Structure of tyrosine aminotransferase from<i>Leishmania infantum</i>

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

doi:10.1107/s2053230x14007845

Cited by 19 publications

(20 citation statements)

References 35 publications

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“…Cell extracts of L. infantum promastigotes were obtained as described previously ( Alcolea et al, 2011 ). A specific polyclonal antibody against LiTAT was obtained with 2 mg of purified native recombinant LiTAT as described ( Moreno et al, 2014 ) in a New Zealand rabbit. For this purpose it was administered in four weekly subcutaneous shots together with the Freund’s Adjuvant.…”

Section: Methodsmentioning

confidence: 99%

“…The first structure released corresponds to the trypanosomatid T. cruzi (TcTAT) (PDB code: 1BW0) ( Blankenfeldt et al, 1999 ), followed by the human (PDB code: 3DYD) and the mouse TAT (PDB code: 3PDX) ( Mehere et al, 2010 ). Recently, the structure of LiTAT has been solved to 2.3 Å (PDB code: 4IX8) ( Moreno et al, 2014 ). On the basis of this background, the aim of the work is the characterization of the protein regarding its cellular localization and expression at the different stages as well as the excretion of the final product p -hydroxyphenyllactate (pHPL) to the culture medium.…”

Section: Introductionmentioning

confidence: 99%

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Tyrosine aminotransferase from Leishmania infantum: A new drug target candidate

Moreno

Alonso

Alcolea

et al. 2014

International Journal for Parasitology: Drugs and Drug Resistan

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Tyrosine aminotransferase from Leishmania infantum: A new drug target candidate

Moreno

Alonso

Alcolea

et al. 2014

International Journal for Parasitology: Drugs and Drug Resistan

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“…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%

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

Nayak

Akpunarlieva

Barrett

et al. 2018

Experimental Parasitology

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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.

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“…Structural studies suggest that TAT is only fully functional in the dimeric state [75]. TAT is overexpressed in T .…”

Section: Resultsmentioning

confidence: 99%

Essential multimeric enzymes in kinetoplastid parasites: A host of potentially druggable protein-protein interactions

2017

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Parasitic diseases caused by kinetoplastid parasites of the genera Trypanosoma and Leishmania are an urgent public health crisis in the developing world. These closely related species possess a number of multimeric enzymes in highly conserved pathways involved in vital functions, such as redox homeostasis and nucleotide synthesis. Computational alanine scanning of these protein-protein interfaces has revealed a host of potentially ligandable sites on several established and emerging anti-parasitic drug targets. Analysis of interfaces with multiple clustered hotspots has suggested several potentially inhibitable protein-protein interactions that may have been overlooked by previous large-scale analyses focusing solely on secondary structure. These protein-protein interactions provide a promising lead for the development of new peptide and macrocycle inhibitors of these enzymes.

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Structure of tyrosine aminotransferase fromLeishmania infantum

Cited by 19 publications

References 35 publications

Tyrosine aminotransferase from Leishmania infantum: A new drug target candidate

Tyrosine aminotransferase from Leishmania infantum: A new drug target candidate

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

Essential multimeric enzymes in kinetoplastid parasites: A host of potentially druggable protein-protein interactions

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