Natural resorcylic lactones derived from alternariol

• Joachim Podlech

Beilstein J. Org. Chem. 2024, 20, 2171–2207, doi:10.3762/bjoc.20.187

Chemo-enzymatic total synthesis: current approaches toward the integration of chemical and enzymatic transformations

• Ryo Tanifuji and
• Hiroki Oguri

Beilstein J. Org. Chem. 2024, 20, 1693–1712, doi:10.3762/bjoc.20.151

• TylGI loads a methylmalonyl-CoA onto the acyl carrier protein (ACP) in module 1. The ketosynthase-like decarboxylase (KSQ) domain catalyzes the decarboxylation of the loaded methylmalonyl moiety, and subsequent modules 2 and 3 extend the carbon chain using two molecules of malonyl-CoA. The β

Bioinformatic prediction of the stereoselectivity of modular polyketide synthase: an update of the sequence motifs in ketoreductase domain

• Changjun Xiang,
• Shunyu Yao,
• Ruoyu Wang and
• Lihan Zhang

Beilstein J. Org. Chem. 2024, 20, 1476–1485, doi:10.3762/bjoc.20.131

• embedded in the assembly line or not. All cis-AT PKS modules contain a ketosynthase (KS), an acyltransferase (AT), and an acyl carrier protein (ACP) to produce β-keto-intermediates, and some modules contain additional β-processing domains such as ketoreductase (KR), dehydratase (DH), and enoylreductase (ER

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

• second ketosynthase of the polyketide synthase BaeJ involved in bacillaene biosynthesis (BaeJ-KS2). For this purpose, both enantiomers of a 13C-labelled N-acetylcysteamine thioester (SNAC ester) surrogate of the proposed natural intermediate of BaeJ-KS2 were synthesised, including an enzymatic step with

• -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

• : epimerization domain, TE: thioesterase domain, KS: ketosynthase domain, AT: acyl transferase domain, KR: ketoreductase domain, TauD: taurine dioxygenase domain. Substrate specificity of A and KS domains is presented at the top of each module (FA: fatty acyl, Arg: arginine, MM: methyl malonyl, Asp: aspartic acid

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

• [26]), acyltransferase (AT) (for cis-AT PKS [15]), or ketosynthase (KS) domains (in trans-acyltransferase PKS systems [19][27]). Moreover, in the large majority of cases, the gene order within a BGC reflects the order of the corresponding enzymes during the biosynthesis of the associated NP [19

• harbor non-canonical module architectures and cryptic domains [19][22]. As a result, the colinearity rule cannot be applied to predict trans-AT PKS-derived polyketide core structures [19]. Instead, it has been observed that the amino acid sequences of the ketosynthase domains in trans-AT PKSs correlate

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

• biosynthesis start at FclJ (the Figures were adapted and modified from [20] and [22]. KS: ketosynthase, AT: acyltransferase, T: thiolation domain, KR: ketoreductase, CLF: chain length factor domain, DH: dehydratase, Ox: 2-nitropropane dioxygenase (enoyl reductase), AMT: aminotransferase, TR: thioester

• . stockiae, g: KK7.4, h: KJ12.1, i: X. bovienii, j: P. temperata. KS: ketosynthase, AT: acyltransferase, T: thiolation domain, KR: ketoreductase, CLF: chain length factor domain, DH: dehydratase, Ox: 2-nitropropane dioxygenase (enoyl reductase), AMT: aminotransferase, TR: thioester reductase, Nit: nitrilase

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

• PKSs [29], and ketosynthase domains in trans-AT PKSs [30][31] are highly substrate-specific and function as gatekeepers to ensure that a single natural product is produced with high efficiency. Erroneous or stalled intermediates are removed from the assembly lines [32][33]. Novelty in these assembly

Volatiles from the hypoxylaceous fungi Hypoxylon griseobrunneum and Hypoxylon macrocarpum

• Jan Rinkel,
• Alexander Babczyk,
• Tao Wang,
• Marc Stadler and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2018, 14, 2974–2990, doi:10.3762/bjoc.14.277

