Molecule Information

General Information of the Molecule (ID: Mol01059)

• Name: Putative chloroquine resistance transporter (PVCRT) ,Plasmodium vivax
• Synonyms: Probable transporter cg10; pvcg10; pfcrt ortholog; pvcrt-o; CRT-O; PVX_087980
• Molecule Type: Protein
• Gene Name: CG10
• Gene ID: 5472721
• Sequence:
  MTILKKKKKGSPQITPDERYRELDSHAQNESEIQEDVPISRKIANFLKLAYNEIRENISI
  YLLIIVYLCVCVMNKLLAKRTLKKIGNYSFVTSETHNCICMVVFFALYFMFGRRVMSAKE
  RHRNFGVQFLLISLLDACSVIIAFIGLTRTTGNIQSFVMQLSIPINMFFCFLILRYRYHL
  FNYVGAFIIVVTIAVVEFMLSFETQEENSIVFNLVLIASLIPLSFSNMTREIVFKKYKIN
  ILRLNAVVSFFQIFTSCLMLPMYTLPFLKQINLPFSEIGTNIKNGFRCLFLGQNTIVENC
  GLGMSKMCDDCEGAWKTFIAYSFFNICDNLITSFIIEKFSTMTYTIVSCIQGPAIAIAYY
  FKFLAGDAVMQPRMLDFVTLFGYLFGSIIYRIGNIILEKKRMMEAGNDDDSEGELTNADS
  IITH
• Function: May regulate endogenous transporter.
• Uniprot ID: CRT_PLAVS

Kingdom: N.A.
Phylum: Apicomplexa
Class: Aconoidasida
Order: Haemosporida
Family: Plasmodiidae
Genus: Plasmodium
Species: Plasmodium vivax

Type(s) of Resistant Mechanism of This Molecule

  IDUE: Irregularity in Drug Uptake and Drug Efflux

Drug Resistance Data Categorized by Drug

Approved Drug(s) 2 drug(s) in total

Chloroquine

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Disease Class: Malaria [1]

• Resistant Disease: Malaria [ICD-11: 1F45.0]
• Resistant Drug: Chloroquine
• Molecule Alteration: Missense mutation; p.K10 insertion (c.AAG)
• Experimental Note: Discovered Using In-vivo Testing Model
• Mechanism Description: Mutations in k10 insertion in the Pvcrt-o gene have been identified as a possible molecular marker of CQ resistance in P.vivax.

Disease Class: Malaria [1]

• Resistant Disease: Malaria [ICD-11: 1F45.0]
• Resistant Drug: Chloroquine
• Molecule Alteration: Missense mutation; p.K10 insertion (c.AAG)
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Plasmodium vivax isolates; 5855
• Experiment for Molecule Alteration: Nested PCR
• Mechanism Description: Mutations in k10 insertion in the Pvcrt-o gene have been identified as a possible molecular marker of CQ resistance in P.vivax.

Disease Class: Malaria [2]

• Resistant Disease: Malaria [ICD-11: 1F45.0]
• Resistant Drug: Chloroquine
• Molecule Alteration: Missense mutation; p.S249P
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Yeast CH1305; 4932
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Quantitative Growth Rate assay
• Mechanism Description: It is surprising then that the data presented here suggests a single mutation (S249P in PvCRT isoform CQR3) can increase CQ transport by 32% relative to wild type.

Disease Class: Malaria [3]

• Resistant Disease: Malaria [ICD-11: 1F45.0]
• Resistant Drug: Chloroquine
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Plasmodium vivax strains; 5855
• Mechanism Description: Patients with CQ-resistant P. vivax parasites presented a higher gene expression of pvcrt-o and pvmdr-1 at D0 and DR when compared to the susceptible group. For the CQR patients, median gene expression values at D0 and DR, presented 2.4 fold (95% CI: 0.96-7.1) and 6.1 fold (95% CI: 3.8-14.3) increase in pvcrt-o levels compared to the susceptible patients at D0 with 0.12 fold (95% CI: 0.034-0.324). Median gene expression for pvmdr-1 presented 2.0 fold (95% CI: 0.95-3.8) and 2.4 fold (95% CI: 0.53-9.1) increase levels at D0 and DR, for the CQR patients versus 0.288 fold (95% CI: 0.068-0.497) for the susceptible patients.

Piperaquine

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Disease Class: Malaria [4]

• Resistant Disease: Malaria [ICD-11: 1F45.0]
• Resistant Drug: Piperaquine
• Molecule Alteration: Missense mutation; p.C350R
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Yeast strain CH1305; 4932
• Experiment for Molecule Alteration: Western blotting analysis
• Mechanism Description: At 300 uM PPQ, C350R/7G8 PfCRT shows a 3.9-fold increased rate of PPQ transport relative to that of 7G8 PfCRT, and F145I/Dd2 PfCRT shows a 2.7-fold increased rate of PPQ transport relative to that of Dd2.

References

• Ref 1: Distribution of Mutations Associated with Antifolate and Chloroquine Resistance among Imported Plasmodium vivax in the State of Qatar. Am J Trop Med Hyg. 2017 Dec;97(6):1797-1803. doi: 10.4269/ajtmh.17-0436. Epub 2017 Sep 28.
• Ref 2: Analysis of Plasmodium vivax Chloroquine Resistance Transporter Mutant Isoforms. Biochemistry. 2017 Oct 17;56(41):5615-5622. doi: 10.1021/acs.biochem.7b00749. Epub 2017 Sep 26.
• Ref 3: Expression levels of pvcrt-o and pvmdr-1 are associated with chloroquine resistance and severe Plasmodium vivax malaria in patients of the Brazilian Amazon. PLoS One. 2014 Aug 26;9(8):e105922. doi: 10.1371/journal.pone.0105922. eCollection 2014.
• Ref 4: Altered Drug Transport by Plasmodium falciparum Chloroquine Resistance Transporter Isoforms Harboring Mutations Associated with Piperaquine Resistance. Biochemistry. 2020 Jul 14;59(27):2484-2493. doi: 10.1021/acs.biochem.0c00247. Epub 2020 Jul 1.