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Daniel Kalb Dr. Gerald Lackner Marcus Rappe Prof. Dr. Dirk Hoffmeister 《Chembiochem : a European journal of chemical biology》2015,16(10):1426-1430
L ‐α‐Aminoadipic acid reductases catalyze the ATP‐ and NADPH‐dependent reduction of L ‐α‐aminoadipic acid to the corresponding 6‐semialdehyde during fungal L ‐lysine biosynthesis. These reductases resemble peptide synthetases with regard to their multidomain composition but feature a unique domain of elusive function—now referred to as an adenylation activating (ADA) domain—that extends the reductase N‐terminally. Truncated enzymes based on NPS3, the L ‐α‐aminoadipic acid reductase of the basidiomycete Ceriporiopsis subvermispora, lacking the ADA domain either partially or entirely were tested for activity in vitro, together with an ADA‐adenylation didomain and the ADA domainless adenylation domain. We provide evidence that the ADA domain is required for substrate adenylation: that is, the initial step of the catalytic turnover. Our biochemical data are supported by in silico modeling that identified the ADA domain as a partial peptide synthetase condensation domain. 相似文献
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V Bučević-Popović M Sprung B Soldo M Pavela-Vrančič 《Chembiochem : a European journal of chemical biology》2012,13(13):1913-1920
The adenylation (A) domain in nonribosomal peptide synthetases catalyses a two-step reaction in which an amino acid is activated and then transferred to the neighbouring thiolation (T) domain. In this study, we investigated the role of the conserved A9 core sequence of the A-domain of tyrocidine synthetase 1, by analysis of single amino acid mutations in the A9 region. Mutation of an absolutely conserved proline (P490G) significantly reduced the conformational stability of the protein, as evidenced by increased susceptibility to proteolytic cleavage and denaturation. All mutant A-domains were capable of amino acid activation, but the activity in the overall reaction was reduced. Surprisingly, the S491R mutant (mutation at the first residue following the A9 motif) showed elevated overall activity compared to the wild-type protein. Our results suggest that the A9 core sequence plays a role in the second reaction step, in which it could serve as a "clip" for the proper positioning of residues important for the interaction with the T-domain, and/or stabilisation of the thioester-forming conformation. 相似文献
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Maiya S Grundmann A Li SM Turner G 《Chembiochem : a European journal of chemical biology》2006,7(7):1062-1069
A gene encoding a putative dimodular nonribosomal peptide synthetase (NRPS) was identified within a gene cluster of Aspergillus fumigatus, a species reported to produce fumitremorgins and other prenylated alkaloids. The gene was deleted and overexpressed in the genome reference strain Af293, and was also expressed in the naïve host Aspergillus nidulans, which lacks the equivalent gene cluster. While neither fumitremorgins nor the dipeptide brevianamide F (cyclo‐L ‐Trp‐L ‐Pro), an early intermediate, were detected in wild‐type and deletion strains of A. fumigatus, brevianamide F accumulated in fungal cultures following increased expression of the NRPS gene in both A. fumigatus and A. nidulans. We conclude that the gene Afu8g00170, named ftmA, encodes the NRPS brevianamide synthetase. Brevianamide F is the precursor of a variety of fungal prenylated alkaloids with biological activity, including fumitremorgins A, B and C and tryprostatin B. 相似文献
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Dr. Matthias Hauf Dr. Florian Richter Tobias Schneider Thomas Faidt Dr. Berta M. Martins Dr. Tobias Baumann Dr. Patrick Durkin Prof. Dr. Holger Dobbek Prof. Dr. Karin Jacobs Prof. Dr. Andreas Möglich Prof. Dr. Nediljko Budisa 《Chembiochem : a European journal of chemical biology》2017,18(18):1771-1771
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Nonribosomal Peptides Produced by Minimal and Engineered Synthetases with Terminal Reductase Domains
Andreas Tietze Dr. Yan-Ni Shi Dr. Max Kronenwerth Prof. Dr. Helge B. Bode 《Chembiochem : a European journal of chemical biology》2020,21(19):2750-2754
Nonribosomal peptide synthetases (NRPSs) use terminal reductase domains for 2-electron reduction of the enzyme-bound thioester releasing the generated peptides as C-terminal aldehydes. Herein, we reveal the biosynthesis of a pyrazine that originates from an aldehyde-generating minimal NRPS termed ATRed in entomopathogenic Xenorhabdus indica. Reductase domains were also investigated in terms of NRPS engineering and, although no general applicable approach was deduced, we show that they can indeed be used for the production of similar natural and unnatural pyrazinones. 相似文献
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Luping Pang Stephen D. Weeks Arthur Van Aerschot 《International journal of molecular sciences》2021,22(4)
Aminoacyl-tRNA synthetases (aaRSs) catalyze the esterification of tRNA with a cognate amino acid and are essential enzymes in all three kingdoms of life. Due to their important role in the translation of the genetic code, aaRSs have been recognized as suitable targets for the development of small molecule anti-infectives. In this review, following a concise discussion of aaRS catalytic and proof-reading activities, the various inhibitory mechanisms of reported natural and synthetic aaRS inhibitors are discussed. Using the expanding repository of ligand-bound X-ray crystal structures, we classified these compounds based on their binding sites, focusing on their ability to compete with the association of one, or more of the canonical aaRS substrates. In parallel, we examined the determinants of species-selectivity and discuss potential resistance mechanisms of some of the inhibitor classes. Combined, this structural perspective highlights the opportunities for further exploration of the aaRS enzyme family as antimicrobial targets. 相似文献
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Lombó F Velasco A Castro A de la Calle F Braña AF Sánchez-Puelles JM Méndez C Salas JA 《Chembiochem : a European journal of chemical biology》2006,7(2):366-376
Thiocoraline is a thiodepsipeptide antitumor compound produced by two actinomycetes Micromonospora sp. ACM2-092 and Micromonospora sp. ML1, isolated from two marine invertebrates (a soft coral and a mollusc) found of the Indian Ocean coast of Mozambique. By using oligoprimers derived from nonribosomal peptide synthetase (NRPS) consensus sequences, six PCR fragments containing putative NRPS adenylation domains were amplified from the chromosome of Micromonospora sp. ML1. Insertional inactivation of each adenylation domain showed that two of them generated nonproducing mutants, thereby indicating that these domains were involved in thiocoraline biosynthesis. Sequencing of a 64.6 kbp DNA region revealed the presence of 36 complete open reading frames (ORFs) and two incomplete ones. Heterologous expression of a region of about 53 kbp, containing 26 of the ORFs, in Streptomyces albus and S. lividans led to the production of thiocoraline in these streptomycetes. Surprisingly, the identified gene cluster contains more NRPS modules than expected on the basis of the number of amino acids of thiocoraline. TioR and TioS would most probably constitute the NRPS involved in the biosynthesis of the thiocoraline backbone, according to the colinearity of the respective modules. It is proposed that two other NRPSs, TioY and TioZ, could be responsible for the biosynthesis of a small peptide molecule which could be involved in regulation of the biosynthesis of thicoraline in Micromonospora sp. ML1. In addition, a pathway is proposed for the biosynthesis of the unusual starter unit, 3-hydroxy-quinaldic acid. 相似文献
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