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Exploring the binding mechanisms of diaminopimelic acid analogs to meso-diaminopimelate dehydrogenase by molecular modeling.

ABSTRACT: Meso-Diaminopimelic acid (meso-2,6-diamino-heptanedioic acid, DAP) is an important component of the cell wall of many bacteria. Meso-diaminopimelate dehydrogenase (m-Ddh) is a critical enzyme in the process of converting tetrahydrodipicolinate to DAP. Here, we are proposing that DAP analogs targeting m-Ddh may be considered as potential antibiotics. Four DAP analogs without significant structural change from DAP have been obtained and their inhibitory potencies against m-Ddh from the P. gingivalis strain W83 show significant differences from that of DAP. However, their inhibitory mechanisms as for how simple structural change influences the inhibitory potency remain unknown. Therefore, we employed molecular modeling methods to obtain insight into the inhibitory mechanisms of DAP and analogs with m-Ddh. The predicted binding mode of DAP was highly consistent with the experimental structural data and disclosed the important roles played by the binding pocket residues. According to our predictions, the isoxazoline ring of compounds 1 and 2 and the double bonds in compounds 3 and 4 had distinct influences on these compounds' binding to m-Ddh. This enriched understanding of the inhibitory mechanisms of DAP and these four analogs to m-Ddh has provided new and relevant information for future rational development of potent inhibitors targeting m-Ddh.

SUBMITTER: Wang H

PROVIDER: S-EPMC6026047 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Exploring the binding mechanisms of diaminopimelic acid analogs to meso-diaminopimelate dehydrogenase by molecular modeling.

Wang Huiqun H Kellogg Glen E GE Xu Ping P Zhang Yan Y

Journal of molecular graphics & modelling 20180602

Meso-Diaminopimelic acid (meso-2,6-diamino-heptanedioic acid, DAP) is an important component of the cell wall of many bacteria. Meso-diaminopimelate dehydrogenase (m-Ddh) is a critical enzyme in the process of converting tetrahydrodipicolinate to DAP. Here, we are proposing that DAP analogs targeting m-Ddh may be considered as potential antibiotics. Four DAP analogs without significant structural change from DAP have been obtained and their inhibitory potencies against m-Ddh from the P. gingival ...[more]

PMID: 29885593

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Project description:meso-Diaminopimelate dehydrogenase (meso-DAPDH) from Symbiobacterium thermophilum (StDAPDH) is the first member of the meso-DAPDH family known to catalyze the asymmetric reductive amination of 2-keto acids to produce d-amino acids. It is important to understand the catalytic mechanisms of StDAPDH and other enzymes in this family. In this study, based on an evolutionary analysis and examination of catalytic activity, the meso-DAPDH enzymes can be divided into two types. Type I showed highly preferable activity toward meso-diaminopimelate (meso-DAP), and type II exhibited obviously reversible amination activity with a broad substrate spectrum. StDAPDH belongs to type II. A quaternary structure analysis revealed that insertions/deletions (indels) and a loss of quaternary structure resulted in divergence among members of the meso-DAPDH family. A structure alignment of StDAPDH with a representative of type I, the meso-DAPDH from Corynebacterium glutamicum (CgDAPDH), indicated that they had the same folding. Based on sequence and conservation analyses, two amino acid residues of StDAPDH, R35 and R71, were found to be highly conserved within type II while also distinct from each other between the subtypes. Site mutagenesis studies identified R71 as a substrate preference-related residue of StDAPDH, which may serve as an indicator of the amination preference of type II. These results deepen the present understanding of the meso-DAPDH family and provide a solid foundation for the discovery and engineering of meso-DAPDH for d-amino acid biosynthesis.IMPORTANCE The l-form of amino acids is typically more abundant than the d-form. However, the d-form has many important pharmaceutical applications. meso-Diaminopimelate dehydrogenase (meso-DAPDH) from Symbiobacterium thermophilum (StDAPDH) was the first member of meso-DAPDH known to catalyze the amination of 2-keto acids to produce d-amino acids. Accordingly, we analyzed the evolution of meso-DAPDH proteins and found that they form two groups, i.e., type I proteins, which show high preference toward meso-diaminopimelate (meso-DAP), and type II proteins, which show a broad substrate spectrum. We examined the differences in sequence, ternary structure, and quaternary structure to determine the mechanisms underlying the functional differences between the type I and type II lineages. These results will facilitate the identification of additional meso-DAPDHs and may provide guidance to protein engineering studies for d-amino acid biosynthesis.

Dataset Information

Exploring the binding mechanisms of diaminopimelic acid analogs to meso-diaminopimelate dehydrogenase by molecular modeling.

Publications

Exploring the binding mechanisms of diaminopimelic acid analogs to meso-diaminopimelate dehydrogenase by molecular modeling.

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