Substrate specificity of a ketosynthase domain involved in bacillaene biosynthesis

• Zhiyong Yin and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2024, 20, 734–740, doi:10.3762/bjoc.20.67

• -labelled carbons. Biosynthetic model for bacillaene (1). M1–M17 indicate modules 1–17. A = adenylation domain, ACP = acyl carrier protein, AT = acyltransferase, C = condensation domain, DH = dehydratase, KR = ketoreductase, KS = ketosynthase, MT = methyltransferase, PCP = peptidyl carrier protein, TE

Chemoenzymatic synthesis of macrocyclic peptides and polyketides via thioesterase-catalyzed macrocyclization

• Senze Qiao,
• Zhongyu Cheng and
• Fuzhuo Li

Beilstein J. Org. Chem. 2024, 20, 721–733, doi:10.3762/bjoc.20.66

• essential domains, namely adenylation (A), condensation (C), and peptidyl carrier protein (PCP). Each type I PKS module consists of three core domains containing acyltransferase (AT), ketosynthase (KS), and acyl carrier protein (ACP). PCP and ACP are collectively called thiolation domain (T). The sequence

New variochelins from soil-isolated Variovorax sp. H002

• Jabal Rahmat Haedar,
• Aya Yoshimura and
• Toshiyuki Wakimoto

Beilstein J. Org. Chem. 2024, 20, 692–700, doi:10.3762/bjoc.20.63

• by diamonds. EIMS of DMOX derivatized free fatty acids derived from variochelins C–E (3–5). (a) 3, (b) 4, and (c) 5. (a) Plausible biosynthetic pathway of variochelin A–E (1–5). The circles represent domains: A: adenylation domain, C: condensation domain, PCP: peptide carrier protein, E

Development of a chemical scaffold for inhibiting nonribosomal peptide synthetases in live bacterial cells

• Fumihiro Ishikawa,
• Sho Konno,
• Hideaki Kakeya and
• Genzoh Tanabe

Beilstein J. Org. Chem. 2024, 20, 445–451, doi:10.3762/bjoc.20.39

• University, Sakyo, Kyoto 606-8501, Japan 10.3762/bjoc.20.39 Abstract The adenylation (A) domain is essential for non-ribosomal peptide synthetases (NRPSs), which synthesize various peptide-based natural products, including virulence factors, such as siderophores and genotoxins. Hence, the inhibition of A

• synthetase A (GrsA) in the gramicidin S-producer Aneurinibacillus migulanus ATCC 9999, providing an alternative scaffold to develop novel A-domain inhibitors. Keywords: adenylation domain inhibitor; gramicidin S synthetase; natural product; nonribosomal peptide; nonribosomal peptide synthetase

• (Figure 1) [3]. The adenylation (A) domain in NRPSs is responsible for the selection and activation of amino acids, hydroxy acids, and aryl acids upon ATP consumption (Figure 2a) [4]. The activated aminoacyladenosine monophosphate (AMP) is transferred to the thiol group of a phosphopantetheine prosthetic

Discovery of unguisin J, a new cyclic peptide from Aspergillus heteromorphus CBS 117.55, and phylogeny-based bioinformatic analysis of UngA NRPS domains

• Sharmila Neupane,
• Marcelo Rodrigues de Amorim and
• Elizabeth Skellam

Beilstein J. Org. Chem. 2024, 20, 321–330, doi:10.3762/bjoc.20.32

• of the UngA NRPS were analyzed in an attempt to understand the lack of substrate specificity observed. Keywords: adenylation domain; condensation domain; fungal non-ribosomal peptide synthetase; heptapeptide; unguisin biosynthesis; Introduction Unguisins are a small family of fungal cyclic

• of several catalytic domains organized into modules. Typically, a module possesses an adenylation (A) domain for selecting and activating amino- or keto acids, a thiolation (T) domain for shuttling intermediates between catalytic domains, and a condensation (C) domain that catalyzes amide or ester

Intermediates and shunt products of massiliachelin biosynthesis in Massilia sp. NR 4-1

