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[v]
Accession (species, protease name) E-score
Domain ID (name) E-score
AsparticA1 PM I PF14_0076 P39898(P. falciparum, PM I)0PF00026 (eukaryotic  asp protease)1.5e-59+
PM II PF14_0077 P46925(P. falciparum, PM II)0PF00026 (eukaryotic  asp protease)8.9e-52−
HAP(PM III) PF14_0078 CAB40630 (P. falciparum, HAP)0PF00026 (eukaryotic  asp protease)3.3e-30+
PM IV PF14_0075 AAC15794 (P. malariae, PM)0PF00026 (eukaryotic  asp protease)5.1e-56−
PM V PF13_0133 Q05744 (Chicken, Cathepsin D)9e-08PF00026 (eukaryotic  asp protease)0.00037+
PM VI PFC0495w CAC20153 (Eimeria tenella,  eimepsin)2e-99PF00026 (eukaryotic  asp protease)1.1e-40−
PM VII PF10_0329 CAC20153 (Eimeria tenella,  eimepsin)8e-28PF00026 (eukaryotic  asp protease)1.3e-11+
PM VIIIPF14_0623 CAC20153 (Eimeria tenella,  eimepsin)1e-35PF00026 (eukaryotic  asp protease)7.5e-11−
PM IX PF14_0281 AAD56283(Pseudopleuronectes  americanus, pepsinogen A  form IIa)1e-33PF00026 (eukaryotic  asp protease)4.5e-26−
PM XPF08_0108 AAA31096 (Pig, pepsinogen A)1e-42PF00026 (eukaryotic  asp protease)2.5e-26+
CysteineC1 Falcipain-1 PF14_0553 P25805(P. falciparum,  falcipain-1)0PF00112 (Papain  family)9.5e-92−
Falcipain-2 PF11_0165 AAF63497(P. falciparum,  falcipain 2)0PF00112 (Papain  family)3.0e-84+
Falcipain-3 PF11_0162 AAF86352(P. falciparum,  falcipain-3)0PF00112 (Papain  family)4.8e-79−
PapainPF11_0161 AAF97809(P. falciparum,  Falcipain 2)1e-134PF00112 (Papain  family)8.8e-84+
DPP IPFL2290w AAD02704 (Dog, DPP I)5e-30PF00112 (Papain  family)9.9e-16−
DPP I PFD0230c AAD02704 (Dog, DPP I)6e-06PF00112 (Papain  family)2.7e-05+
Cathepsin CPF11_0174 AAL48191 (Human,  Cathepsin C)5e-23PF00112 (Papain  family)3.3e-14+
SERA PFB0360c H71617(P. falciparum, SERA)0PF00112 (Papain  family)2.1e-51−
SERA PFB0325c F71617(P. falciparum, SERA)0PF00112 (Papain  family)2.9e-10−
SERA PFB0330c G71617(P. falciparum, SERA)0PF00112 (Papain  family)2.9e-46−
SERA PFB0335c H71617(P. falciparum, SERA)0PF00112 (Papain  family)3.4e-16−
SERA PFB0340c B71617(P. falciparum, SERA)0PF00112 (Papain  family)1.5e-53−
SERA PFB0345c C71617(P. falciparum, SERA)0PF00112 (Papain  family)1.2e-47−
SERA PFB0350c D71617(P. falciparum, SERA)0PF00112 (Papain  family)8.8e-51−
SERA PFB0355c H71617(P. falciparum, SERA)0PF00112 (Papain  family)1.5e-49−
Papain PFI0135c G71617(P. falciparum, SERA)1e-177PF00112 (Papain  family)2.2e-34−
C2 Calpain MAL13P1.310 NP_497964 (C. elegans,  Calpain)2e-35PF00648 (Calpain  family)8.0e-13−
C12UCH1PF14_0577 BAB47136(Rat, UCH 13)5e-31PF01088 (UCH 1)1.3e-37−
UCH1PF11_0177NP_062508 (Mouse, UCH37)6e-30PF01088 (UCH 1)1.5e-17−
C13GPI8p  transamidasePF11_0298 CAB96076(P. falciparum,  GPI8p transamidase)1e-179PF01650 (Peptidase  C13)2.7e-13+
C14 Metacaspase PF13_0289 CAD24804(T. brucei,  metacaspase)5e-32No hits−−
C19UCH2PFA0220wNP_566486 (Arabidopsis,  UBP25)1e-12PF00442 (UCH2)1.2e-09−
