Ascaris Lumbricoides β Carbonic Anhydrase: a Potential Target Enzyme for Treatment of Ascariasis

Overview

Journal Parasit Vectors

Publisher Biomed Central

Specialties Parasitology
Tropical Medicine

Date 2015 Sep 20

PMID 26385556

Citations 15

Authors

Reza Zolfaghari Emameh

Marianne Kuuslahti

Daniela Vullo

Harlan R Barker

Claudiu T Supuran

Seppo Parkkila

Affiliations

Soon will be listed here.

Abstract

Background: A parasitic roundworm, Ascaris lumbricoides, is the causative agent of ascariasis, with approximately 760 million cases around the world. Helminthic infections occur with a high prevalence mostly in tropical and developing xcountries. Therefore, design of affordable broad-spectrum anti-helminthic agents against a variety of pathogens, including not only A. lumbricoides but also hookworms and whipworms, is desirable. Beta carbonic anhydrases (β-CAs) are considered promising targets of novel anthelminthics because these enzymes are present in various parasites, while completely absent in vertebrates.

Methods: In this study, we identified an A. lumbricoides β-CA (AIBCA) protein from protein sequence data using bioinformatics tools. We used computational biology resources and methods (including InterPro, CATH/Gene3D, KEGG, and METACYC) to analyze AlBCA and define potential roles of this enzyme in biological pathways. The AlBCA gene was cloned into pFastBac1, and recombinant AIBCA was produced in sf-9 insect cells. Kinetics of AlBCA were analyzed by a stopped-flow method.

Results: Multiple sequence alignment revealed that AIBCA contains the two sequence motifs, CXDXR and HXXC, typical for β-CAs. Recombinant AIBCA showed significant CA catalytic activity with kcat of 6.0 × 10(5) s(-1) and kcat/KM of 4.3 × 10(7) M(-1) s(-1). The classical CA inhibitor, acetazolamide, showed an inhibition constant of 84.1 nM. Computational modeling suggests that the molecular architecture of AIBCA is highly similar to several other known β-CA structures. Functional predictions suggest that AIBCA might play a role in bicarbonate-mediated metabolic pathways, such as gluconeogenesis and removal of metabolically produced cyanate.

Conclusions: These results open new avenues to further investigate the precise functions of β-CAs in parasites and suggest that novel β-CA specific inhibitors should be developed and tested against helminthic diseases.

Citing Articles

Genome Study of α-, β-, and γ-Carbonic Anhydrases from the Thermophilic Microbiome of Marine Hydrothermal Vent Ecosystems.

Gheibzadeh M, Manyumwa C, Tastan Bishop O, Shahbani Zahiri H, Parkkila S, Zolfaghari Emameh R Biology (Basel). 2023; 12(6).

PMID: 37372055 PMC: 10295459. DOI: 10.3390/biology12060770.

Cloning, characterization, and inhibition of the novel β-carbonic anhydrase from parasitic blood fluke, .

Haapanen S, Angeli A, Tolvanen M, Zolfaghari Emameh R, Supuran C, Parkkila S J Enzyme Inhib Med Chem. 2023; 38(1):2184299.

PMID: 36856011 PMC: 9980027. DOI: 10.1080/14756366.2023.2184299.

Sulphonamide inhibition studies of the β-carbonic anhydrase GsaCAβ present in the salmon platyhelminth parasite .

Aspatwar A, Bonardi A, Aisala H, Zueva K, Primmer C, Lumme J J Enzyme Inhib Med Chem. 2023; 38(1):2167988.

PMID: 36647786 PMC: 9848252. DOI: 10.1080/14756366.2023.2167988.

A reverse vaccinology approach on transmembrane carbonic anhydrases from Plasmodium species as vaccine candidates for malaria prevention.

Zolfaghari Emameh R, Barker H, Turpeinen H, Parkkila S, Hytonen V Malar J. 2022; 21(1):189.

PMID: 35706028 PMC: 9199335. DOI: 10.1186/s12936-022-04186-7.

The Targeting of Noncoding RNAs by Quercetin in Cancer Prevention and Therapy.

Wang M, Chen X, Yu F, Zhang L, Zhang Y, Chang W Oxid Med Cell Longev. 2022; 2022:4330681.

PMID: 35656022 PMC: 9155922. DOI: 10.1155/2022/4330681.

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