PDBsum entry 6r8h

Isomerase

PDB id: 6r8h

Contents

Protein chains

(+ 0 more) 250 a.a.

Ligands

SO4 ×6

Waters ×1116

PDB id:

6r8h

Name:

Isomerase

Title:

Triosephosphate isomerase from liver fluke (fasciola hepatica).

Structure:

Triosephosphate isomerase. Chain: a, b, c, d, e, f. Engineered: yes

Source:

Fasciola hepatica. Liver fluke. Organism_taxid: 6192. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

1.90Å R-factor: 0.196 R-free: 0.224

Authors:

F.Ferraro,I.Corvo,L.Bergalli,A.Ilarraz,M.Cabrera,J.Gil,B.Susuki, C.Caffrey,D.J.Timson,X.Robert,C.Guillon,G.Alvarez

Key ref:

F.Ferraro et al. (2020). Novel and selective inactivators of Triosephosphate isomerase with anti-trematode activity. Sci Rep, 10, 2587. PubMed id: 32054976 DOI: 10.1038/s41598-020-59460-y

Date:

01-Apr-19 Release date: 12-Feb-20

Protein chains

S4UI50  (S4UI50_FASHE) -  Triosephosphate isomerase from Fasciola hepatica

Seq: 253 a.a.

Struc: 250 a.a.

Enzyme reactions

• Enzyme class: E.C.5.3.1.1 - triose-phosphate isomerase.
• Reaction: D-glyceraldehyde 3-phosphate = dihydroxyacetone phosphate

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Added reference

DOI no: 10.1038/s41598-020-59460-y

Sci Rep 10:2587 (2020)

PubMed id: 32054976

Novel and selective inactivators of Triosephosphate isomerase with anti-trematode activity.

F.Ferraro, I.Corvo, L.Bergalli, A.Ilarraz, M.Cabrera, J.Gil, B.M.Susuki, C.R.Caffrey, D.J.Timson, X.Robert, C.Guillon, T.Freire, G.Álvarez.

ABSTRACT

Trematode infections such as schistosomiasis and fascioliasis cause significant morbidity in an estimated 250 million people worldwide and the associated agricultural losses are estimated at more than US$ 6 billion per year. Current chemotherapy is limited. Triosephosphate isomerase (TIM), an enzyme of the glycolytic pathway, has emerged as a useful drug target in many parasites, including Fasciola hepatica TIM (FhTIM). We identified 21 novel compounds that selectively inhibit this enzyme. Using microscale thermophoresis we explored the interaction between target and compounds and identified a potent interaction between the sulfonyl-1,2,4-thiadiazole (compound 187) and FhTIM, which showed an IC₅₀ of 5 µM and a K_d of 66 nM. In only 4 hours, this compound killed the juvenile form of F. hepatica with an IC₅₀ of 3 µM, better than the reference drug triclabendazole (TCZ). Interestingly, we discovered in vitro inhibition of FhTIM by TCZ, with an IC₅₀ of 7 µM suggesting a previously uncharacterized role of FhTIM in the mechanism of action of this drug. Compound 187 was also active against various developmental stages of Schistosoma mansoni. The low toxicity in vitro in different cell types and lack of acute toxicity in mice was demonstrated for this compound, as was demonstrated the efficacy of 187 in vivo in F. hepatica infected mice. Finally, we obtained the first crystal structure of FhTIM at 1.9 Å resolution which allows us using docking to suggest a mechanism of interaction between compound 187 and TIM. In conclusion, we describe a promising drug candidate to control neglected trematode infections in human and animal health.