Plasmodium falciparum proteasome subunit beta type-5

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Peptidases and proteinases (Plasmodium spp.)
Plasmodium falciparum proteasome subunit beta type-5

Target not currently curated in GtoImmuPdb

Target has curated data in GtoMPdb

Target id: 3088

Nomenclature: Plasmodium falciparum proteasome subunit beta type-5

Family: Peptidases and proteinases (Plasmodium spp.)

Gene and Protein Information
Species	TM	AA	Chromosomal Location	Gene Symbol	Gene Name	Reference
Plasmodium falciparum 3D7	-	271		PF3D7_1011400	proteasome subunit beta type-5
Gene and Protein Information Comments
Our proteasome 20S subunit beta 5 summary page provides information about the homologous human target.

Previous and Unofficial Names
PF3D7_1011400 \| Pf3D7_10_v3:440,646..442,154(-) \| PF10_0111

Previous and Unofficial Names

PF3D7_1011400 | Pf3D7_10_v3:440,646..442,154(-) | PF10_0111

Database Links
Alphafold	Q8IJT1 (Pf3D7)
PlasmoDB	PF3D7_1011400 (Pf3D7)
UniProtKB	Q8IJT1 (Pf3D7)

Download all structure-activity data for this target as a CSV file go icon to follow link

Inhibitors

Key to terms and symbols

View all chemical structures

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Ligand		Sp.	Action	Value	Parameter	Reference
bortezomib		Pf Plasmodium falciparum P. falciparum (Pf) is one of five protozoan parasite species of the genus Plasmodium that cause malaria in humans. Pf is responsible for the majority of malaria related deaths and is the most prevalent species in sub-Saharan Africa. ✖	Inhibition	7.3	pIC₅₀	12
⤷	pIC₅₀ 7.3 (IC₅₀ 5.3x10^-8 M) Fluorogenic peptide assay used to assess purified Pf20S proteasome activity [12]
WLL-vs		Pf Plasmodium falciparum P. falciparum (Pf) is one of five protozoan parasite species of the genus Plasmodium that cause malaria in humans. Pf is responsible for the majority of malaria related deaths and is the most prevalent species in sub-Saharan Africa. ✖	Inhibition	6.1	pIC₅₀	9
⤷	pIC₅₀ 6.1 (IC₅₀ 8x10^-7 M) [9]