• Till Steinmetz,
• Blaise Kimbadi Lombe and
• Markus Nett

Beilstein J. Org. Chem. 2023, 19, 909–917, doi:10.3762/bjoc.19.69

• protein RS02200: FAAL: fatty acyl-AMP ligase; ACP: acyl carrier protein; KS: β-ketoacyl synthase; AT: acyltransferase; KR: ketoreductase; C: condensation; A: adenylation; MT: methyltransferase; PCP: peptidyl carrier protein. A discrete enzyme, the thiazolinyl imide reductase RS02195 (Red), catalyzes the

Navigating and expanding the roadmap of natural product genome mining tools

• Friederike Biermann,
• Sebastian L. Wenski and
• Eric J. N. Helfrich

Beilstein J. Org. Chem. 2022, 18, 1656–1671, doi:10.3762/bjoc.18.178

• -like pathways are canonical type I cis-acyltransferase polyketide synthases (PKSs) and type A non-ribosomal peptide synthetases (NRPSs) (Figure 2A) [25][26]. The substrate specificity of the specificity conferring domains in each module can be predicted from the sequences of adenylation (A) (for NRPS

Fabclavine diversity in Xenorhabdus bacteria

• Sebastian L. Wenski,
• Harun Cimen,
• Natalie Berghaus,
• Sebastian W. Fuchs,
• Selcuk Hazir and
• Helge B. Bode

Beilstein J. Org. Chem. 2020, 16, 956–965, doi:10.3762/bjoc.16.84

• reductase, Nit: nitrilase, A: adenylation, C: condensation, E: epimerization, TP: transport. Comparison of the fcl BGCs in Xenorhabdus and Photorhabdus strains responsible for the fabclavine biosynthesis. a: X. szentirmaii, b: X. budapestensis, c: X. cabanillasii, d: X. indica, e: X. hominickii, f: X

• , A: adenylation, C: condensation, E: epimerization, TP: transport. Compound list of the fabclavine derivatives identified in this work. The structures are based on MALDI–HRMS and MALDI–MS2 analyses using the known structure of 1 as a reference [20]. The derivatives 1–4 and 17–22 were described

Bacterial terpene biosynthesis: challenges and opportunities for pathway engineering

• Eric J. N. Helfrich,
• Geng-Min Lin,
• Christopher A. Voigt and
• Jon Clardy

Beilstein J. Org. Chem. 2019, 15, 2889–2906, doi:10.3762/bjoc.15.283

• . Biosynthetic core enzymes of well-characterized classes of natural products, such as modular thiotemplate assembly lines (NRPSs, PKSs), are usually highly specific and produce only a few closely related natural product analogs. Adenylation domains in NRPSs [26][27][28], acyltransferase (AT) domains in cis-AT

Genomics-inspired discovery of massiliachelin, an agrochelin epimer from Massilia sp. NR 4-1

• Jan Diettrich,
• Hirokazu Kage and
• Markus Nett

Beilstein J. Org. Chem. 2019, 15, 1298–1303, doi:10.3762/bjoc.15.128

• stereochemistry at the C2 position derived from L-cysteine. This is because the MicC homolog from Massilia sp. NR 4-1 features only a single adenylation domain for the activation of L-cysteine, which corresponds to the micacocidin and yersiniabactin assembly lines [13][16]. An inspection of the ketoreductase (KR

• , fatty acyl-AMP ligase; ACP, acyl carrier protein; KS, β-ketoacyl synthase; AT, acyltransferase; KR, ketoreductase; C, condensation; A, adenylation; MT, methyltransferase; PCP, peptidyl carrier protein; TE, thioesterase. The asterisk indicates a methyltransferase-like epimerization domain. C) UV

Biochemical and structural characterisation of the second oxidative crosslinking step during the biosynthesis of the glycopeptide antibiotic A47934

• Veronika Ulrich,
• Clara Brieke and
• Max J. Cryle

Beilstein J. Org. Chem. 2016, 12, 2849–2864, doi:10.3762/bjoc.12.284

• cryoprotectant solution). (a) Schematic representation of the biosynthesis of A47934 by the heterotetrameric non-ribosomal peptide synthetase; the 7 modules of the A47934 NRPS machinery are distributed over 4 proteins (StaA to StaD) and exhibit the typical NRPS domain architecture with adenylation (A; purple

