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Cyanobacterial toxins
Published in Ingrid Chorus, Martin Welker, Toxic Cyanobacteria in Water, 2021
The biosynthesis of the ATXs involves a polyketide synthase (PKS) family of multifunctional enzymes with a modular structural organisation as described in Méjean et al. (2014). A detailed biochemical description of the adenylation domain protein AnaC revealed the activation of proline as starter, and not glutamate as previously proposed (Dittmann et al., 2013). The biosynthetic pathway describes AnaB, AnaC and AnaD as acting in the first steps (which have been fully reproduced in vitro; Méjean et al., 2009; Méjean et al., 2010; Mann et al., 2011), and AnaE, AnaF, Ana J and AnaG catalysing the following steps, with the latter adding two carbons and methylating the substrate to produce HTX. The release of ATXs may be catalysed by the thioesterase AnaA, although this has not been experimentally verified (Pearson et al., 2016) or a spontaneous decarboxylation step may occur to yield the amine alkaloid ATX (Dittmann et al., 2013).
Novel Metabolites from Endophytes
Published in Gustavo Molina, Zeba Usmani, Minaxi Sharma, Abdelaziz Yasri, Vijai Kumar Gupta, Microbes in Agri-Forestry Biotechnology, 2023
Jhumishree Meher, Raina Bajpai, Md. Mahtab Rashid, Basavaraj Teli, Birinchi Kumar Sarma
It is considered that the secondary metabolites are generally the chemical signals for communication between the host and endophyte, which further helps to inhibit pathogenic microbes (Brakhage and Schroeckh, 2011). In the bacterial genomes, the clusters of functional genes are organized as operons, which are transcribed together as a single unit (Koonin, 2009). Similarly, in fungi also it is quite evident that genes in clusters regulate an array of biological functions in cells (Gutierrez et al., 1999; Rosewich and Kistler, 2000). These gene clusters also regulate the secondary metabolites production in endophytes (Trail et al., 1995; Lo et al., 2012). In fungi, usually these gene clusters code for two important classes of multimodular enzyme complexes, that is, non-ribosomal peptide synthetases [NRPS] and polyketide synthases [PKS], which consists of various domains with well-defined functions (Cane and Walsh, 1999; Brakhage and Schroeckh, 2011; Evans et al., 2011; Wang et al., 2014; Amoutzias et al., 2016). These form the backbone for the majority of secondary metabolites. A classical modular PKS consist of acyltransferase (AT), ketosynthase (KS), and acyl-carrier protein domains (Crawford et al. 2009). However, the NRPS system is composed of an adenylation (A) domain, a peptidyl carrier protein domain and a condensation (C) domain (Nikolouli and Mossialos, 2012). Examples of important derivatives of NRP used as antibiotics are penicillin and cephalosporin. The immune suppressant such as cyclosporine is also a derivative of NRP, while the lovastatin is a derivative of polyketide (Brakhage, 1998; Hoffmeister and Keller, 2007). Furthermore, mixed PKS-NRP hybrid origin compounds have also been isolated, for example, aspyridones (Bergmann et al., 2007).
