Virulence of Leishmania major in macrophages and mice requires the gluconeogenic enzyme fructose-1,6-bisphosphatase
Details
Publication Year 2006-04-04, Volume 103, Issue #14, Page 5502-5507
Journal Title
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Publication Type
Journal Article
Abstract
Leishmania are protozoan parasites that replicate within mature phagolysosomes of mammalian macrophages. To define the biochemical composition of the phagosome and carbon source requirements of intracellular stages of L. major, we investigated the role and requirement for the gluconeogenic enzyme fructose-1,6-bisphosphatase (FBP). L. major FBP was constitutively expressed in both extracellular and intracellular stages and was primarily targeted to glycosomes, modified peroxisomes that also contain glycolytic enzymes. A L. major FBP-null mutant was unable to grow in the absence of hexose, and suspension in glycerol-containing medium resulted in rapid depletion of internal carbohydrate re- serves. L. major Delta fbp promastigotes were internalized by macrophages and differentiated into amastigotes but were unable to replicate in the macrophage phagolysosome. Similarly, the mutant persisted in mice but failed to generate normal lesions. The data suggest that Leishmania amastigotes reside in a glucose-poor phagosome and depend heavily on nonglucose carbon sources. Feeding experiments with [C-13]fatty acids showed that fatty acids are poor gluconeogenic substrates, indicating that amino acids are the major carbon source in vivo. The need for amino acids may have forced Leishmania spp. to adapt to life in the mature phagolysosome.
Publisher
NATL ACAD SCIENCES
Keywords
MYCOBACTERIUM-TUBERCULOSIS; CANDIDA-ALBICANS; GLYOXYLATE CYCLE; SYNTHASE GENE; MEXICANA; VACCINATION; PARASITES; CHROMATOGRAPHY; GLYCOSYLATION; CHEMOTHERAPY
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Creation Date: 2006-04-04 12:00:00
Last Modified: 0001-01-01 12:00:00
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