A non-canonical peptide synthetase adenylates 3-methyl-2-oxovaleric acid for auriculamide biosynthesis

• Daniel Braga,
• Dirk Hoffmeister and
• Markus Nett

Beilstein J. Org. Chem. 2016, 12, 2766–2770, doi:10.3762/bjoc.12.274

• enzymes. Among them, the non-canonical 199 kDa four-domain nonribosomal peptide synthetase, AulA, is extraordinary in that it features two consecutive adenylation domains. Here, we describe the functional characterization of the recombinantly produced AulA. The observed activation of 3-methyl-2-oxovaleric

• acid by the enzyme supports the hypothesis that it participates in the biosynthesis of auriculamide. An artificially truncated version of AulA that lacks the first adenylation domain activated this substrate like the full-length enzyme which shows that the first adenylation domain is dispensable

• enzymatic activity, molecules with methylene α-carbons led to low turnover. Such enzymatic plasticity is an important attribute to help in the perpetual search for novel molecules and to access a greater structural diversity by mutasynthesis. Keywords: adenylation; auriculamide; biosynthesis; Herpetosiphon

Biosynthesis of oxygen and nitrogen-containing heterocycles in polyketides

• Franziska Hemmerling and
• Frank Hahn

Beilstein J. Org. Chem. 2016, 12, 1512–1550, doi:10.3762/bjoc.12.148

Cyclisation mechanisms in the biosynthesis of ribosomally synthesised and post-translationally modified peptides

• Andrew W. Truman

Beilstein J. Org. Chem. 2016, 12, 1250–1268, doi:10.3762/bjoc.12.120

• phosphate. This points to an adenylation-type mechanism, and the authors also proposed a hemiorthoamide mechanism to account for the absence of wasted ATP hydrolysis (Figure 3B, pathway a). An alternative mechanism that would also account for the [18O]-labelling results involves direct activation of the

Recent highlights in biosynthesis research using stable isotopes

• Jan Rinkel and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2015, 11, 2493–2508, doi:10.3762/bjoc.11.271

• : formyltransferase, A: adenylation, CP: peptidyl carrier protein, C: condensation, E/C: condensation + epimerization, TE: thioesterase). For the absolute configuration of incorporated amino acids relevant domains are highlighted with arrows. Modules not shown consist of alternating C and E/C. Asterisks indicate

The regulation and biosynthesis of antimycins

• Ryan F. Seipke and
• Matthew I. Hutchings

Beilstein J. Org. Chem. 2013, 9, 2556–2563, doi:10.3762/bjoc.9.290

• . griseoflavus Tü4000, which truncates the truncates C1 of AntC into a discrete protein. CCR, crotonyl-CoA reductase. Proposed biosynthetic pathway for antimycins. The antimycin biosynthetic pathway is described in detail in the text. C = condensation; A, adenylation; T, thiolation; KR, ketoreduction; KS

Natural product biosyntheses in cyanobacteria: A treasure trove of unique enzymes

• Jan-Christoph Kehr,
• Douglas Gatte Picchi and
• Elke Dittmann

Beilstein J. Org. Chem. 2011, 7, 1622–1635, doi:10.3762/bjoc.7.191

• modules, each being responsible for the incorporation of a single amino acid. The order of these modules typically follows a colinearity rule, i.e., the succession of modules corresponds to the order of amino acids in the final product. A minimal module is composed of an amino acid-activating adenylation

• [27], the exact roles of AerE and AerF remain to be elucidated (Figure 4B). The succeeding NRPS adenylation domain is then directly activating Choi as a substrate. The aeruginoside assembly line does not contain a thioesterase or reductase domain [26]. It is thus currently unclear how the final

• between the condensation and adenylation domain. This sequence stretch does not show homology to any of the anabaenopeptin (Apt) biosynthesis proteins, suggesting a different mechanism of ureido bond formation for anabaenopeptins and syringolin [33]. Anatoxin Anatoxin-a (6) and homoanatoxin-a are potent