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Information on EC 4.99.1.8 - heme ligase
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4.99.1.8 heme ligaseIUBMB Comments
This heme detoxifying enzyme is found in Plasmodium parasites and converts toxic heme to crystalline hemozoin. These organisms lack the mammalian heme oxygenase for elimination of heme.
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Word Map
- 4.99.1.8
- plasmodium
- malaria
- hemozoin
- falciparum
- hemoglobin
-
antimalarial
- vacuole
- chloroquine
-
detoxify
- medicine
- artemisinins
-
reductase-thymidylate
-
byproduct
- dihydrofolate
-
heme-binding
- polymerization
- yoelii
- analysis
The enzyme appears in viruses and cellular organisms
Synonyms
heme detoxification protein, heme-detoxification protein, heme ligase, 
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SYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
HDP
heme detoxification protein
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REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
2 ferriprotoporphyrin IX = beta-hematin
-
-
-
-
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PATHWAY SOURCE
PATHWAYS
-
-
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SYSTEMATIC NAME
IUBMB Comments
Fe3+:ferriprotoporphyrin IX ligase (beta-hematin-forming)
This heme detoxifying enzyme is found in Plasmodium parasites and converts toxic heme to crystalline hemozoin. These organisms lack the mammalian heme oxygenase for elimination of heme.
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SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
ferriprotoporphyrin IX
beta-hematin
-
-
beta-hematin is also called hemozoin
-
?
ferriprotoporphyrin IX
beta-hematin
-
-
beta-hematin is also called hemozoin or Malaria pigment
-
?
ferriprotoporphyrin IX
beta-hematin
-
hemozoin consists of an unusual polymer of hemes linked between the central ferric ion of one heme and a carboxylate side-group oxygen of another. The hemes are sequestered via this linkage into an insoluble product, providing a unique way for the malaria parasite to avoid the toxicity associated with soluble heme
-
-
?
ferriprotoporphyrin IX
beta-hematin
-
hemozoin consists of an unusual polymer of hemes linked between the central ferric ion of one heme and a carboxylate side-group oxygen of another
-
-
?
ferriprotoporphyrin IX
beta-hematin
-
HDP possesses 2.7 heme binding sites
-
-
?
heme
hemozoin
enzyme binds heme with a very high affinity, KD value 89 nM
-
-
?
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NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
ferriprotoporphyrin IX
beta-hematin
-
hemozoin consists of an unusual polymer of hemes linked between the central ferric ion of one heme and a carboxylate side-group oxygen of another. The hemes are sequestered via this linkage into an insoluble product, providing a unique way for the malaria parasite to avoid the toxicity associated with soluble heme
-
-
?
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INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
diethyldicarbonate
histidine modification using diethyldicarbonate leads to reduction in heme binding and hemozoin formation
N-[2-[(7-methyl-2,3-dihydro-1H-inden-4-yl)oxy]-3-pyridinyl]-3,4-dihydro-2H-1,5-benzodioxepine-7-carboxamide
compound binds the modeled HDP structure in the heme/hemoglobin-binding pockets, and inhibits parasite growth in a dose-dependent manner
additional information
not inhibitory up to 0.04 mM: pyrimethamine
-
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DISEASE
TITLE OF PUBLICATION
LINK TO PUBMED
Infections
Evaluation of antigen detection tests, microscopy, and polymerase chain reaction for diagnosis of malaria in peripheral blood in asymptomatic pregnant women in nanoro, burkina faso.
Malaria
Cloning, expression and functional characterization of heme detoxification protein (HDP) from the rodent malaria parasite Plasmodium vinckei.
Malaria
Evaluation of antigen detection tests, microscopy, and polymerase chain reaction for diagnosis of malaria in peripheral blood in asymptomatic pregnant women in nanoro, burkina faso.
Malaria
New developments in malaria diagnostics: Monoclonal antibodies against Plasmodium dihydrofolate reductase-thymidylate synthase, heme detoxification protein and glutamate rich protein.