Whole Organism Assay Data Linked to This Target

Key to terms and symbols

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Ligand		Sp.	Assay description	Type	Action	Value	Parameter	Reference
WLL-vs		Pf Plasmodium falciparum P. falciparum (Pf) is one of five protozoan parasite species of the genus Plasmodium that cause malaria in humans. Pf is responsible for the majority of malaria related deaths and is the most prevalent species in sub-Saharan Africa. ✖	Parasite growth inhibition assay	-	-	8.2	pEC₅₀	13
⤷	pEC₅₀ 8.2 (EC₅₀ 6x10^-9 M) [13] Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
analog 18 [PMID: 28696697]		PfDd2 Plasmodium falciparum Dd2 P. falciparum strain Dd2 (PfDd2) is a clone derived from PfW2, following continuous culture in mefloquine. PfW2 was cloned from the Indochina III/CDC isolate, originally derived from a Laotian patient who failed chloroquine therapy. PfDd2 can be obtained from the Malaria Research and Reference Reagent Resource Center (MR4) and is reported to be resistant to chloroquine, pyrimethamine and mefloquine. ✖	Parasite growth inhibition assay	-	-	8.5	pIC₅₀	8
⤷	pIC₅₀ 8.5 (IC₅₀ 3.27x10^-9 M) SYBR Green I assay (72h) [8] Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
bortezomib		Pf3D7 Plasmodium falciparum 3D7 P. falciparum strain 3D7 (Pf3D7) was derived from isolate NF54 by limiting dilution. The complete genome of Pf3D7 has been sequenced (GenBank: LN999946.1). Pf3D7 can be obtained from the European Malaria Reagent Repository or the Malaria Research and Reference Reagent Resource Center (MR4) and is sensitive to a panel of antimalarial compounds including chloroquine and pyrimethamine. ✖	Parasite growth inhibition assay	-	-	7.5	pIC₅₀	10
⤷	pIC₅₀ 7.5 (IC₅₀ 3.1x10^-8 M) [³H]-hypoxanthine incorporation [10] Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
bortezomib		PfHB3 Plasmodium falciparum HB3 P. falciparum strain HB3 (PfHB3) was cloned from the Honduras I/CDC strain, originally isolated from a patient in Choluteca, Honduras, during an outbreak of urban malaria in January 1980. PfHB3 can be obtained from the European Malaria Reagent Repository or the Malaria Research and Reference Reagent Resource Center (MR4) and is reported to be chloroquine sensitive. ✖	Parasite growth inhibition assay	-	-	7.5	pIC₅₀	10
⤷	pIC₅₀ 7.5 (IC₅₀ 3.1x10^-8 M) [³H]-hypoxanthine incorporation [10] Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
bortezomib		PfDd2 Plasmodium falciparum Dd2 P. falciparum strain Dd2 (PfDd2) is a clone derived from PfW2, following continuous culture in mefloquine. PfW2 was cloned from the Indochina III/CDC isolate, originally derived from a Laotian patient who failed chloroquine therapy. PfDd2 can be obtained from the Malaria Research and Reference Reagent Resource Center (MR4) and is reported to be resistant to chloroquine, pyrimethamine and mefloquine. ✖	Parasite growth inhibition assay	-	-	7.4	pIC₅₀	10
⤷	pIC₅₀ 7.4 (IC₅₀ 3.7x10^-8 M) [³H]-hypoxanthine incorporation [10] Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
bortezomib		PfW2 Plasmodium falciparum W2 P. falciparum strain W2 (PfW2) was cloned from the Indochina III/CDC isolate, originally derived from a Laotian patient who failed chloroquine therapy. PfW2 can be obtained from the European Malaria Reagent Repository or the Malaria Research and Reference Reagent Resource Center (MR4) and is reported to be resistant to chloroquine and susceptible to mefloquine. ✖	Parasite growth inhibition assay	-	-	7.4	pIC₅₀	10
⤷	pIC₅₀ 7.4 (IC₅₀ 4.3x10^-8 M) [³H]-hypoxanthine incorporation [10] Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
analog 18 [PMID: 28696697]		PfNF54 Plasmodium falciparum NF54 P. falciparum strain NF54 (PfNF54) was derived from a patient who had never left the Netherlands. PfNF54 can be obtained from the European Malaria Reagent Repository or the Malaria Research and Reference Reagent Resource Center (MR4) and is sensitive to a panel of antimalarial compounds including chloroquine and pyrimethamine. ✖	Parasite late stage (V) gametocyte assay	-	-	6.9	pIC₅₀	8
⤷	pIC₅₀ 6.9 (IC₅₀ 1.3x10^-7 M) [8]

Malaria Pharmacology Comments
The eukaryotic 26S proteasome is a highly conserved, multi-subunit protease complex that is involved in diverse cellular processes [2]. It consists of a 20S catalytic core capped at one or both ends by 19S regulatory complexes. A recent study has elucidated the structure of the P. falciparum 20S catalytic core (PDB ID: 5FMG) which is comprised of the proteolytic β1 (caspase-like), β2 (trypsin-like), and β5 (chymotrysin-like) subunits [9]. Functional studies performed in S. cerevisiae suggest that of the three subunits, β5 shows the highest involvement in protein degradation and is therefeore most attractive as a drug target [1,6]. Proteasome inhibitors have been shown to have potential as antimalarial therapies that are effective against multiple stages of the P. falciparum lifecycle [3,5] and that demonstrate synergy with artemisinin-based medicines [4], but have been precluded from clinical development because of low species selectivity. Next-generation proteasome inhibitors that target the β2 and β5 subunits of the P. falciparum 20S core have been developed and these exhibit improved selectivity for the malaria parasite [7,9,11].

Malaria Pharmacology Comments

The eukaryotic 26S proteasome is a highly conserved, multi-subunit protease complex that is involved in diverse cellular processes [2]. It consists of a 20S catalytic core capped at one or both ends by 19S regulatory complexes. A recent study has elucidated the structure of the P. falciparum 20S catalytic core (PDB ID: 5FMG) which is comprised of the proteolytic β1 (caspase-like), β2 (trypsin-like), and β5 (chymotrysin-like) subunits [9]. Functional studies performed in S. cerevisiae suggest that of the three subunits, β5 shows the highest involvement in protein degradation and is therefeore most attractive as a drug target [1,6].
Proteasome inhibitors have been shown to have potential as antimalarial therapies that are effective against multiple stages of the P. falciparum lifecycle [3,5] and that demonstrate synergy with artemisinin-based medicines [4], but have been precluded from clinical development because of low species selectivity. Next-generation proteasome inhibitors that target the β2 and β5 subunits of the P. falciparum 20S core have been developed and these exhibit improved selectivity for the malaria parasite [7,9,11].

