Structure of homoserine<i>O</i>-acetyltransferase from<i>Staphylococcus aureus</i>: the first Gram-positive ortholog structure

Thangavelu, Bharani; Pavlovsky, A.G.; Viola, Ronald E.

doi:10.1107/s2053230x14018664

Cited by 11 publications

(18 citation statements)

References 23 publications

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“…Est22 forms stable dimers in solution (Fig. 4B), consistent with HTAs and HTA-like acetyl esterases, including MekB and CgHle (13,14,21). The topological structure of Est22 is similar to those of HTAs and HTA-like acetyl esterases (Fig.…”

Section: Resultsmentioning

confidence: 57%

“…The root mean square deviations between Est22 and reported HTA-like esterases are greater than 1.667 Å. Like HTAs and HTA-like acetyl esterases (14,16,21), monomeric Est22 consists of two domains, i.e., an ␣/␤ hydrolase domain (residues Met 25 to Asp 205 and Phe 313 to Asn 393 ) and a helical bundle domain (residues Ala 206 to Leu 312 ) (Fig. 4D).…”

Section: Resultsmentioning

confidence: 99%

“…Catalytic residues Ser 175 , Asp 340 , and His 373 are all located in the ␣/␤ hydrolase domain. Similar to HTA dimers (14,16), the Est22 dimer is stabilized by the helical bundle domains, mainly by forming a classic antiparallel four-helix bundle between helices ␣LC and ␣LD of each monomer.…”

Section: Resultsmentioning

confidence: 99%

“…HTAs have a catalytic triad and an oxyanion hole similar to those of esterases, but they catalyze the transfer of an acetyl group from acetyl-coenzyme A (CoA) to homoserine (Hse) in the biosynthesis of methionine in vivo (12). HTAs form stable dimers in solution (13)(14)(15), and monomeric HTAs contain two domains, i.e., an ␣/␤ hydrolase domain and a helical bundle domain (16). The juxtaposition of two domains in each HTA monomer forms a deep tunnel, and the catalytic Ser residue is located at the base of the tunnel.…”

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confidence: 99%

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A Novel Subfamily Esterase with a Homoserine Transacetylase-like Fold but No Transferase Activity

Yao

Wang

et al. 2017

Appl Environ Microbiol

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Microbial esterases play important roles in deep-sea organic carbon degradation and cycling. Although they have similar catalytic triads and oxyanion holes, esterases are hydrolases and homoserine transacetylases (HTAs) are transferases. Because two HTA homologs were identified as acetyl esterases, the HTA family was recently divided into the bona fide acetyltransferase subfamily and the acetyl esterase subfamily. Here, we identified and characterized a novel HTA-like esterase, Est22, from a deep-sea sedimentary metagenomic library. Est22 could efficiently hydrolyze esters with acyl lengths of up to six carbon atoms but had no transacetylase activity, which is different from HTAs and HTA-like acetyl esterases. Phylogenetic analysis also showed that Est22 and its homologs form a separate branch of the HTA family. We solved the structures of Est22 and its L374D mutant and modeled the structure of the L374D mutant with p-nitrophenyl butyrate. Based on structural, mutational, and biochemical analyses, Phe 71 and Met 176 in the oxyanion hole and Arg 294 were revealed to be the key substrate-binding residues. A detailed structural comparison indicated that differences in their catalytic tunnels lead to the different substrate specificities of Est22 and the other two HTA subfamilies. Biochemical and sequence analyses suggested that Est22 homologs may have the same substrate recognition and catalysis mechanisms as Est22. Due to the significant differences in sequences, structures, and substrate specificities between Est22 (and its homologs) and the other two HTA subfamilies, we suggest that Est22 and its homologs represent a new subfamily in the HTA family.IMPORTANCE Microbial esterases play important roles in the turnover of organic carbon in the deep sea. Esterases and HTAs represent two groups of ␣/␤ hydrolases. Esterases catalyze the hydrolysis of simple esters and are widely used in the pharmaceutical and agrochemical industries, while HTAs catalyze the transfer of an acetyl group from acetyl-coenzyme A (CoA) to homoserine and are essential for microbial growth. Here, we report on a novel HTA-like esterase, Est22, from a deep-sea sediment. Because of the significant differences in sequences, structures, and substrate specificities of HTAs and HTA-like acetyl esterases, Est22 and its homologs represent a new subfamily in the HTA family. This study offers new knowledge regarding marine esterases.

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Section: Resultsmentioning

confidence: 57%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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A Novel Subfamily Esterase with a Homoserine Transacetylase-like Fold but No Transferase Activity

Yao

Wang

et al. 2017

Appl Environ Microbiol

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“…HiHTA (PDB entry 2B61) 22 , SaHTA (PDB entry 4QLO) 20 , LiHTA (PDB entry 2PL5) 19 . The three solved MetAs are most similar in length to MsHTA (374 residues), with LiHTA (366 residues)…”

Section: Structural Comparisons To Other Htasmentioning

confidence: 99%

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

Chaton

Rodriguez

Reed

et al. 2019

Preprint

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Mycobacterium tuberculosis is 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 MetA converts L-homoserine to O-acetyl-Lhomoserine at the committed step of this pathway. In order to facilitate structure-based drug design, we determined the high-resolution crystal structures of three MetA proteins, including M. tuberculosis (MtMetA), Mycolicibacterium abscessus (MaMetA), and Mycolicibacterium hassiacum (MhMetA). Comparison to other homoserine transacetylase family-members reveals a high degree of structural conservation. Utilizing homologous structures with bound cofactors, we analyzed the potential ligandability of MetA. The deep active-site tunnel surrounding the catalytic serine yielded a number of consensus clusters during mapping, suggesting thatMtMetA is highly druggable.

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A novel esterase subfamily with α/β‐hydrolase fold suggested by structures of two bacterial enzymes homologous to l‐homoserine O‐acetyl transferases

et al. 2015

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MekB from Pseudomonas veronii and CgHle from Corynebacteriumglutamicum belong to the superfamily of α/β‐hydrolase fold proteins. Based on sequence comparisons, they are annotated as homoserine transacetylases in popular databases like UNIPROT, PFAM or ESTHER. However, experimentally, MekB and CgHle were shown to be esterases that hydrolyse preferentially acetic acid esters. We describe the x‐ray structures of these enzymes solved to high resolution. The overall structures confirm the close relatedness to experimentally validated homoserine acetyl transferases, but simultaneously the structures exclude the ability of MekB and CgHle to bind homoserine and acetyl‐CoA. Insofar the MekB and CgHle structures suggest dividing the homoserine transacetylase family into subfamilies, namely genuine acetyl transferases and acetyl esterases with MekB and CgHle as constituting members of the latter.

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Structure of homoserineO-acetyltransferase fromStaphylococcus aureus: the first Gram-positive ortholog structure

Cited by 11 publications

References 23 publications

A Novel Subfamily Esterase with a Homoserine Transacetylase-like Fold but No Transferase Activity

A Novel Subfamily Esterase with a Homoserine Transacetylase-like Fold but No Transferase Activity

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

A novel esterase subfamily with α/β‐hydrolase fold suggested by structures of two bacterial enzymes homologous to l‐homoserine O‐acetyl transferases

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