Table 1.
Ninety-two (92) P. falciparum Protease Homologs Predicted From Comparative Genomic Analysis
| Catalytic class | Protease family | Protease nomenclature | Gene ID | Protease homolog with highest BLAST score | Pfam domain structure | AP | |||||||
| Accession (species, protease name) | E-score | ||||||||||||
| Domain ID (name) | E-score | ||||||||||||
| Aspartic | A1 | PM I | PF14_0076 | P39898(P. falciparum, PM I) | 0 | PF00026 (eukaryotic asp protease) | 1.5e-59 | + | |||||
| PM II | PF14_0077 | P46925(P. falciparum, PM II) | 0 | PF00026 (eukaryotic asp protease) | 8.9e-52 | − | |||||||
| HAP(PM III) | PF14_0078 | CAB40630 (P. falciparum, HAP) | 0 | PF00026 (eukaryotic asp protease) | 3.3e-30 | + | |||||||
| PM IV | PF14_0075 | AAC15794 (P. malariae, PM) | 0 | PF00026 (eukaryotic asp protease) | 5.1e-56 | − | |||||||
| PM V | PF13_0133 | Q05744 (Chicken, Cathepsin D) | 9e-08 | PF00026 (eukaryotic asp protease) | 0.00037 | + | |||||||
| PM VI | PFC0495w | CAC20153 (Eimeria tenella, eimepsin) | 2e-99 | PF00026 (eukaryotic asp protease) | 1.1e-40 | − | |||||||
| PM VII | PF10_0329 | CAC20153 (Eimeria tenella, eimepsin) | 8e-28 | PF00026 (eukaryotic asp protease) | 1.3e-11 | + | |||||||
| PM VIII | PF14_0623 | CAC20153 (Eimeria tenella, eimepsin) | 1e-35 | PF00026 (eukaryotic asp protease) | 7.5e-11 | − | |||||||
| PM IX | PF14_0281 | AAD56283(Pseudopleuronectes americanus, pepsinogen A form IIa) | 1e-33 | PF00026 (eukaryotic asp protease) | 4.5e-26 | − | |||||||
| PM X | PF08_0108 | AAA31096 (Pig, pepsinogen A) | 1e-42 | PF00026 (eukaryotic asp protease) | 2.5e-26 | + | |||||||
| Cysteine | C1 | Falcipain-1 | PF14_0553 | P25805(P. falciparum, falcipain-1) | 0 | PF00112 (Papain family) | 9.5e-92 | − | |||||
| Falcipain-2 | PF11_0165 | AAF63497(P. falciparum, falcipain 2) | 0 | PF00112 (Papain family) | 3.0e-84 | + | |||||||
| Falcipain-3 | PF11_0162 | AAF86352(P. falciparum, falcipain-3) | 0 | PF00112 (Papain family) | 4.8e-79 | − | |||||||
| Papain | PF11_0161 | AAF97809(P. falciparum, Falcipain 2) | 1e-134 | PF00112 (Papain family) | 8.8e-84 | + | |||||||
| DPP I | PFL2290w | AAD02704 (Dog, DPP I) | 5e-30 | PF00112 (Papain family) | 9.9e-16 | − | |||||||
| DPP I | PFD0230c | AAD02704 (Dog, DPP I) | 6e-06 | PF00112 (Papain family) | 2.7e-05 | + | |||||||
| Cathepsin C | PF11_0174 | AAL48191 (Human, Cathepsin C) | 5e-23 | PF00112 (Papain family) | 3.3e-14 | + | |||||||
| SERA | PFB0360c | H71617(P. falciparum, SERA) | 0 | PF00112 (Papain family) | 2.1e-51 | − | |||||||
| SERA | PFB0325c | F71617(P. falciparum, SERA) | 0 | PF00112 (Papain family) | 2.9e-10 | − | |||||||
| SERA | PFB0330c | G71617(P. falciparum, SERA) | 0 | PF00112 (Papain family) | 2.9e-46 | − | |||||||
| SERA | PFB0335c | H71617(P. falciparum, SERA) | 0 | PF00112 (Papain family) | 3.4e-16 | − | |||||||
| SERA | PFB0340c | B71617(P. falciparum, SERA) | 0 | PF00112 (Papain family) | 1.5e-53 | − | |||||||
| SERA | PFB0345c | C71617(P. falciparum, SERA) | 0 | PF00112 (Papain family) | 1.2e-47 | − | |||||||
| SERA | PFB0350c | D71617(P. falciparum, SERA) | 0 | PF00112 (Papain family) | 8.8e-51 | − | |||||||
| SERA | PFB0355c | H71617(P. falciparum, SERA) | 0 | PF00112 (Papain family) | 1.5e-49 | − | |||||||
