Journal article
A single Leishmania adenylate forming enzyme of the ANL superfamily generates both acetyl- and acetoacetyl-CoA
The Journal of biological chemistry, Vol.300(11), 107879
11/2024
DOI: 10.1016/j.jbc.2024.107879
PMCID: PMC11584562
PMID: 39395803
Abstract
Leishmania, a protozoan parasite, is responsible for significant morbidity and mortality worldwide, manifesting as cutaneous, mucocutaneous, and visceral leishmaniasis. These diseases pose a substantial burden, especially in impoverished regions with limited access to effective medical treatments. Current therapies are toxic, have low efficacy, and face growing resistance. Understanding the metabolic pathways of Leishmania, particularly those differing from its host, can unveil potential therapeutic targets. In this study, we investigated the acetyl-CoA synthetase (ACS) enzyme from Leishmania infantum (LiAcs1), which, unlike many organisms, also exhibits acetoacetyl-CoA synthetase (KBC) activity. This dual functionality is unique among ANL superfamily enzymes and crucial for the parasite's reliance on leucine catabolism, energy production and sterol biosynthesis. Our biochemical characterization of LiAcs1 revealed its ability to utilize both acetate and acetoacetate substrates. Additionally, LiAcs1 displayed a distinct CoA substrate inhibition pattern, partially alleviated by acetoacetate. Structural analysis provided insights into the substrate binding flexibility of LiAcs1, highlighting a more promiscuous substrate pocket compared to other ACS or KBC-specific enzymes. Substrate mimetics elucidated its ability to accommodate both small and large AMP-ester derivatives, contributing to its dual ACS/KBC functionality. These findings not only advance our understanding of Leishmania metabolism but also present LiAcs1 as a promising drug target. The dual functionality of LiAcs1 underscores the potential for developing selective inhibitors that could disrupt critical metabolic pathways across Leishmania spp. as it appears this enzyme is highly conserved across this genus. This paves the way for developing novel effective treatments against this devastating disease.
Details
- Title: Subtitle
- A single Leishmania adenylate forming enzyme of the ANL superfamily generates both acetyl- and acetoacetyl-CoA
- Creators
- Andrew J. Jezewski - University of IowaTaiwo E. Esan - Northern Illinois UniversityJonah Propp - University of Iowa, Stead Family Department of PediatricsAndrew J. Fuller - University of IowaDrashti G. Daraji - Northern Illinois UniversityCharles Lail - Northern Illinois UniversityBart L. Staker - Center for Infectious Disease ResearchElijah L. Woodward - Seattle Structural Genomics Center for Infectious Disease (SSGCID), Seattle, Washington, 98109, USALinjun Liu - Seattle Structural Genomics Center for Infectious Disease (SSGCID), Seattle, Washington, 98109, USAKevin P. Battaile - New York Structural Biology CenterScott Lovell - University of KansasTimothy J. Hagen - Northern Illinois UniversityDamian J. Krysan - University of Iowa
- Resource Type
- Journal article
- Publication Details
- The Journal of biological chemistry, Vol.300(11), 107879
- DOI
- 10.1016/j.jbc.2024.107879
- PMID
- 39395803
- PMCID
- PMC11584562
- NLM abbreviation
- J Biol Chem
- ISSN
- 0021-9258
- eISSN
- 1083-351X
- Publisher
- Elsevier Inc
- Grant note
- NIH: 5R01AI161973, T32AI007511 Federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services: 75N93022C00036 National Science Foundation under the MRI: CHE-2117776
This work was supported by NIH grants 5R01AI161973 (D. J. K.) , T32AI007511 (A. J. J.) This project has been funded in whole or in part with Federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under Contract No. 75N93022C00036. The purchase of the NMR spectrometer used to obtain results included in this publication was supported by the National Science Foundation under the MRI award CHE-2117776 (T. J. H.) . The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
- Language
- English
- Electronic publication date
- 10/10/2024
- Date published
- 11/2024
- Academic Unit
- Molecular Physiology and Biophysics; Stead Family Department of Pediatrics; Infectious Disease (Pediatrics)
- Record Identifier
- 9984722576002771
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