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IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
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pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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pH RANGE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
3.3 - 5.2
-
pH 3.3-4.4: optimum, pH 5.2: about 75% of maximal activity, no activity above pH 5.6
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ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
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SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
expression is increased in late trophozoite and schizont stages of parasite
brenda
additional information
enzyme is expressed throughout the intra erythrocytic stages
brenda
expression is increased in late trophozoite and schizont stages of parasite
brenda
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LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
-
the parasite utilizes a circuitous outbound-inbound trafficking route by initially secreting HDP into the cytosol of infected red blood cells
-
brenda
falcipain 2 coexists with heme detoxification protein and forms a hemozoin formation complex in the Plasmodium food vacuole
brenda
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GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
physiological function
physiological function
-
hemozoin is the main protective mechanism against heme toxicity in malaria parasites
physiological function
identification of two heme binding sites and a hemoglobin binding site in Pf HDP. Treatment of Plasmodium falciparum 3D7 parasites with peptide corresponding to the hemoglobin binding domain results in food vacuole abnormalities similar to that seen with cysteine protease inhibitor, E-64
physiological function
non-crystalline heme is stored within hemoglobin in the digestive vacuole, and then converted to crystallized heme with the assistance of the heme detoxification protein. A coupling exists between the rate of hemoglobin digestion and the rate of heme dimerization and crystallization. In vivo heme crystallization occurs at a rate of about 1000/s, which is close to the in vitro rate of heme dimerization measured for the heme detoxification protein (HDP). HDP may be primarily responsible for heme crystallization
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UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable).
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable). HDP_PLAF7
205
0
24337
Swiss-Prot
other Location (Reliability: 5)
A0A1N6LWP5_BABMR
Babesia microti (strain RI)
199
0
22778
TrEMBL
other Location (Reliability: 5)
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MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
H192A
the mutant shows decreased hemozoin formation activity compared to the wild type enzyme
H44A
the mutant shows decreased hemozoin formation activity compared to the wild type enzyme
H44A/H58A/H70A/H79A/H122A/H172A/H175A/H192A/H197A
the mutant shows less than half of the wild type activity
H58A
the mutant shows decreased hemozoin formation activity compared to the wild type enzyme
H70A
the mutant shows decreased hemozoin formation activity compared to the wild type enzyme
H79A
the mutant shows decreased hemozoin formation activity compared to the wild type enzyme
additional information
-
the truncated enzyme proteins HDP3 (encoded by amino acids 88-205 of the full-length protein, representing the fasciclin domain) and HDP2 (encoded by amino acids 187 and lacking the fasciclin domain) are unable to produce hemozoin. The full-length enzyme is required for heme binding and hemozoin production activities of the protein
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TEMPERATURE STABILITY
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
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CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
expressed in Escherichia coli BL21(DE3) cells
expression in Escherichia coli
expression of full length enzyme in Escherichia coli, expression of two truncated enzyme proteins (HDP3 encoded by amino acids 88-205 of the full-length protein, representing the fasciclin domain and HDP2 encoded by amino acids 187 and lacking the fasciclin domain)
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RENATURED/Commentary
ORGANISM
UNIPROT
LITERATURE
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APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
analysis
development of a high resolution correlative combination of cryo soft X-ray tomography to obtain 3D parasite ultrastructure with cryo X-ray fluorescence microscopy to measure heme concentrations
medicine
medicine
-
HDP is a conserved target for future antimalarial development
medicine
-
involvement of heme detoxification protein in the process of formation of hemozoin suggests that it could be a malaria drug target
medicine
-
involvement of heme detoxification protein in the process of formation of hemozoin suggests that it could be a malaria drug target
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REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Vinayak, S.; Rathore, D.; Kariuki, S.; Slutsker, L.; Shi, Y.P.; Villegas, L.; Escalante, A.A.; Udhayakumar, V.
Limited genetic variation in the Plasmodium falciparum heme detoxification protein (HDP)
Infect. Genet. Evol.
