Product Description: cysteine proteinase falcipain 2a
SignalP Peptide: N/A
# Transmembrane Domains: 1
EC Numbers: 3.4.22.- (Cysteine endopeptidases.)
Curated GO (PlasmoDB):
| Type | GO Term | Name |
|---|---|---|
| Component | GO:0005615 | extracellular space |
| Component | GO:0020020 | food vacuole |
| Component | GO:0005764 | lysosome |
| Component | GO:0016020 | membrane |
| Function | GO:0004197 | cysteine-type endopeptidase activity |
| Function | GO:0005515 | protein binding |
| Process | GO:0006508 | proteolysis |
| Process | GO:0051603 | proteolysis involved in cellular protein catabolic process |
Expression by stage (LR - Le Roch et al., and MCA - Malaria Cell Atlas):
| Stage | LR class | MCA mean | MCA prop. zeros |
|---|---|---|---|
| Sporozoite | not expressed | N/A | N/A |
| Ring | expressed | 0.51 | 0.76 |
| Trophozoite | expressed | 0.93 | 0.60 |
| Schizont | expressed | 0.07 | 0.96 |
| Gametocyte | not expressed | 0.23 | 0.87 |
More info:
Old (Pf3D7v3) Gene ID: PF3D7_1115700
Resistome Missense Mutations: R185K
Resistome Compounds with Missense Mutations: MMV665794
Resistome # Samples with Disruptive Mutations: 3 (1 missense, 1 "interesting" missense)
Zhang Phenotype: Non - Mutable in CDS
MIS: 0.12 | MFS: -2.998 | #Insertions: 0
PlasmoGEM Phenotype: Slow (Pb ortholog: PBANKA_1321700)
RMgmDB ABS Phenotype: Different from wild type (Pb ortholog: PBANKA_0932400)
Modification: Disrupted | RMgm-817
More info: PhenoPlasm Link
AlphaFill Uniprot ID: Q8I6U4
"Best" AlphaFill ligand hit: MHA (n-(2-acetamido)iminodiacetic acid, Local RMSD=0.10) with 6QLM (Global RMSD=2.96)
BRENDA EC Inhibitors:
| EC # | Name | EC Inhibitors |
|---|---|---|
| 3.4.22.- | Ex: staphylococcal cysteine proteinase | NEME64SpiSDSCysEDTAPCMBEGTAPMSFTLCKTPCKMENT... |
Orthology to BindingDB Entries:
| UniProt | Protein Name | Species | Homology Source | BindingDB Ligands |
|---|---|---|---|---|
| P25774 | Cathepsin S | Homo sapiens | HOGENOM | US8524710, 841, 2, 3 -Triazole Nitrile Inhibitor, 11a1, 2, 3 -Triazole Nitrile Inhibitor, 11b1, 2, 3 -Triazole Nitrile Inhibitor, 11c... |
| O60911 | Cathepsin L2 | Homo sapiens | HOGENOM | Azepan-3-one compound 1Azepan-3-one compound 10Dipeptidyl nitrile inhibitor, 1Dipeptidyl nitrile inhibitor, 4... |
| P07711 | Procathepsin L | Homo sapiens | HOGENOM | Aldehyde Inhibitor, 2Aldehyde Inhibitor, 12dL-873724trifluoroethylamine inhibitor, 1... |
| P43236 | Cathepsin K | Oryctolagus cuniculus | HOGENOM | L-873724trifluoroethylamine inhibitor, 1CHEMBL400387trifluoroethylamine inhibitor, 3... |
| O70370 | Cathepsin S | HOGENOM | CHEMBL426819BalicatibCHEMBL184514aryl-morpholino-containing analogue, 12... | |
| P07154 | Procathepsin L | Rattus norvegicus | HOGENOM | CHEMBL116910CHEMBL115734CHEMBL419772CHEMBL113761... |
| O35186 | Cathepsin K | Rattus norvegicus | HOGENOM | Azepan-3-one compound 1Azepan-3-one compound 7Azepan-3-one compound 9Azepan-3-one compound 10... |
| Q8IIL0 | Cysteine proteinase falcipain 3 | Plasmodium falciparum | HOGENOM, OrthoDB, OrthoMCL BLAST | Ac-Leu-Leu-Arg-HAc-Leu-Leu-Arg-HE-64CHEMBL3120849... |
| P25975 | Procathepsin L | Bos taurus | HOGENOM | dipeptide-derived nitrile, 5dipeptide-derived nitrile, 7dipeptidyl nitrile, 1dipeptide-derived nitrile, 9... |
| P06797 | Procathepsin L | Mus musculus | HOGENOM | CID644294Gallinamide ACHEMBL4594870CHEMBL4598338... |
| P43235 | Cathepsin K | Homo sapiens | HOGENOM | 1, 2, 3 -Triazole Nitrile Inhibitor, 11a1, 2, 3 -Triazole Nitrile Inhibitor, 11b1, 2, 3 -Triazole Nitrile Inhibitor, 11dAldehyde Inhibitor, 2... |
| P25805 | Trophozoite cysteine proteinase | OrthoDB, OrthoMCL BLAST | CHEMBL2237705CHEMBL2237700CHEMBL146137CHEMBL146192... | |
| P07688 | Cathepsin B | Bos taurus | OrthoDB | epoxysuccinyl derivative 2epoxysuccinyl derivative 3epoxysuccinyl derivative 4epoxysuccinyl derivative 5... |