• (42), B) 3,4,5-trimethoxytoluene (44), and C) 2,4,5-trimethoxytoluene (45). Synthesis of trimethylanisoles 24 and 24d. Hypothetical biosynthesis of 24. ACP: acyl carrier protein, AT: acyl transferase, KR: ketoreductase, KS: ketosynthase, mal-SCoA: malonyl-SCoA, MT: methyl transferase, SAM: S-adenosyl

Volatiles from the tropical ascomycete Daldinia clavata (Hypoxylaceae, Xylariales)

• Tao Wang,
• Kathrin I. Mohr,
• Marc Stadler and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2018, 14, 135–147, doi:10.3762/bjoc.14.9

• is shown in Scheme 7 that is likely performed by a typical fungal iterative polyketide synthase (PKS). Starting from acyl-carrier-protein (ACP) bound acetate a first elongation step with malonyl-SCoA (Mal-SCoA) catalysed by an acyl transferase (AT) and a ketosynthase (KS) domain yields acetoacetyl

Sulfation and amidinohydrolysis in the biosynthesis of giant linear polyenes

• Hui Hong,
• Markiyan Samborskyy,
• Katsiaryna Usachova,
• Katharina Schnatz and
• Peter F. Leadlay

Beilstein J. Org. Chem. 2017, 13, 2408–2415, doi:10.3762/bjoc.13.238

• each of the characteristic active site sequence motifs for the ketosynthase (KS), acyltransferase (AT), ketoreductase (KR), dehydratase (DH), and enoylreductase (ER) domains of each of the 27 extension modules, including the newly-recognised YGP motif of active DH domains [8] between the three PKS

Polyketide stereocontrol: a study in chemical biology

• Kira J. Weissman

Beilstein J. Org. Chem. 2017, 13, 348–371, doi:10.3762/bjoc.13.39

• appropriate precursor from the cellular pool, a ketosynthase (KS) which extends the chain via a Claisen-like decarboxylative condensation, and a non-catalytic acyl carrier protein (ACP) to which the intermediates are covalently tethered through a phosphopantetheine prosthetic group. The modules can also

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

• carrier protein; AT, acyl transferase; C, condensation; KR, ketoreductase; KS, ketosynthase; PCP, peptidyl carrier protein; TE, thioesterase. The gene aulD encodes a type II thioesterase. Testing of AulA (A1-A2-KR-PCP) and a truncated variant (A2-KR-PCP) in the ATP-[32P]pyrophosphate exchange assay using

Evidence for an iterative module in chain elongation on the azalomycin polyketide synthase

• Hui Hong,
• Yuhui Sun,
• Yongjun Zhou,
• Emily Stephens,
• Markiyan Samborskyy and
• Peter F. Leadlay

Beilstein J. Org. Chem. 2016, 12, 2164–2172, doi:10.3762/bjoc.12.206

• the eventual product is often referred to as colinearity. Each module contains a ketosynthase (KS) domain, which recruits the growing polyketide acyl chain from the previous module and catalyses its Claisen-like carbon–carbon bond condensation with the incoming (alkyl)malonyl extender unit, tethered

• loading acyl carrier protein (ACP) by the action of a dedicated acyltransferase (AT) [35]. The starter unit is then transferred from the loading ACP to the ketosynthase (KS) (step a). In the first cycle of chain extension (step b), the starter is condensed with malonyl-ACP and the resulting β-ketoacyl-ACP

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

• ]. Polyketides Polyketide natural products are biosynthesised by polyketide synthases (PKSs) of the types I–III. Type I PKS are multimodular megaenzyme complexes that produce linear, reduced polyketides in an assembly line process that uses acyl carrier proteins (ACP), ketosynthase (KS) and acyl transferase (AT

Biosynthesis of α-pyrones

• Till F. Schäberle

Beilstein J. Org. Chem. 2016, 12, 571–588, doi:10.3762/bjoc.12.56

• moiety, was identified in Pseudomonas sp. GM30, and it was subsequently proven by heterologous expression experiments with ketosynthase which is responsible for the biosynthesis of these derivatives [63]. 1.3 Monobenzo-α-pyrones Synthetic derivatives of the natural product 4-hydroxycoumarin are widely

• malonyl-CoA-derived extender units. This process is catalyzed by the concerted action of a ketosynthase (KS), an acyltransferase (AT), and either a phosphopantetheinylated acyl carrier protein (ACP), or CoA to which the nascent chain is attached. After each elongation step the β-keto functionality can be

