scholarly journals Fungal homoserine transacetylase: A potential antifungal target

2021 ◽  
Vol 51 (1) ◽  
pp. 137-140
Author(s):  
Esra Seyran
Keyword(s):  
Homoserine Transacetylase

Enzyme-Catalyzed Acylation of Homoserine:  Mechanistic Characterization of theHaemophilus influenzaemet2-Encoded Homoserine Transacetylase†

Biochemistry ◽  
2000 ◽  
Vol 39 (29) ◽  
pp. 8556-8564 ◽  
Author(s):  
Timothy L. Born ◽  
Matthew Franklin ◽  
John S. Blanchard
Keyword(s):  
Homoserine Transacetylase

Catalytic Mechanism of Fungal Homoserine Transacetylase†

Biochemistry ◽  
2005 ◽  
Vol 44 (41) ◽  
pp. 13560-13566 ◽  
Author(s):  
Ishac Nazi ◽  
Gerard D. Wright
Keyword(s):  
Catalytic Mechanism ◽  
Homoserine Transacetylase

scholarly journals Structural analysis of mycobacterial homoserine transacetylases central to methionine biosynthesis reveals druggable active site

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Catherine T. Chaton ◽  
Emily S. Rodriguez ◽  
Robert W. Reed ◽  
Jian Li ◽  
Cameron W. Kenner ◽  
...  
Keyword(s):  
Infectious Disease ◽  
Mycobacterium Tuberculosis ◽  
Active Site ◽  
Fungal Species ◽  
Biosynthesis Pathway ◽  
Methionine Biosynthesis ◽  
Structure Based Drug Design ◽  
High Degree ◽  
Homoserine Transacetylase ◽  
Host Metabolism

AbstractMycobacterium tuberculosis is the cause of the world’s most deadly infectious disease. Efforts are underway to target the methionine biosynthesis pathway, as it is not part of the host metabolism. The homoserine transacetylase MetX converts l-homoserine to O-acetyl-l-homoserine at the committed step of this pathway. In order to facilitate structure-based drug design, we determined the high-resolution crystal structures of three MetX proteins, including M. tuberculosis (MtMetX), Mycolicibacterium abscessus (MaMetX), and Mycolicibacterium hassiacum (MhMetX). A comparison of homoserine transacetylases from other bacterial and fungal species reveals a high degree of structural conservation amongst the enzymes. Utilizing homologous structures with bound cofactors, we analyzed the potential ligandability of MetX. The deep active-site tunnel surrounding the catalytic serine yielded many consensus clusters during mapping, suggesting that MtMetX is highly druggable.

scholarly journals Role of Homoserine Transacetylase as a New Target for Antifungal Agents

2007 ◽  
Vol 51 (5) ◽  
pp. 1731-1736 ◽  
Author(s):  
Ishac Nazi ◽  
Adam Scott ◽  
Anita Sham ◽  
Laura Rossi ◽  
Peter R. Williamson ◽  
...  
Keyword(s):  
Small Molecules ◽  
Antifungal Agents ◽  
Acid Biosynthesis ◽  
Gene Encoding ◽  
Small Molecule Inhibition ◽  
Steady State Kinetic ◽  
Antibiotic Discovery ◽  
Homoserine Transacetylase ◽  
State Kinetic

ABSTRACT Microbial amino acid biosynthesis is a proven yet underexploited target of antibiotics. The biosynthesis of methionine in particular has been shown to be susceptible to small-molecule inhibition in fungi. The first committed step in Met biosynthesis is the acylation of homoserine (Hse) by the enzyme homoserine transacetylase (HTA). We have identified the MET2 gene of Cryptococcus neoformans H99 that encodes HTA (CnHTA) by complementation of an Escherichia coli metA mutant that lacks the gene encoding homoserine transsuccinylase (HTS). We cloned, expressed, and purified CnHTA and determined its steady-state kinetic parameters for the acetylation of L-Hse by acetyl coenzyme A. We next constructed a MET2 mutant in C. neoformans H99 and tested its growth behavior in Met-deficient media, confirming the expected Met auxotrophy. Furthermore, we used this mutant in a mouse inhalation model of infection and determined that MET2 is required for virulence. This makes fungal HTA a viable target for new antibiotic discovery. We screened a 1,000-compound library of small molecules for HTA inhibitors and report the identification of the first inhibitor of fungal HTA. This work validates HTA as an attractive drug-susceptible target for new antifungal agent design.

Crystal Structure of Homoserine Transacetylase fromHaemophilus influenzaeReveals a New Family of α/β-Hydrolases†,‡

Biochemistry ◽  
2005 ◽  
Vol 44 (48) ◽  
pp. 15768-15773 ◽  
Author(s):  
I. Ahmad Mirza ◽  
Ishac Nazi ◽  
Magdalena Korczynska ◽  
Gerard D. Wright ◽  
Albert M. Berghuis
Keyword(s):  
Crystal Structure ◽  
New Family ◽  
Homoserine Transacetylase

scholarly journals Structural analysis of mycobacterial homoserine transacetylases central to methionine biosynthesis reveals druggable active site

2019 ◽  
Author(s):  
Catherine T. Chaton ◽  
Emily S. Rodriguez ◽  
Robert W. Reed ◽  
Jian Li ◽  
Cameron W. Kenner ◽  
...  
Keyword(s):  
Infectious Disease ◽  
Mycobacterium Tuberculosis ◽  
Active Site ◽  
Fungal Species ◽  
Biosynthesis Pathway ◽  
Methionine Biosynthesis ◽  
Structure Based Drug Design ◽  
High Degree ◽  
Homoserine Transacetylase ◽  
Host Metabolism

AbstractMycobacterium tuberculosis is the cause of the world’s most deadly infectious disease. Efforts are underway to target the methionine biosynthesis pathway, as it is not part of the host metabolism. The homoserine transacetylase MetX converts L-homoserine to O-acetyl-L-homoserine at the committed step of this pathway. In order to facilitate structure-based drug design, we determined the high-resolution crystal structures of three MetX proteins, including M. tuberculosis (MtMetX), Mycolicibacterium abscessus (MaMetX), and Mycolicibacterium hassiacum (MhMetX). A comparison of homoserine transacetylases from other bacterial and fungal species reveals a high degree of structural conservation amongst the enzymes. Utilizing homologous structures with bound cofactors, we analyzed the potential ligandability of MetX. The deep active-site tunnel surrounding the catalytic serine yielded many consensus clusters during mapping, suggesting that MtMetX is highly druggable.

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