| P10605 | Cathepsin B | Mus musculus | OrthoDB | CID644294 |
| P07858 | Cathepsin B | Homo sapiens | OrthoDB | L-873724trifluoroethylamine inhibitor, 1CHEMBL400387trifluoroethylamine inhibitor, 3... |
| H9B8T9 | Cathepsin B | OrthoDB | N-formyl-3,5-diphenylpyrazoline (1a)N-formyl-5-(-2'-chlorophenyl)-3-phenylpyrazoline (1b)N-formyl-5-(-3'-chlorophenyl)-3-phenylpyrazoline (1c)N-formyl-5-(-4'-chlorophenyl)-3-phenylpyrazoline (1d)... | |
| Q9NBD4 | Cysteine proteinase falcipain 2a | Plasmodium falciparum | OrthoMCL BLAST | Trisubsituted thiazole, 14Ac-Leu-Leu-Arg-HAc-Leu-Leu-Arg-HCHEMBL3120848... |
| Q9NAW4 | Cysteine protease falcipain-3 [5-492] | Plasmodium falciparum | OrthoMCL BLAST | GNF-PF-5434CHEMBL224801CHEMBL221833CHEMBL222870... |
| Q3HTL5 | Falcipain 2B | Plasmodium falciparum | OrthoMCL BLAST | CHEMBL207102MDL-28170 |
| Q9NAW2 | Falcipain-2 | Plasmodium falciparum | OrthoMCL BLAST | Phenylurenyl Chalcone deriv. 23Phenylurenyl Chalcone deriv. 24Phenylurenyl Chalcone deriv. 25Phenylurenyl Chalcone deriv. 26... |
| Q9N6S8 | Falcipain 2 | Plasmodium falciparum | OrthoMCL BLAST | thiosemicarbazone derivative, 3bthiosemicarbazone derivative, 3cthiosemicarbazone derivative, 3f4-aminoquinoline semicarbazone derivative, 8a... |
Ortholog Group (OrthoMCL): OG6_100116
Most Similar Human Ortholog: A0A7P0TAQ0
TM-align score: 0.90 | RMSD: 1.94
Seq Identity: 0.35 | Length: 261 / 484
All Human Orthologs (OrthoMCL):
| Gene ID | Description |
|---|---|
| ENSG00000135047 | cathepsin L |
| ENSG00000136943 | cathepsin V |
| ENSG00000143387 | cathepsin K |
| ENSG00000163131 | cathepsin S |
| ENSG00000174080 | cathepsin F |
Protein Length: 484 | Molecular Weight (kDa): 55.927
UniProt ID(s): A0A346CM80, A0A5J6BZ75, A0A5J6BZ93, A0A5J6BZ94, A0A5J6C066, A0A5J6C0E3, A0A5J6C0H6, A0A5J6C2I4, A0A5J6C3C3, A0A5J6C4G4, Q8I6U4
PDB ID(s): 1YVB, 2OUL, 7EI0, 8GT7
Isoelectric Point: 7.39
Protein Domain Annotations:
| Source | Family ID | Description |
|---|---|---|
| InterPro | IPR000169 | Cysteine peptidase, cysteine active site |
| InterPro | IPR000668 | Peptidase C1A, papain C-terminal |
| InterPro | IPR013201 | Cathepsin propeptide inhibitor domain (I29) |
| InterPro | IPR025660 | Cysteine peptidase, histidine active site |
| InterPro | IPR038765 | Papain-like cysteine peptidase superfamily |
| InterPro | IPR039417 | Papain-like cysteine endopeptidase |
| PFam | PF00112 | Peptidase C1A, papain C-terminal |
| PFam | PF08246 | Cathepsin propeptide inhibitor domain (I29) |
| Superfamily | SSF54001 | Papain-like cysteine peptidase superfamily |
MalariaGEN Pf7 (worldwide samples) # unique SNV/indels:
Homozygous genotype calls only
| variant type | common | rare | doubleton | singleton |
|---|---|---|---|---|
| synonymous | 2 | 2 | 0 | 5 |
| disruptive | 2 | 14 | 7 | 11 |
| missense | 2 | 14 | 7 | 11 |
Any inclusion in genotype call
| variant type | common | rare | doubleton | singleton |
|---|---|---|---|---|
| synonymous | 4 | 3 | 6 | 5 |
| disruptive | 6 | 22 | 13 | 22 |
| missense | 5 | 20 | 10 | 12 |
PlasmoDB Total SNPs: 238
Non-coding: 136 | Synonymous: 70 | Nonsynonymous: 32 | Stop Codon: 0
| PMID | Title | Authors | DOI/Link |
|---|---|---|---|
| 9343345 | Hemoglobin metabolism in the malaria parasite Plasmodium falciparum. | Francis SE, Sullivan DJ Jr, Goldberg DE | 10.1146/annurev.micro.51.1.97 |
| 11152613 | Predicting transmembrane protein topology with a hidden Markov model: applicationto complete genomes. | Krogh A, Larsson B, von Heijne G, Sonnhammer EL | 10.1006/jmbi.2000.4315 |
| 12368864 | Genome sequence of the human malaria parasite Plasmodium falciparum. | Gardner MJ, Hall N, ..., Barrell B | 10.1038/nature01097 |