| Papain | PFI0135c | G71617(P. falciparum, SERA) | 1e-177 | PF00112 (Papain family) | 2.2e-34 | − | |||||||
| C2 | Calpain | MAL13P1.310 | NP_497964 (C. elegans, Calpain) | 2e-35 | PF00648 (Calpain family) | 8.0e-13 | − | ||||||
| C12 | UCH1 | PF14_0577 | BAB47136(Rat, UCH 13) | 5e-31 | PF01088 (UCH 1) | 1.3e-37 | − | ||||||
| UCH1 | PF11_0177 | NP_062508 (Mouse, UCH37) | 6e-30 | PF01088 (UCH 1) | 1.5e-17 | − | |||||||
| C13 | GPI8p transamidase | PF11_0298 | CAB96076(P. falciparum, GPI8p transamidase) | 1e-179 | PF01650 (Peptidase C13) | 2.7e-13 | + | ||||||
| C14 | Metacaspase | PF13_0289 | CAD24804(T. brucei, metacaspase) | 5e-32 | No hits | − | − | ||||||
| C19 | UCH2 | PFA0220w | NP_566486 (Arabidopsis, UBP25) | 1e-12 | PF00442 (UCH2) | 1.2e-09 | − | ||||||
| UCH2 | PFD0165w | O57429(Chicken, UCH2) | 5e-13 | PF00442 (UCH2) PF00443 (UCH2) | 1.9e-06 9.2e-07 | − | |||||||
| UCH2 | PFD0680c | AAG42755(Arabidopsis, UBP14) | 1e-34 | PR00442 (UCH2) | 8.5e-11 | − | |||||||
| UCH2 | PFE1355c | NP_566680 (Arabidopsis, UBP7) | 3e-30 | PF00442 (UCH2) PF00443 (UCH2) | 7.5e-07 1.9e-14 | − | |||||||
| UCH2 | PFE0835w | 094966 (Human, UBP19) | 3e-51 | PF00442 (UCH2) PF00443 (UCH2) | 1.8e-11 1.7e-20 | − | |||||||
| UCH2 | MAL7P1.147 | NP_568171 (Arabidopsis, UBP12) | 1e-54 | PF00442 (UCH2) PF00443 (UCH2) | 3.7e-10 1.9e-16 | − | |||||||
| UCH2 | PFI0225w | AAC68865(Chicken, UBP66) | 1e-18 | PF00442 (UCH2) | 9.9e-23 | − | |||||||
| UCH2 | PF13_0096 | NP_494298 (C. elegans, UBP) | 5e-58 | PF00442 (UCH2) PF00443 (UCH2) | 4.3e-08 0.00048 | − | |||||||
| UCH2 | PF14_0145 | T41069(Fission yeast, UCH) | 1e-20 | PF00442 (UCH2) PF00443 (UCH2) | 4.8e-05 3.1e-08 | − | |||||||
| C48 | Sumo1 protease | PFL1635w | XP_128236 (Mouse, SUMO protease) | 7e-33 | PF02902 (Ulp1 protease) | 2.3e-38 | − | ||||||
| Ulp2 peptidase | MAL8P1.157 | O13769 (Fission yeast, Ulp2) | 1e-06 | PF02902 (Ulp1 protease) | 9.2e-07 | − | |||||||
| C56 | DJ-1 peptidase | MAL6P1.153 | BAB79527 (Chicken, DJ-1 protease) | 6e-16 | PF01965 (DJ-1/PfpI protease) | 8.1e-18 | − | ||||||
| Metallo | M1 | AMPN | MAL13P1.56 | O96935(P. falciparum, M1 peptidase) | 0 | PF01433 (Peptidase family M1) | 6.2e-74 | − | |||||
| M3 | Dcp | PF10-0058 | NP_601500 (Corynebacterium glutamicum, Zn-dependent peptidases) | 1e-04 | PF01432 (Peptidase family M3) | 6.4e-10 | − | ||||||
| Neurolysin | MAL13P1.184 | Q02038(Pig, neurolysin) | 4e-09 | PF01432 (Peptidase family M3) | 1.8e-07 | − | |||||||
| M16 | MPPa | PFE1155c | AAF00541(Toxoplama gondii, MPPa) | 1e-109 | PF00675 (Insulinase, family M16) | 6.4e-19 | − | ||||||
| MPPb | PFI1625c | AAK51086(Avicennia marina, MPPb) | 1e-108 | PF00675 (Insulinase, family M16) | 1.3e-55 | − | |||||||
| M16 peptidase | PF11_0189 | NP_593544 (yeast metallopeptidase) | 1e-29 | PF00675 (Insulinase, family M16) | 0.0076 | − | |||||||
| Insulysin | PF11_0226 | P35559(Rat, Insulysin) | 3e-10 | PF00675 (Insulinase, family M16) | 1.0e-05 | − | |||||||
| Falcilysin | PF13_0322 | AAF06062(P. falciparum, falcilysin) | 0 | PF00675 (Insulinase, family M16) | 0.19 | − | |||||||
| Pitrilysin | PF14_0382 | T06521(Pea pitrilysin) | 5e-27 | PF00675 (Insulinase, family M16) | 0.0018 | − | |||||||
