28949547"
FT MUTAGEN 172
FT /note="H->A: 50% reduction in catalytic activity. 50%
FT reduction in catalytic activity; when associated with A-44,
FT A-58, A-70, A-79, A-122, A-175, A-192 and A-197."
FT /evidence="ECO:0000269|PubMed:25138161"
FT MUTAGEN 175
FT /note="H->A: 50% reduction in catalytic activity. 50%
FT reduction in catalytic activity; when associated with A-44,
FT A-58, A-70, A-79, A-122, A-172, A-192 and A-197."
FT /evidence="ECO:0000269|PubMed:25138161"
FT MUTAGEN 191..205
FT /note="Missing: 60% reduction in catalytic activity.
FT Decreases heme binding."
FT /evidence="ECO:0000269|PubMed:28949547"
FT MUTAGEN 192
FT /note="H->A: No effect on catalytic activity. 50% reduction
FT in catalytic activity; when associated with A-44, A-58, A-
FT 70, A-79, A-122, A-172, A-175 and A-197."
FT /evidence="ECO:0000269|PubMed:25138161"
FT MUTAGEN 197
FT /note="H->A: 50% reduction in catalytic activity. 50%
FT reduction in catalytic activity; when associated with A-44,
FT A-58, A-70, A-79, A-122, A-172, A-175 and A-192."
FT /evidence="ECO:0000269|PubMed:25138161"
SQ SEQUENCE 205 AA; 24337 MW; C4DDCB978236C3CF CRC64;
MKNRFYYNLI IKRLYTRSGG LRKPQKVTND PESINRKVYW CFEHKPVKRT IINLIYSHNE
LKIFSNLLNH PTVGSSLIHE LSLDGPYTAF FPSNEAMQLI NIESFNKLYN DENKLSEFVL
NHVTKEYWLY RDLYGSSYQP WLMYNEKREA PEKLRNLLNN DLIVKIEGEF KHCNHSIYLN
GSKIIRPNMK CHNGVVHIVD KPIIF