UCH2 PFD0165w O57429(Chicken, UCH2)5e-13PF00442 (UCH2) PF00443 (UCH2)1.9e-06 9.2e-07−
UCH2PFD0680c AAG42755(Arabidopsis,  UBP14)1e-34PR00442 (UCH2)8.5e-11−
UCH2PFE1355cNP_566680 (Arabidopsis,  UBP7)3e-30PF00442 (UCH2) PF00443 (UCH2)7.5e-07 1.9e-14−
UCH2PFE0835w094966 (Human, UBP19)3e-51PF00442 (UCH2) PF00443 (UCH2)1.8e-11 1.7e-20−
UCH2MAL7P1.147NP_568171 (Arabidopsis,  UBP12)1e-54PF00442 (UCH2) PF00443 (UCH2)3.7e-10 1.9e-16−
UCH2PFI0225w AAC68865(Chicken, UBP66)1e-18PF00442 (UCH2)9.9e-23−
UCH2PF13_0096NP_494298 (C. elegans, UBP)5e-58PF00442 (UCH2) PF00443 (UCH2)4.3e-08 0.00048−
UCH2PF14_0145 T41069(Fission yeast, UCH)1e-20PF00442 (UCH2) PF00443 (UCH2)4.8e-05 3.1e-08−
C48Sumo1 proteasePFL1635wXP_128236 (Mouse, SUMO  protease)7e-33PF02902 (Ulp1  protease)2.3e-38−
Ulp2 peptidaseMAL8P1.157 O13769 (Fission yeast, Ulp2)1e-06PF02902 (Ulp1  protease)9.2e-07−
C56DJ-1 peptidaseMAL6P1.153 BAB79527 (Chicken, DJ-1  protease)6e-16PF01965 (DJ-1/PfpI  protease)8.1e-18−
MetalloM1 AMPN MAL13P1.56 O96935(P. falciparum,  M1 peptidase)0PF01433 (Peptidase  family M1)6.2e-74−
M3DcpPF10-0058NP_601500 (Corynebacterium  glutamicum, Zn-dependent  peptidases)1e-04PF01432 (Peptidase  family M3)6.4e-10−
NeurolysinMAL13P1.184 Q02038(Pig, neurolysin)4e-09PF01432 (Peptidase  family M3)1.8e-07−
M16MPPaPFE1155c AAF00541(Toxoplama gondii,  MPPa)1e-109PF00675 (Insulinase,  family M16)6.4e-19−
MPPbPFI1625c AAK51086(Avicennia  marina, MPPb)1e-108PF00675 (Insulinase,  family M16)1.3e-55−
M16 peptidasePF11_0189NP_593544 (yeast  metallopeptidase)1e-29PF00675 (Insulinase,  family M16)0.0076−
InsulysinPF11_0226 P35559(Rat, Insulysin)3e-10PF00675 (Insulinase,  family M16)1.0e-05−
FalcilysinPF13_0322 AAF06062(P. falciparum,   falcilysin)0PF00675 (Insulinase,  family M16)0.19−
PitrilysinPF14_0382 T06521(Pea pitrilysin)5e-27PF00675 (Insulinase,  family M16)0.0018−
M17AMPLPF14_0439NP_194821 (Arabidopsis  AMPL)2e-83PF00883 (Peptidase  family M17)9e-150−
M18DNPEPFI1570c AAL16034(Coccidioides  immitis, DNPE)7e-55PF02127 (Peptidase  family M18)3.6e-31−
M22GCPPF10_0299NP_194003 (Arabidopsis  GCP)4e-54PF00814 (Glycoprotease family)1.3e-53−
M24AAMPMPFE1360c AAG33975(Arabidopsis,  AMPM)3e-61PF00557 (Peptidase  family M24)2.5e-48−
AMPMMAL8P1.140 P53582(Human, AMP1)1e-26PF00557 (Peptidase  family M24)9.1e-06+
AMPMPF10_0150 P53582(Human, AMP1)1e-104PF00557 (Peptidase  family M24)5.4e-67−
AMPM PF14_0327 AAL76285(P. falciparum,  AMPM2)0PF00557 (Peptidase  family M24)8.7e-50−
M24BAMPPPF14_0517 CAC59823(Tomato, AMPP)3e-85PF00557 (Peptidase  family M24)2.8e-07−
M41Ftsh peptidasePF11_0203NP_006787 (Human, AFG3)1e-163PF01434 (Peptidase  family M41) PF00004 (AAA)2.6e-80 4.0e-80−
Ftsh peptidasePFL1925wNP_422020 (Caulobacter  crescentus, cell division  protein FtsH)1e-122PF01434 (Peptidase  family M41) PF00004 (AAA)3.2e-93 5.7e-90−