| M17 | AMPL | PF14_0439 | NP_194821 (Arabidopsis AMPL) | 2e-83 | PF00883 (Peptidase family M17) | 9e-150 | − | ||||||
| M18 | DNPE | PFI1570c | AAL16034(Coccidioides immitis, DNPE) | 7e-55 | PF02127 (Peptidase family M18) | 3.6e-31 | − | ||||||
| M22 | GCP | PF10_0299 | NP_194003 (Arabidopsis GCP) | 4e-54 | PF00814 (Glycoprotease family) | 1.3e-53 | − | ||||||
| M24A | AMPM | PFE1360c | AAG33975(Arabidopsis, AMPM) | 3e-61 | PF00557 (Peptidase family M24) | 2.5e-48 | − | ||||||
| AMPM | MAL8P1.140 | P53582(Human, AMP1) | 1e-26 | PF00557 (Peptidase family M24) | 9.1e-06 | + | |||||||
| AMPM | PF10_0150 | P53582(Human, AMP1) | 1e-104 | PF00557 (Peptidase family M24) | 5.4e-67 | − | |||||||
| AMPM | PF14_0327 | AAL76285(P. falciparum, AMPM2) | 0 | PF00557 (Peptidase family M24) | 8.7e-50 | − | |||||||
| M24B | AMPP | PF14_0517 | CAC59823(Tomato, AMPP) | 3e-85 | PF00557 (Peptidase family M24) | 2.8e-07 | − | ||||||
| M41 | Ftsh peptidase | PF11_0203 | NP_006787 (Human, AFG3) | 1e-163 | PF01434 (Peptidase family M41) PF00004 (AAA) | 2.6e-80 4.0e-80 | − | ||||||
| Ftsh peptidase | PFL1925w | NP_422020 (Caulobacter crescentus, cell division protein FtsH) | 1e-122 | PF01434 (Peptidase family M41) PF00004 (AAA) | 3.2e-93 5.7e-90 | − | |||||||
| Ftsh peptidase | PF14_0616 | NP_568787 (Arabidopsis, FtsH) | 1e-141 | PF01434 (Peptidase family M41) | 2.7e-69 | − | |||||||
| PF00004 (AAA | 9.9e-85 | ||||||||||||
| Serine | S1 | DegP protease | MAL8P1.126 | NP_568577 (Arabidopsis, DegP protease) | 4e-52 | PF00089 (Trypsin) | 1.8e-07 | − | |||||
| Neurotypsin-like | PF14_0067 | BAA23986 (Mouse, neurotrypsin) | 7e-17 | PF01477 (PLAT/LH2 domain) | 1.4e-09 | − | |||||||
| S8 | Subtilase-1 | PFE0370c | CAA05627 (P. falciparum, subtilase-1) | 0 | PF00082 (Subtilase family) | 2.6e-15 | − | ||||||
| Subtilase-2 | PF11_0381 | CAB43592 (P. falciparum, Subtilase-2) | 0 | PF00082 (Subtilase family) | 1.6e-35 | − | |||||||
| Subtilase-like | PFE0355c | CAA05627 (P. falciparum, subtilase-1) | 2e-22 | PF00082 (Subtilase family) | 5.6e-19 | − | |||||||
| S9 | ACPH | PFC0950c | P13676 (Rat, ACPH) | 1e-17 | PF00561 (α/β hydrolase fold) | 0.021 | − | ||||||
| S14 | Clp | PFC0310c | P54416 (Synechocystis sp Clp1) | 6e-42 | PF00574 (Clp protease) | 1.8e-65 | + | ||||||
| Clp | PF14_0348 | NP_567521 (Arabidopsis clp) | 2e-29 | PF00574 (Clp protease) | 3.0e-37 | + | |||||||
| ClpB | PF08_0063 | AAA88777 (P. berghei, ClpB) | 0 | PF00574 (Clp protease) | 1.0-16 | − | |||||||
| ClpB | PF14_0063 | NP_439019 (Haemophilus influenzae ClpB) | 3e-95 | PF00004 (AAA) | 7.1e-06 | + | |||||||
| ClpC | PF11_0175 | T07807 (Soybean clp) | 1e-154 | PF00574 (Clp protease) | 0.0026 | − | |||||||
| S16 | Lon | PF14_0147 | AAA61616 (Human, Lon) | 4e-53 | PF00004 (AAA) | 1.4e-17 | − | ||||||
| S26A | SP1 | PF13_0118 | T40251 (Fission yeast, IMP) | 2e-10 | PF00461 (Signal peptidase) | 0.055 | − | ||||||
| S26B | signalase | MAL13P1.167 | AAD19813 (Drosophila, signalase SPC21) | 3e-46 | PF00461 (Signal peptidase) | 3.7e-19 | − | ||||||
| S54 | Rhomboid | PFE0340c | NP_523536 (Drosophila, rhomboid-5) | 6e-07 | PF01694 (Rhomboid family) | 5.5e-27 | − | ||||||
| Rhomboid | MAL8P1.16 | NP_654179 (Bacillus anthracis rhomboid) | 2e-07 | PF01694 (Rhomboid family) | 3.8e-27 | − | |||||||
