Targeting Host Glycolysis as a Strategy for Antimalarial Development
Glycolysis controls cellular energy, redox balance, and biosynthesis. Antiglycolytic therapies are under investigation for treatment of obesity, cancer, aging, autoimmunity, and microbial diseases. Interrupting glycolysis is highly valued as a therapeutic strategy, because glycolytic disruption is g...
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doaj-22d7e09907934e49a2840c1a4cc95da12021-09-16T13:30:04ZengFrontiers Media S.A.Frontiers in Cellular and Infection Microbiology2235-29882021-09-011110.3389/fcimb.2021.730413730413Targeting Host Glycolysis as a Strategy for Antimalarial DevelopmentAndrew J. Jezewski0Andrew J. Jezewski1Yu-Hsi Lin2Julie A. Reisz3Rachel Culp-Hill4Yasaman Barekatain5Victoria C. Yan6Angelo D’Alessandro7Florian L. Muller8Florian L. Muller9Audrey R. Odom John10Audrey R. Odom John11Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United StatesDepartment of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO, United StatesDepartment of Cancer Systems Imaging, Division of Diagnostic Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, United StatesDepartment of Biochemistry and Molecular Genetics, Aurora, CO, United StatesDepartment of Biochemistry and Molecular Genetics, Aurora, CO, United StatesDepartment of Cancer Systems Imaging, Division of Diagnostic Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, United StatesDepartment of Cancer Systems Imaging, Division of Diagnostic Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, United StatesDepartment of Biochemistry and Molecular Genetics, Aurora, CO, United StatesDepartment of Cancer Systems Imaging, Division of Diagnostic Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, United StatesDepartment of Neuro-Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United StatesDepartment of Pediatrics, Washington University School of Medicine, St. Louis, MO, United StatesDepartment of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO, United StatesGlycolysis controls cellular energy, redox balance, and biosynthesis. Antiglycolytic therapies are under investigation for treatment of obesity, cancer, aging, autoimmunity, and microbial diseases. Interrupting glycolysis is highly valued as a therapeutic strategy, because glycolytic disruption is generally tolerated in mammals. Unfortunately, anemia is a known dose-limiting side effect of these inhibitors and presents a major caveat to development of antiglycolytic therapies. We developed specific inhibitors of enolase – a critical enzyme in glycolysis – and validated their metabolic and cellular effects on human erythrocytes. Enolase inhibition increases erythrocyte susceptibility to oxidative damage and induces rapid and premature erythrocyte senescence, rather than direct hemolysis. We apply our model of red cell toxicity to address questions regarding erythrocyte glycolytic disruption in the context of Plasmodium falciparum malaria pathogenesis. Our study provides a framework for understanding red blood cell homeostasis under normal and disease states and clarifies the importance of erythrocyte reductive capacity in malaria parasite growth.https://www.frontiersin.org/articles/10.3389/fcimb.2021.730413/fullPlasmodiumantimalarialred blood cellserythrocyteenolaseglycolysis |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Andrew J. Jezewski Andrew J. Jezewski Yu-Hsi Lin Julie A. Reisz Rachel Culp-Hill Yasaman Barekatain Victoria C. Yan Angelo D’Alessandro Florian L. Muller Florian L. Muller Audrey R. Odom John Audrey R. Odom John |
spellingShingle |
Andrew J. Jezewski Andrew J. Jezewski Yu-Hsi Lin Julie A. Reisz Rachel Culp-Hill Yasaman Barekatain Victoria C. Yan Angelo D’Alessandro Florian L. Muller Florian L. Muller Audrey R. Odom John Audrey R. Odom John Targeting Host Glycolysis as a Strategy for Antimalarial Development Frontiers in Cellular and Infection Microbiology Plasmodium antimalarial red blood cells erythrocyte enolase glycolysis |
author_facet |
Andrew J. Jezewski Andrew J. Jezewski Yu-Hsi Lin Julie A. Reisz Rachel Culp-Hill Yasaman Barekatain Victoria C. Yan Angelo D’Alessandro Florian L. Muller Florian L. Muller Audrey R. Odom John Audrey R. Odom John |
author_sort |
Andrew J. Jezewski |
title |
Targeting Host Glycolysis as a Strategy for Antimalarial Development |
title_short |
Targeting Host Glycolysis as a Strategy for Antimalarial Development |
title_full |
Targeting Host Glycolysis as a Strategy for Antimalarial Development |
title_fullStr |
Targeting Host Glycolysis as a Strategy for Antimalarial Development |
title_full_unstemmed |
Targeting Host Glycolysis as a Strategy for Antimalarial Development |
title_sort |
targeting host glycolysis as a strategy for antimalarial development |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Cellular and Infection Microbiology |
issn |
2235-2988 |
publishDate |
2021-09-01 |
description |
Glycolysis controls cellular energy, redox balance, and biosynthesis. Antiglycolytic therapies are under investigation for treatment of obesity, cancer, aging, autoimmunity, and microbial diseases. Interrupting glycolysis is highly valued as a therapeutic strategy, because glycolytic disruption is generally tolerated in mammals. Unfortunately, anemia is a known dose-limiting side effect of these inhibitors and presents a major caveat to development of antiglycolytic therapies. We developed specific inhibitors of enolase – a critical enzyme in glycolysis – and validated their metabolic and cellular effects on human erythrocytes. Enolase inhibition increases erythrocyte susceptibility to oxidative damage and induces rapid and premature erythrocyte senescence, rather than direct hemolysis. We apply our model of red cell toxicity to address questions regarding erythrocyte glycolytic disruption in the context of Plasmodium falciparum malaria pathogenesis. Our study provides a framework for understanding red blood cell homeostasis under normal and disease states and clarifies the importance of erythrocyte reductive capacity in malaria parasite growth. |
topic |
Plasmodium antimalarial red blood cells erythrocyte enolase glycolysis |
url |
https://www.frontiersin.org/articles/10.3389/fcimb.2021.730413/full |
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