Tyrosine aminotransferase from Leishmania infantum: A new drug target candidate

Moreno, M.; Alonso, Ana; Alcolea, Pedro J.; Abramov, Ariel; Lacoba, Mario Garcı́a de; Abendroth, Jan; Zhang, Sunny; Edwards, Thomas E.; Lorimer, Don; Myler, Peter J.; Larraga, Vicente

doi:10.1016/j.ijpddr.2014.06.001

Cited by 27 publications

(29 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…No intracellular metabolic function has been assigned to these metabolites. It has been proposed, however, that when excreted, the products of aromatic amino acid breakdown are involved in parasitehost interactions and pathogenesis [63,64]. Table 3.…”

Section: Arginine Leucine Lysine Phenylalanine Tryptophan and Vamentioning

confidence: 99%

“…Tyrosine can be synthesized from phenylalanine and excreted as 3-(4-hydroxyphenyl)lactate and 4-hydroxyphenil pyruvate [42,57]. In 2014, Moreno and colleagues elucidated the crystal structure of L. infantum tyrosine aminotransferase (TAT) and showed that TAT is a cytoplasmic enzyme of the Iγ subfamily of aminotransferases that is expressed at a higher rate in amastigotes [63,64]. The latter suggests that tyrosine, similar to other aromatic amino acids whose oxidation end-products have been related to Leishmania infectivity in macrophages [63,64], could be more important, and even vital, for Leishmania amastigotes.…”

Section: Amino Acids Required For Growth and Protein Synthesis In Leimentioning

confidence: 99%

See 1 more Smart Citation

A defined medium for Leishmania culture allows definition of essential amino acids

Nayak

Akpunarlieva

Barrett

et al. 2018

Experimental Parasitology

View full text Add to dashboard Cite

Axenic culture of Leishmania is generally performed in rich, serum-supplemented media which sustain robust growth over multiple passages. The use of such undefined media, however, obscures proteomic analyses and confounds the study of metabolism. We have established a simple, defined culture medium that supports the sustained growth of promastigotes over multiple passages and which yields parasites that have similar infectivity to macrophages to parasites grown in a conventional semi-defined medium. We have exploited this medium to investigate the amino acid requirements of promastigotes in culture and have found that phenylalanine, tryptophan, arginine, leucine, lysine and valine are essential for viability in culture. Most of the 20 proteogenic amino acids promote growth of Leishmania promastigotes, with the exception of alanine, asparagine, and glycine. This defined medium will be useful for further studies of promastigote substrate requirements, and will facilitate future proteomic and metabolomic analyses.

show abstract

Section: Arginine Leucine Lysine Phenylalanine Tryptophan and Vamentioning

confidence: 99%

Section: Amino Acids Required For Growth and Protein Synthesis In Leimentioning

confidence: 99%

A defined medium for Leishmania culture allows definition of essential amino acids

Nayak

Akpunarlieva

Barrett

et al. 2018

Experimental Parasitology

View full text Add to dashboard Cite

show abstract

“…The degradation starts when the enzyme tyrosine aminotransferase cleaves the amino group of the amino acid. Subsequently, the deaminated tyrosine is reduced by the 4‐hydroxyphenylpyruvate dioxygenase (http://www.chem.qmul.ac.uk/iubmb/enzyme/EC1/13/11/27.html), whose activity has been already detected in leishmanial extracts . Thus, vitamin E or tocopherol biosynthesis is an attractive target for investigation because Leishmania lives in a pro‐oxidant environment in the vertebrate host and must therefore have an efficient antioxidant defence in order to ensure its survival .…”

mentioning

confidence: 99%

Tocopherol biosynthesis in Leishmania (L.) amazonensis promastigotes

et al. 2019

View full text Add to dashboard Cite

Leishmaniasis is a neglected disease caused by a trypanosomatid protozoan of the genus Leishmania. Most drugs used to treat leishmaniasis are highly toxic, and the emergence of drug‐resistant strains has been observed. Therefore, new therapeutic targets against leishmaniasis are required. Several isoprenoid compounds, including dolichols or ubiquinones, have been shown to be important for cell viability and proliferation in various trypanosomatid species. Here, we detected the biosynthesis of tocopherol in Leishmania (L.) amazonensis promastigotes in vitro through metabolic labelling with [1‐(n)‐3H]‐phytol. Subsequently, we confirmed the presence of vitamin E in the parasite by gas chromatography–mass spectrometry. Treatment with usnic acid or nitisinone, inhibitors of precursors of vitamin E synthesis, inhibited growth of the parasite in a concentration‐dependent manner. This study provides the first evidence of tocopherol biosynthesis in a trypanosomatid and suggests that inhibitors of the enzyme 4‐hydroxyphenylpyruvate dioxygenase may be suitable for use as antileishmanial compounds. Database The amino acid sequence of a conserved hypothetical protein [Leishmania mexicana MHOM/GT/2001/U1103] has been deposited in GenBank ()

show abstract

“…3 Visceral leishmaniasis (VL) is the most severe form, in which vital organs are affected causing chronic fever, liver issues, spleen enlargement, anemia, and other blood problems. 4,5 …”

mentioning

confidence: 99%

“…Thus, there is an urgent need for the discovery of new drugs and targets for this neglected disease. 4 …”

mentioning

confidence: 99%

Computer-aided discovery of two novel chalcone-like compounds active and selective against Leishmania infantum

Gomes

Alcântara

Neves

et al. 2017

Bioorganic & Medicinal Chemistry Letters

View full text Add to dashboard Cite

Leishmaniasis are infectious diseases caused by parasites of genus Leishmania that affects 12 million people in 98 countries mainly in Africa, Asia, and Latin America. Effective treatments for this disease are urgently needed. In this study, we present a computer-aided approach to investigate a set of 32 recently synthesized chalcones and chalcone-like compounds to act as anti-leishmanial agents. As a result, nine most promising compounds and three potentially inactive compounds were experimentally evaluated against Leishmania infantum amastigotes and mammalian cells. Four compounds exhibited EC50 in the range of 6.2–10.98 μM. In addition, two compounds, LabMol-65 and LabMol-73, exhibited cytotoxicity in macrophages >50 μM that resulted in better selectivity than Amphotericin B. These two compounds also demonstrated low cytotoxicity and high selectivity towards Vero cells. The results of target fishing followed by homology modeling and docking suggest that these chalcone compounds could act in Leishmania because of their interaction with cysteine proteases, such as procathepsin L. Finally, we have provided structural recommendations for designing of new anti-leishmanial chalcones.

show abstract

Tyrosine aminotransferase from Leishmania infantum: A new drug target candidate

Abstract: Graphical abstract

Cited by 27 publications

References 44 publications

A defined medium for Leishmania culture allows definition of essential amino acids

A defined medium for Leishmania culture allows definition of essential amino acids

Tocopherol biosynthesis in Leishmania (L.) amazonensis promastigotes

Computer-aided discovery of two novel chalcone-like compounds active and selective against Leishmania infantum

Contact Info

Product

Resources

About