References

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1. Arendt CS, Hochstrasser M. (1997) Identification of the yeast 20S proteasome catalytic centers and subunit interactions required for active-site formation. Proc Natl Acad Sci U S A, 94 (14): 7156-61. [PMID:9207060]

2. Coux O, Tanaka K, Goldberg AL. (1996) Structure and functions of the 20S and 26S proteasomes. Annu Rev Biochem, 65: 801-47. [PMID:8811196]

3. Czesny B, Goshu S, Cook JL, Williamson KC. (2009) The proteasome inhibitor epoxomicin has potent Plasmodium falciparum gametocytocidal activity. Antimicrob Agents Chemother, 53 (10): 4080-5. [PMID:19651911]

4. Dogovski C, Xie SC, Burgio G, Bridgford J, Mok S, McCaw JM, Chotivanich K, Kenny S, Gnädig N, Straimer J et al.. (2015) Targeting the cell stress response of Plasmodium falciparum to overcome artemisinin resistance. PLoS Biol, 13 (4): e1002132. [PMID:25901609]

5. Gantt SM, Myung JM, Briones MR, Li WD, Corey EJ, Omura S, Nussenzweig V, Sinnis P. (1998) Proteasome inhibitors block development of Plasmodium spp. Antimicrob Agents Chemother, 42 (10): 2731-8. [PMID:9756786]

6. Heinemeyer W, Fischer M, Krimmer T, Stachon U, Wolf DH. (1997) The active sites of the eukaryotic 20 S proteasome and their involvement in subunit precursor processing. J Biol Chem, 272 (40): 25200-9. [PMID:9312134]

7. Kirkman LA, Zhan W, Visone J, Dziedziech A, Singh PK, Fan H, Tong X, Bruzual I, Hara R, Kawasaki M et al.. (2018) Antimalarial proteasome inhibitor reveals collateral sensitivity from intersubunit interactions and fitness cost of resistance. Proc Natl Acad Sci USA, 115 (29): E6863-E6870. [PMID:29967165]

8. LaMonte GM, Almaliti J, Bibo-Verdugo B, Keller L, Zou BY, Yang J, Antonova-Koch Y, Orjuela-Sanchez P, Boyle CA, Vigil E et al.. (2017) Development of a Potent Inhibitor of the Plasmodium Proteasome with Reduced Mammalian Toxicity. J Med Chem, 60 (15): 6721-6732. [PMID:28696697]

9. Li H, O'Donoghue AJ, van der Linden WA, Xie SC, Yoo E, Foe IT, Tilley L, Craik CS, da Fonseca PC, Bogyo M. (2016) Structure- and function-based design of Plasmodium-selective proteasome inhibitors. Nature, 530 (7589): 233-6. [PMID:26863983]

10. Reynolds JM, El Bissati K, Brandenburg J, Günzl A, Mamoun CB. (2007) Antimalarial activity of the anticancer and proteasome inhibitor bortezomib and its analog ZL3B. BMC Clin Pharmacol, 7: 13. [PMID:17956613]

11. Stokes BH, Yoo E, Murithi JM, Luth MR, Afanasyev P, da Fonseca PCA, Winzeler EA, Ng CL, Bogyo M, Fidock DA. (2019) Covalent Plasmodium falciparum-selective proteasome inhibitors exhibit a low propensity for generating resistance in vitro and synergize with multiple antimalarial agents. PLoS Pathog, 15 (6): e1007722. [PMID:31170268]

12. Xie SC, Gillett DL, Spillman NJ, Tsu C, Luth MR, Ottilie S, Duffy S, Gould AE, Hales P, Seager BA et al.. (2018) Target Validation and Identification of Novel Boronate Inhibitors of the Plasmodium falciparum Proteasome. J Med Chem, 61 (22): 10053-10066. [PMID:30373366]

13. Yoo E, Stokes BH, de Jong H, Vanaerschot M, Kumar T, Lawrence N, Njoroge M, Garcia A, Van der Westhuyzen R, Momper JD et al.. (2018) Defining the Determinants of Specificity of Plasmodium Proteasome Inhibitors. J Am Chem Soc, 140 (36): 11424-11437. [PMID:30107725]

How to cite this page

Peptidases and proteinases (Plasmodium spp.): Plasmodium falciparum proteasome subunit beta type-5. Last modified on 12/10/2021. Accessed on 19/04/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=3088.