New Strategies to Discover Non-Ribosomal Peptides as a Source of Antibiotics Molecules
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Mario Alberto Martínez-Núñez, Zuemy Rodríguez-Escamilla, Víctor López y López
Nonribosomal peptides (NRPs) are secondary metabolites with antibiotics properties. They are synthesized on large nonribosomal peptide synthetase (NRPS) enzyme complexes, which means that their synthesis is independent of ribosomes (Finking and Marahiel, 2004). The NRPSs are modularly organized, with each module consisting of several domains, and at least three domains must be present for the formation of the NRPs: adenylation (A) domain, peptidyl carrier protein (PCP) or thiolation (T) domain, and condensation (C) domain which carry out the synthesis of nonribosomal peptides (Drake et al., 2016). The A-domain is responsible for picking the specific amino acid monomers that are incorporated into final NRPs; there are hundreds of different A-domains with different specificities and they have been classified using the Stachelhaus code, each one incorporating a specific amino acid as a monomer (Mohimani et al., 2014). The biosynthesis of the NRPs can be carried out by three types of NRPSs: type A, a linear NRPS in which each enzymatic domain, and therefore each module, is used once during the biosynthesis of the NRPs; type B, an iterative NRPS that uses all its modules more than once during the biosynthesis of a single NRP; whereas Type C is a non-linear NRPS that deviates from the C-A-T domain rule of module formation with certain domains that work more than once during the biosynthesis of a single NRP (Felnagle et al., 2008). Soil-inhabiting microorganisms, such as Actinomycetes and Bacilli, and eukaryotic filamentous fungi are mostly producers of nonribosomal peptides, but marine microorganisms have also emerged as a source for such peptides (Mootz et al., 2002). The first NRP with antibiotic activity used as a drug was the penicillin extracted from the fungus Penicillium notatum by Alexander Fleming (Bennett and Chung, 2001). Today, P. chrysogenum is the most important organism used in the pharmaceutical industry to produce penicillin at the industrial scale, and despite the alarming increase in the dissemination of pathogens resistant to penicillin, the worldwide demand for this antibiotic is still enormous (Prauße et al., 2016). These secondary metabolites represent promising scaffolds for the development of new drugs (Sieber and Marahiel, 2005) due to the great structural diversity they have, derived from having more than 300 different precursors and are not limited to only 20 proteinogenic amino acids (Von Döhren, 1990); for example, NRPs contain amino acids like ornithine or imino acids (Singh et al., 2012). In addition to the above, the amount of modules used by the NRPSs for the synthesis of the NRP, whether the peptide is cyclized (macrocyclic, branched macrocyclic) or not, and its decoration by various modifying enzymes, including glycosyltransferases, carbamoyltransferases, and oxidases, generates an enormous structural diversity (Losey et al., 2001; Walsh et al., 2001; Etchegaray et al., 2004; Felnagle et al., 2008).
Kurstakin molecules facilitate diesel oil assimilation by Acinetobacter haemolyticus strain 2SA through overexpression of alkane hydroxylase genes
Published in Environmental Technology, 2021
Mamadou Malick Diallo, Caner Vural, Umut Şahar, Guven Ozdemir
In this study, surfactin and fengycin synthetase genes were not detected upon amplification by PCR. However, the kurstakin synthetase gene was amplified using kurstF and kurstR primers. The protein BLAST indicated 96% similarity with the KursB adenylation module of Bacillus thuringiensis bthur0010_59530 (accession number EEM74023; from 1056 to 1285) (Figures S2 and S3). Moreover, this result was confirmed by CapLC ESI-Ion trap-MS/MS analysis.
Improvement of lipopeptide production in Bacillus subtilis HNDF2-3 by overexpression of the sfp and comA genes
Published in Preparative Biochemistry & Biotechnology, 2023
Jiawen Wang, Yuan Ping, Wei Liu, Xin He, Chunmei Du
In recent years, with the in-depth study of key enzymes and transcription factors of the lipopeptide synthesis pathway, the high production of microbial lipopeptide using more targeted genetically engineered methods has become a major research topic. The basic synthesis of lipopeptide is as follows: a branched-chain fatty acid is synthesized and activated and then connects with amino acids; the peptide chain continuously extends and finally cyclizes to form lipopeptide (Figure 1). The peptide part of the lipopeptide is synthesized in a ribosome-independent manner by complexes of non-ribosomal peptide synthetase (NRPS) enzymes.[14] NRPSs are composed of multiple multifunctional modules that cooperate with each other, and peptide extension can be performed among the modules to further extend a cycle.[15] A typical NRPS extension module consists of an adenylation (A) domain used for activating specific amino acids, a condensation (C) domain used for forming peptide bonds, and a thiolation (T) domain (i.e., peptidyl carrier protein (PCP) domain) used for delivery.[16] Acyl carrier proteins (ACPs) are key functional domains of fatty acid synthetase (FAS), which is required for the biosynthesis of the fatty acid part of the lipopeptide.[17] In Bacillus subtilis, the type II PPTase encoded by sfp gene can use for posttranslational modification of PCPs and ACPs, converting them from the inactive apo-form to the active holo-form.[18,19] Wang et al.[20] increased the iturin A production of B. amyloliquefacienss by 3.2 times, to 17.0 mg/L by overexpressing the sfp gene and knockout of kinA, bdh, dhbF and rapA. Tan et al.[21] increased the fengycin production of B. subtilis 168 that could not produce lipopeptide to 10.4 mg/L by introducing the sfp gene and replacing the original promoter of the degQ gene with the P43 promoter. Therefore, overexpression of the sfp gene is a feasible method to increase lipopeptide production.