| Threonine | T1 | Proteasome α1 | PF14_0716 | P92188 (Trypanosoma cruzi,α1) | 8e-57 | PF00227 (Proteasome) | 7.7e-39 | − | |||||
| Proteasome α2 | MAL6P1.88 | O9LSU2 (Rice, α2) | 3e-73 | PF00227 (Proteasome) | 1.4e-49 | − | |||||||
| Proteasome α3 | PFC0745c | O24362 (Spinach, α3) | 3e-44 | PF00227 (Proteasome) | 2.0e-21 | − | |||||||
| Proteasome α4 | PF13_0282 | O81148 (Arabidopsis,α4) | 1e-64 | PF00227 (Proteasome) | 7.4e-47 | − | |||||||
| Proteasome α5 | PF07_0112 | Q95083 (Drosophila,α5) | 4e-70 | PF00227 (Proteasome) | 2.1e-47 | − | |||||||
| Proteasome α6 | MAL8P1.128 | Q9LSU3 (Rice, α6) | 4e-52 | PF00227 (Proteasome) | 2.8e-30 | − | |||||||
| Proteasome α7 | MAL13P1.270 | O24616 (Arabidopsis,α7) | 3e-66 | PF00227 (Proteasome) | 8.5e-43 | − | |||||||
| Proteasome β1 | PFE0915c | P42742 (Arabidopsis,β1) | 3e-44 | PF00227 (Proteasome) | 1.2e-39 | − | |||||||
| Proteasome β2 | MAL8P1.142 | Q9LST6 (Rice, β2) | 1e-35 | PF00227 (Proteasome) | 2.9e-17 | − | |||||||
| Proteasome β3 | PFA0400c | P25451 (Yeast, β3) | 8e-35 | PF00227 (Proteasome) | 1.5e-18 | − | |||||||
| Proteasome β4 | PF14_0676 | XP_079788 (Drosophila,β4) | 4e-36 | PF00227 (Proteasome) | 1.4e-22 | − | |||||||
| Proteasome β6 | PFI1545c | O43063 (Fission yeast, β6) | 4e-26 | PF00227 (Proteasome) | 1.1e-10 | − | |||||||
| Proteasome β7 | PF13_0156 | Q99436 (Human, β7) | 1e-74 | PF00227 (Proteasome) | 5.5e-35 | − | |||||||
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The cut-off criteria of E-score ≤ 1e-04 was employed to define protease homologs. The nomenclature of the protease family is: A1 (pepsin), C1 (papain), C2 (calpain), C12 (ubiquitin carboxyl-terminal hydrolase, family 1, UCH1), C13 (hemoglobinase), C14 (caspase), C19 (ubiquitin C-terminal hydrolase family 2, UCH2), C48 (Ubiquitin-like protease, Ulp), C56 (DJ-1 peptidase), M1 (alanyl aminopeptidase, AMPN), M3 (thimet oligopeptidase), M16 (pitrilysin and mitochondrial processing peptidase, MPP), M17 (leucyl aminopeptidase, AMPL), M18 (aspartyl aminopeptidase, DNPE), M22 (O-sialoglycoprotein endopeptidase, GCP), M24A (methionyl aminopeptidase, AMPM), M24B (X-Pro dipeptidase, AMPP), M41 (FtsH endopeptidase), S1 (trypsin), S8 (subtilsin), S9 (acylaminoacyl-peptidase, ACPH), S14 (clp), S16 (Lon protease, La), S26A (prokarytotic signal peptidase I, SP1), S26B (signalase), S54 (rhomboid), and T1 (threonine endopeptidase).
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Abbreviations for proteases include: PM, plasmepsin; DPPI, dipeptidyl-peptidase I; UBP, ubiquitin-specific protease; IMP, mitochondrial inner membrane peptidase; SPC21, microsomal signal peptide 21 kDa subunit.
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Previously characterized proteases with proteolytic activity are highlighted in bold. The 23 proteases predicted by the official annotation published in PlasmoDB are highlighted in italic.
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Potential candidate proteases Calpain, Metacaspase, and Signal peptidase I (SP1) are highlighted in bold italic.
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↵± indicate the gene is predicted to contain/not contain an apicoplast transit peptide.
