Molecular and functional characterization of two malic enzymes from Leishmania parasites

Giordana, Lucila; Sosa, María de los Ángeles; Leroux, Alejandro E.; Mendoza, Elkin Fernando Rodas; Petray, Patricia; Nowicki, Cristina

doi:10.1016/j.molbiopara.2017.11.001

Cited by 8 publications

(10 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Synonymous variants do not alter the primary structure of polypeptide, but may have negative effects on the stability and structure of mRNA and proteins, and may contribute to the complexity of the infectious diseases, being interesting targets for the identification of genetic factors associated with virulence 35 . For example, in L. infantum , nine silent SNPs were detected in the malic enzyme gene (class of enzymes that catalyze the reduction of NADP + and needed to maintain intracellular redox homeostasis of the parasite), one of which distinguishes strains from the same zymodemo 36 , 37 . Also, several genes associated with drug resistance development were shown to contain non-synonymous SNPs or nonsense mutations 34 .…”

Section: Discussionmentioning

confidence: 99%

Application of next generation sequencing (NGS) for descriptive analysis of 30 genomes of Leishmania infantum isolates in Middle-North Brazil

Carvalho

Júnior

Regueira-Neto

et al. 2020

Sci Rep

View full text Add to dashboard Cite

Visceral leishmaniasis (VL) is a life-threatening disease caused by the protozoa Leishmania donovani and L. infantum. Likely, L. infantum was introduced in the new World by the iberic colonizers. Due to recent introduction, the genetic diversity is low. Access to genomic information through the sequencing of Leishmania isolates allows the characterization of populations through the identification and analysis of variations. Population structure information may reveal important data on disease dynamics. Aiming to describe the genetic diversity of L. infantum from the Middle-North, Brazil, next generation sequencing of 30 Leishmania isolates obtained in the city of Teresina, from where the disease dispersed, was performed. The variations were categorized accordingly to the genome region and impact and provided the basis for chromosomal ploidy and population structure analysis. The results showed low diversity between the isolates and the Iberic reference genome JPCM5. Most variations were seen in non-coding regions, with modifying impact. The ploidy number analysis showed aneuploid profile. The population structure analysis revealed the presence of two L. infantum populations identified in Teresina. Further population genetics studies with a larger number of isolates should be performed in order to identify the genetic background associated with virulence and parasite ecology.

show abstract

Section: Discussionmentioning

confidence: 99%

Application of next generation sequencing (NGS) for descriptive analysis of 30 genomes of Leishmania infantum isolates in Middle-North Brazil

Carvalho

Júnior

Regueira-Neto

et al. 2020

Sci Rep

View full text Add to dashboard Cite

show abstract

“…This notion was strengthened by a functional ME from L. major recently being identified by Giordana et al [37]. Although the kinetic and structural properties of this enzyme (henceforth referred to as LmME) were reported, its physiological function is still unknown [37]. Thus, to investigate the physiological function of this enzyme and its possible role in gluconeogenesis, we first looked for a potent pharmacological inhibitor of LmME.…”

Section: Functional Cooperation Between Lmca1 and Lmme In Promoting Gluconeogenesis And In Sustaining Parasite Growth Under Glucose-limitmentioning

confidence: 99%

“…Furthermore, the presence of a functionally active ME from L. major [henceforth referred to as L. major malic enzyme (LmME)] has recently been identified. However, its role in Leishmania physiology has yet to be deciphered [37]. We were thus provoked to hypothesize that LmCA1 might be functionally cooperating with LmME in facilitating pyruvate carboxylation and in driving gluconeogenesis through the pyruvate–malate–oxaloacetate bypass pathway.…”

Section: Introductionmentioning

confidence: 99%

Functional partnership between carbonic anhydrase and malic enzyme in promoting gluconeogenesis in Leishmania major

et al. 2021

View full text Add to dashboard Cite

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 CO 2 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.

show abstract

“…al. Although kinetic and structural properties of this enzyme (henceforth referred to as LmME) were reported, its physiological function is still unknown [37]. Thus, in order to study the physiological function of this enzyme and its possible role in gluconeogenesis we first looked for a potent pharmacological inhibitor of LmME.…”

Section: Functional Cooperation Between Lmca1 and Lmme In Promoting Gluconeogenesis And In Sustaining Parasite Growth Under Glucose-limitmentioning

confidence: 99%

“…Furthermore, presence of a functionally active ME from L. major (henceforth referred to as LmME) has recently been identified. Although the kinetic parameters of this enzyme have been determined, its role in Leishmania physiology is yet to be deciphered [37]. We were thus provoked to hypothesize that LmCA1 might be functionally cooperating with LmME in facilitating pyruvate carboxylation and in driving gluconeogenesis through pyruvate -malate -oxaloacetate bypass pathway.…”

Section: Introductionmentioning

confidence: 99%

Functional partnership between carbonic anhydrase and malic enzyme in promoting gluconeogenesis inLeishmania major

Mondal

Pal

Abbasi

et al. 2020

Preprint

View full text Add to dashboard Cite

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 pyruvate carboxylase (PC) gene. PC-catalyzed conversion of pyruvate to oxaloacetate is a key entry point through which gluconeogenic amino acids are funnelled into this pathway. Absence of PC in Leishmania thus raises question about the mechanism of pyruvate entry into the gluconeogenic route. We report here that this task is accomplished in Leishmania major through a novel functional partnership between its mitochondrial malic enzyme (LmME) and cytosolic carbonic anhydrase (LmCA1). Using a combination of pharmacological inhibition studies with genetic manipulation, we showed that both these enzymes are necessary in promoting gluconeogenesis and supporting parasite growth under glucose limiting condition. Functional crosstalk 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 while LmCA1 exhibited constitutive expression, LmME protein level was strongly upregulated in low glucose condition. 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 pyruvate-malate-oxaloacetate bypass pathway. Additionally, our study establishes LmCA1 and LmME as promising therapeutic targets.

show abstract

Molecular and functional characterization of two malic enzymes from Leishmania parasites

Cited by 8 publications

References 37 publications

Application of next generation sequencing (NGS) for descriptive analysis of 30 genomes of Leishmania infantum isolates in Middle-North Brazil

Application of next generation sequencing (NGS) for descriptive analysis of 30 genomes of Leishmania infantum isolates in Middle-North Brazil

Functional partnership between carbonic anhydrase and malic enzyme in promoting gluconeogenesis in Leishmania major

Functional partnership between carbonic anhydrase and malic enzyme in promoting gluconeogenesis inLeishmania major

Contact Info

Product

Resources

About