9
286-289
2009
Plasmodium falciparum
brenda
Jani, D.; Nagakatti, R.; Beatty, W.; Angel, R.; Slebodnick, C.; Andersen, J.; Kumar, S.; Rathore, D.
HDP - a novel heme detoxification protein from the malaria parasite
PLos Pathog.
4
e1000053
2008
Plasmodium falciparum, Plasmodium yoelii
brenda
Slater, A.F.G.; Swiggard, W.J.; Orton, B.R.; Flitter, W.D.; Goldberg, D.E.; Cerami, A.; Henderson, G.B.
An iron-carboxylate bond links the heme units of malaria pigment
Proc. Natl. Acad. Sci. USA
88
325-329
1991
Plasmodium falciparum
brenda
Wagner, H.
Hemozoin: malaria's built-in adjuvant and TLR9 agonist
Cell Host Microbe
7
5-6
2010
Plasmodium falciparum
brenda
Shio, M.; Kassa, F.; Bellemare, M.; Olivier, M.
Innate inflammatory response to the malarial pigment hemozoin
Microbes Infect.
12
889-899
2010
Plasmodium falciparum
brenda
Nakatani, K.; Ishikawa, H.; Aono, S.; Mizutani, Y.
Heme-binding properties of heme detoxification protein from Plasmodium falciparum
Biochem. Biophys. Res. Commun.
439
477-480
2013
Plasmodium falciparum (Q8IL04), Plasmodium falciparum
brenda
Kattenberg, J.H.; Versteeg, I.; Migchelsen, S.J.; Gonzalez, I.J.; Perkins, M.D.; Mens, P.F.; Schallig, H.D.
New developments in malaria diagnostics: monoclonal antibodies against Plasmodium dihydrofolate reductase-thymidylate synthase, heme detoxification protein and glutamate rich protein
mAbs
4
120-126
2012
Plasmodium falciparum (Q8IL04), Plasmodium falciparum, Plasmodium falciparum NF54 (Q8IL04)
brenda
Chugh, M.; Sundararaman, V.; Kumar, S.; Reddy, V.S.; Siddiqui, W.A.; Stuart, K.D.; Malhotra, P.
Protein complex directs hemoglobin-to-hemozoin formation in Plasmodium falciparum
Proc. Natl. Acad. Sci. USA
110
5392-5397
2013
Plasmodium falciparum (Q8IL04), Plasmodium falciparum
brenda
Nakatani, K.; Ishikawa, H.; Aono, S.; Mizutani, Y.
Identification of essential histidine residues involved in heme binding and hemozoin formation in heme detoxification protein from Plasmodium falciparum
Sci. Rep.
4
6137
2014
Plasmodium falciparum (Q8IL04), Plasmodium falciparum
brenda
Soni, A.; Goyal, M.; Prakash, K.; Bhardwaj, J.; Siddiqui, A.J.; Puri, S.K.
Cloning, expression and functional characterization of heme detoxification protein (HDP) from the rodent malaria parasite Plasmodium vinckei
Gene
566
109-119
2015
Plasmodium vinckei petteri (F5BWX4)
brenda
Gupta, P.; Mehrotra, S.; Sharma, A.; Chugh, M.; Pandey, R.; Kaushik, A.; Khurana, S.; Srivastava, N.; Srivastava, T.; Deshmukh, A.; Panda, A.; Aggarwal, P.; Bhavesh, N.S.; Bhatnagar, R.K.; Mohmmed, A.; Gupta, D.; Malhotra, P.
Exploring heme and hemoglobin binding regions of Plasmodium heme detoxification protein for new antimalarial discovery
J. Med. Chem.
60
8298-8308
2017
Plasmodium falciparum (Q8IL04)
brenda
Kapishnikov, S.; Grolimund, D.; Schneider, G.; Pereiro, E.; McNally, J.; Als-Nielsen, J.; Leiserowitz, L.
Unraveling heme detoxification in the malaria parasite by in situ correlative X-ray fluorescence microscopy and soft X-ray tomography
Sci. Rep.
7
7610
2017
Plasmodium falciparum (Q8IL04), Plasmodium falciparum
brenda
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