| 15664655 | Biosynthesis, localization, and processing of falcipain cysteine proteases ofPlasmodium falciparum. | Dahl EL, Rosenthal PJ | https://pubmed.ncbi.nlm.nih.gov/15664655/ |
| 15964982 | The Plasmodium falciparum cysteine protease falcipain-2 captures its substrate,hemoglobin, via a unique motif. | Pandey KC, Wang SX, ..., Rosenthal PJ | https://pubmed.ncbi.nlm.nih.gov/15964982/ |
| 16267556 | A protein interaction network of the malaria parasite Plasmodium falciparum. | LaCount DJ, Vignali M, ..., Hughes RE | 10.1038/nature04104 |
| 16777845 | Structural and functional characterization of Falcipain-2, a hemoglobinase fromthe malarial parasite Plasmodium falciparum. | Hogg T, Nagarajan K, ..., Schmidt CL | 10.1074/jbc.M603776200 |
| 16864794 | Structural basis for unique mechanisms of folding and hemoglobin binding by amalarial protease. | Wang SX, Pandey KC, ..., McKerrow JH | 10.1073/pnas.0600489103 |
| 16890302 | Gene disruptions demonstrate independent roles for the four falcipain cysteineproteases of Plasmodium falciparum. | Sijwali PS, Koo J, Singh N, Rosenthal PJ | 10.1016/j.molbiopara.2006.06.013 |
| 17565983 | Falcipain cysteine proteases require bipartite motifs for trafficking to thePlasmodium falciparum food vacuole. | Subramanian S, Sijwali PS, Rosenthal PJ | 10.1074/jbc.M703316200 |
| 17698213 | Food vacuole targeting and trafficking of falcipain-2, an important cysteineprotease of human malaria parasite Plasmodium falciparum. | Dasaradhi PV, Korde R, ..., Malhotra P | https://pubmed.ncbi.nlm.nih.gov/17698213/ |
| 19357776 | Hemoglobin cleavage site-specificity of the Plasmodium falciparum cysteineproteases falcipain-2 and falcipain-3. | Subramanian S, Hardt M, ..., Rosenthal PJ | 10.1371/journal.pone.0005156 |
| 23077573 | The Ionic and hydrophobic interactions are required for the auto activation ofcysteine proteases of Plasmodium falciparum. | Sundararaj S, Singh D, ..., Pandey KC | 10.1371/journal.pone.0047227 |
| 23471987 | Protein complex directs hemoglobin-to-hemozoin formation in Plasmodiumfalciparum. | Chugh M, Sundararaman V, ..., Malhotra P | 10.1073/pnas.1218412110 |
| 24943200 | Dynamical footprint of falcipain-2 catalytic triad in hemoglobin-beta-bound state. | Omotuyi IO, Hamada T | 10.1080/07391102.2014.924878 |
| 31247344 | Inhibition of Plasmodium falciparum cysteine protease falcipain-2 by a humancross-class inhibitor serpinB3: A mechanistic insight. | Alam B, Biswas S | 10.1016/j.bbapap.2019.06.012 |
| 34974303 | New insights of falcipain 2 structure from Plasmodium falciparum 3D7 strain. | Chakraborty S, Alam B, Biswas S | https://pubmed.ncbi.nlm.nih.gov/34974303/ |
| 16041608 | Cysteine protease falcipain 1 in Plasmodium falciparum is biochemically distinctfrom its isozymes | Goh SL, Goh LL, Sim TS | 10.1007/s00436-005-1430-7 |
| 26439304 | Independent amino acid residues in the S2 pocket of falcipain-3 determine itsspecificity for P2 residues in substrates | Kolla VK, Prasad R, ..., Sijwali PS | 10.1016/j.molbiopara.2015.09.005 |
| 16095562 | Characterization of amino acid variation at strategic positions in parasite andhuman proteases for selective inhibition of falcipains in Plasmodium falciparum | Goh LL, Sim TS | 10.1016/j.bbrc.2005.07.147 |
| 16722625 | Novel peptidomimetic cysteine protease inhibitors as potential antimalarialagents | Micale N, Kozikowski AP, ..., Chishti AH | 10.1021/jm060405f |
| 29659945 | Plasmodium falciparum Falcipain-2a Polymorphisms in Southeast Asia and TheirAssociation With Artemisinin Resistance | Siddiqui FA, Cabrera M, ..., Cui L | 10.1093/infdis/jiy188 |
| 15369788 | Homology modeling and mutagenesis analyses of Plasmodium falciparum falcipain 2A:implications for rational drug design | Goh LL, Sim TS | 10.1016/j.bbrc.2004.08.130 |