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Functional partnership between carbonic anhydrase and malic enzyme in promoting gluconeogenesis in Leishmania major
- Source :
- The FEBS Journal. 288:4129-4152
- Publication Year :
- 2021
- Publisher :
- Wiley, 2021.
-
Abstract
- Leishmania has a remarkable ability to proliferate under widely fluctuating levels of essential nutrients, such as glucose. For this, the parasite is heavily dependent on its gluconeogenic machinery. One perplexing aspect of gluconeogenesis in Leishmania is the lack of the crucial gene for pyruvate carboxylase (PC). PC-catalyzed conversion of pyruvate to oxaloacetate is a key entry point through which gluconeogenic amino acids are funneled into this pathway. The absence of PC in Leishmania thus raises question about the mechanism of pyruvate entry into the gluconeogenic route. In the present study, we report that this task is accomplished in Leishmania major through a novel functional partnership between its mitochondrial malic enzyme (LmME) and carbonic anhydrase 1 (LmCA1). Using a combination of pharmacological inhibition studies with genetic manipulation, we show that both of these enzymes are necessary for promoting gluconeogenesis and supporting parasite growth under glucose-limiting conditions. Functional cross-talk between LmME and LmCA1 was evident when it was observed that the growth retardation caused by inhibition of any one of these enzymes could be protected to a significant extent by overexpressing the other enzyme. We also found that, although LmCA1 exhibited constitutive expression, the LmME protein level was strongly upregulated under low glucose conditions. Notably, both LmME and LmCA1 were found to be important for survival of Leishmania amastigotes within host macrophages. Taken together, our results indicate that LmCA1 by virtue of its CO2 concentrating ability stimulates LmME-catalyzed pyruvate carboxylation, thereby driving gluconeogenesis through the pyruvate-malate-oxaloacetate bypass pathway. Additionally, our study establishes LmCA1 and LmME as promising therapeutic targets.
- Subjects :
- 0301 basic medicine
Protozoan Proteins
Malic enzyme
Biochemistry
Cell Line
Host-Parasite Interactions
Mice
03 medical and health sciences
0302 clinical medicine
Downregulation and upregulation
Malate Dehydrogenase
Carbonic anhydrase
Pyruvic Acid
Animals
Citrate synthase
Leishmania major
Molecular Biology
Carbonic Anhydrases
Pyruvate Carboxylase
chemistry.chemical_classification
biology
Macrophages
Gluconeogenesis
Cell Biology
biology.organism_classification
Mitochondria
Pyruvate carboxylase
Glucose
030104 developmental biology
Enzyme
chemistry
030220 oncology & carcinogenesis
biology.protein
Oxidation-Reduction
Subjects
Details
- ISSN :
- 17424658 and 1742464X
- Volume :
- 288
- Database :
- OpenAIRE
- Journal :
- The FEBS Journal
- Accession number :
- edsair.doi.dedup.....fa901e5c915e2b7745737ff055942237