Ftsh peptidasePF14_0616NP_568787 (Arabidopsis, FtsH)1e-141PF01434 (Peptidase family M41)2.7e-69−
PF00004 (AAA9.9e-85
SerineS1DegP protease MAL8P1.126 NP_568577 (Arabidopsis, DegP protease)4e-52PF00089 (Trypsin)1.8e-07−
Neurotypsin-likePF14_0067BAA23986 (Mouse, neurotrypsin)7e-17PF01477 (PLAT/LH2 domain)1.4e-09−
S8 Subtilase-1 PFE0370c CAA05627 (P. falciparum, subtilase-1)0PF00082 (Subtilase family)2.6e-15−
Subtilase-2 PF11_0381 CAB43592 (P. falciparum, Subtilase-2)0PF00082 (Subtilase family)1.6e-35−
Subtilase-like PFE0355c CAA05627 (P. falciparum, subtilase-1)2e-22PF00082 (Subtilase family)5.6e-19−
S9ACPHPFC0950cP13676 (Rat, ACPH)1e-17PF00561 (α/β hydrolase fold)0.021−
S14Clp PFC0310c P54416 (Synechocystis sp Clp1)6e-42PF00574 (Clp protease)1.8e-65+
Clp PF14_0348 NP_567521 (Arabidopsis clp)2e-29PF00574 (Clp protease)3.0e-37+
ClpBPF08_0063AAA88777 (P. berghei, ClpB)0PF00574 (Clp protease)1.0-16−
ClpB PF14_0063 NP_439019 (Haemophilus influenzae ClpB)3e-95PF00004 (AAA)7.1e-06+
ClpCPF11_0175T07807 (Soybean clp)1e-154PF00574 (Clp protease)0.0026−
S16Lon PF14_0147 AAA61616 (Human, Lon)4e-53PF00004 (AAA)1.4e-17−
S26A SP1 PF13_0118 T40251 (Fission yeast, IMP)2e-10PF00461 (Signal peptidase)0.055−
S26BsignalaseMAL13P1.167AAD19813 (Drosophila, signalase SPC21)3e-46PF00461 (Signal peptidase)3.7e-19−
S54RhomboidPFE0340cNP_523536 (Drosophila, rhomboid-5)6e-07PF01694 (Rhomboid family)5.5e-27−
RhomboidMAL8P1.16NP_654179 (Bacillus anthracis rhomboid)2e-07PF01694 (Rhomboid family)3.8e-27−
ThreonineT1Proteasome α1PF14_0716P92188 (Trypanosoma cruzi,α1)8e-57PF00227 (Proteasome)7.7e-39−
Proteasome α2MAL6P1.88O9LSU2 (Rice, α2)3e-73PF00227 (Proteasome)1.4e-49−
Proteasome α3PFC0745cO24362 (Spinach, α3)3e-44PF00227 (Proteasome)2.0e-21−
Proteasome α4PF13_0282O81148 (Arabidopsis,α4)1e-64PF00227 (Proteasome)7.4e-47−
Proteasome α5PF07_0112Q95083 (Drosophila,α5)4e-70PF00227 (Proteasome)2.1e-47−
Proteasome α6MAL8P1.128Q9LSU3 (Rice, α6)4e-52PF00227 (Proteasome)2.8e-30−
Proteasome α7MAL13P1.270O24616 (Arabidopsis,α7)3e-66PF00227 (Proteasome)8.5e-43−
Proteasome β1PFE0915cP42742 (Arabidopsis,β1)3e-44PF00227 (Proteasome)1.2e-39−
Proteasome β2MAL8P1.142Q9LST6 (Rice, β2)1e-35PF00227 (Proteasome)2.9e-17−
Proteasome β3PFA0400cP25451 (Yeast, β3)8e-35PF00227 (Proteasome)1.5e-18−
Proteasome β4PF14_0676XP_079788 (Drosophila,β4)4e-36PF00227 (Proteasome)1.4e-22−
Proteasome β6PFI1545cO43063 (Fission yeast, β6)4e-26PF00227 (Proteasome)1.1e-10−
Proteasome β7PF13_0156Q99436 (Human, β7)1e-74PF00227 (Proteasome)5.5e-35−

[i] 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).

[ii] 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.

[iii] 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.

[iv] Potential candidate proteases Calpain, Metacaspase, and Signal peptidase I (SP1) are highlighted in bold italic.

[v] ± indicate the gene is predicted to contain/not contain an apicoplast transit peptide.