• and lactonization to yield the polyketide 76. 2.3 Biosynthesis by PKSIII systems Type III PKSs are relatively small molecules, since in contrast to the PKSs of type I and II they solely consist of a single ketosynthase. A single KS connects the CoA-bound starter and extender units; and also in this

A novel and widespread class of ketosynthase is responsible for the head-to-head condensation of two acyl moieties in bacterial pyrone biosynthesis

• Darko Kresovic,
• Florence Schempp,
• Zakaria Cheikh-Ali and
• Helge B. Bode

Beilstein J. Org. Chem. 2015, 11, 1412–1417, doi:10.3762/bjoc.11.152

• including a novel derivative. Moreover this novel class of ketosynthases is only distantly related to other pyrone-forming enzymes identified in the biosynthesis of the potent antibiotics myxopyronin and corallopyronin. Keywords: cell–cell communication; ketosynthase; photopyrones; pseudopyronines; quorum

• PluR, a LuxR-like receptor [7]. The binding of photopyrones by PluR leads to the expression of the Photorhabdus clumping factor (PCF) operon (pcfABCDEF) that causes clumping of cells and results in insect toxicity [7]. Responsible for the formation of photopyrones is an unusual ketosynthase, named

• ], xenocyloin [16] and nonactin biosynthesis [17]. Plasmid integration into the gene plu4844 encoding the ketosynthase PpyS in P. luminescens resulted in the complete loss of photopyrone production as shown previously [7]. Additionally, heterologous expression of ppyS, bkdABC and ngrA in E. coli allowed the

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

• , ketosynthase; AT, acyltransferase; ACP, acyl carrier protein; TE, thioesterase; *AntP is a pathway-specific kynureninase that is encoded by L- and I-form ant gene clusters. σAntA comprises a new subfamily of ECF RNA polymerase σ factors. σAntA amino acid sequences were aligned to amino acid sequences of random

Quantification of N-acetylcysteamine activated methylmalonate incorporation into polyketide biosynthesis

• Stephan Klopries,
• Uschi Sundermann and
• Frank Schulz

Beilstein J. Org. Chem. 2013, 9, 664–674, doi:10.3762/bjoc.9.75

• ][7][8]. Abbreviations: AT: acyltransferase, ACP: acyl carrier protein, KS: ketosynthase, KR: ketoreductase, DH: dehydratase, ER: enoylreductase, TE: thioesterase. Structures of erythromycin (left) and rapamycin (right). In this experiment both compounds were labeled in their methyl side chains with

Novel fatty acid methyl esters from the actinomycete Micromonospora aurantiaca

• Jeroen S. Dickschat,
• Hilke Bruns and
• Ramona Riclea

Beilstein J. Org. Chem. 2011, 7, 1697–1712, doi:10.3762/bjoc.7.200

• to a highly conserved serine residue of the ACP (Scheme 1A). The acetyl moiety is then taken over by a conserved cystein residue of the ketosynthase (KS) making the ACP in turn available for the uptake of an elongation unit, in most cases malonyl-CoA, which is again selected and transferred by the AT

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

• , assembled and optionally modified. The maximal set of domains of an individual PKS module is identical to animal fatty acid synthase (FAS) [13] and consists of ketosynthase (KS), acyltransferase (AT), ketoreductase (KR), dehydratase (DH), enoyl reductase (ER) and acyl carrier protein (ACP) domains [14

• module containing an integrated halogenase and a tandem acyl carrier protein tridomain (ACP3), a discrete ACPIV, a discrete ketosynthase (KS), a 3-hydroxy-3-methylglutaryl CoA synthetase (HMGCS), a dehydratase (ECH1)/decarboxylase (ECH2) pair and an enoyl reductase (ER) domain. HMG-CoA synthetases were

• , including the PKS module with the tandem acyl carrier protein tridomain (ACP3) as well as the discrete ACPIV, the discrete ketosynthase, the 3-hydroxy-3-methylglutaryl CoA synthetase (HMGCS), the dehydratase (ECH1)/decarboxylase (ECH2) pair and the ER domain [42][44]. Notably, the PKS module harbors a