Recent advances in organocatalytic atroposelective reactions

• Henrich Szabados and
• Radovan Šebesta

Beilstein J. Org. Chem. 2025, 21, 55–121, doi:10.3762/bjoc.21.6

Chemical structure metagenomics of microbial natural products: surveying nonribosomal peptides and beyond

• Thomas Ma and
• John Chu

Beilstein J. Org. Chem. 2024, 20, 3050–3060, doi:10.3762/bjoc.20.253

• ., the type of alkylmalonate it incorporates into a growing PK intermediate [61]. Furthermore, Xiang et al. reported recently that the stereochemistry of each new chiral center resulting from each alkylmalonate BB incorporation can be predicted based on the corresponding ketoreductase domain sequence [83

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

• -ketoreductase (KR) and dehydratase (DH) domains, sequentially catalyze the carbonyl reduction and dehydration of the extended polyketide chains to provide thioester 62 connecting to the ACP domain of module 3. TylGII then iterates similar conversions including carbon chain extension reaction, carbonyl reduction

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

• medicines such as erythromycin and rapamycin. They are often rich in stereocenters biosynthesized by the ketoreductase (KR) domain within the polyketide synthase (PKS) assembly line. Previous studies have identified conserved motifs in KR sequences that enable the bioinformatic prediction of product

• : bioinformatics; conserved motifs; ketoreductase; polyketide synthase; stereocontrol; Introduction Type I modular polyketide synthases (PKSs) are large enzyme complexes that play a crucial role in the biosynthesis of bacterial polyketides, including many important clinical drugs such as erythromycin (antibiotic

• 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

• of a ketoreductase (KR) domain in module 1, the starter unit was initially suggested to be α-hydroxyisocaproate [14], but later it was shown that the KR of module 3 acts twice, in the reduction of the β-ketoacyl intermediate of the elongation step of module 3 and in the reduction of the α

• -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

• of monomers in the final product intimately correlates with the order of modules in the assembly line (Scheme 1a). Beyond several additional domains, including ketoreductase (KR), dehydratase (DH), enoyl reductase (ER), and methyltransferase (MT) domains and epimerase (E) domains, which are

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

Identification of the p-coumaric acid biosynthetic gene cluster in Kutzneria albida: insights into the diazotization-dependent deamination pathway

• Seiji Kawai,
• Akito Yamada,
• Yohei Katsuyama and
• Yasuo Ohnishi

Beilstein J. Org. Chem. 2024, 20, 1–11, doi:10.3762/bjoc.20.1

• FAM_00125 (approximately 40 BGCs) do not have avaA8 (FabG-like ketoreductase) and avaC (major facilitator superfamily transporter) homologs, but have a cmaG-like gene encoding an FMN-dependent oxidoreductase and a cmaR-like gene encoding a LysR family transcriptional regulator (Figure 1, Figures S1 and S2

• the activity of CmaG (a putative FMN-dependent oxidoreductase), it is expected to catalyze the reduction of the keto group of an β-ketoacyl intermediate, similar to the ketoreductase of fatty acid synthase (FAS) and highly reducing type II PKS. This hypothesis is supported by the fact that cmaG exists

• in the cma cluster instead of avaA8, which encodes a putative FabG-like ketoreductase, and by the observation that the yield of compound 6 decreased considerably when cmaG was removed from the heterologous expression system (Figure 1A and Figure 2B, and Figures S1 and S2 in Supporting Information

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

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

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

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

• the acyl carrier protein (ACP) of an iterative fungal PKS, can be elongated with malonyl-SCoA (mal-SCoA) followed by C-methylation with S-adenosyl-L-methionine (SAM). Two more rounds of elongation with mal-SCoA, the first extension with C-methylation and action of a ketoreductase (KR), result in a

• (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

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

• incorporate a variable complement of the processing activities which act in each cycle of FA biosynthesis, including ketoreductase (KR), dehydratase (DH) and enoyl reductase (ER) domains; these activities lead successively to hydroxy groups, olefinic moieties or saturated methylene groups at specific

• ketoreductase structures, the role of these residues in shepherding the substrates into their correct orientations remains unclear, possibly because none of the KRs was co-crystallized as a ternary complex with both native polyketide intermediate and cofactor. To date, two alternative mechanisms have been

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

• being tethered to the PCP domain by the PKS-type ketoreductase domain (KR), as reported for other natural products, such as pyridomycin [11], cereulide, valinomycin [12], and bacillaene [13]. Hence, the molecule to be recognized and activated by AulA would be 3-methyl-2-oxovaleric acid (3). Seminal work

• 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

• to an acyl carrier protein (ACP) domain. The choice of extender unit installed onto the ACP is dictated by an acyltransferase (AT domain). In addition to these conserved domains, a module may contain ketoreductase (KR), dehydratase (DH) and enoyl reductase (ER) domains that determine the degree and

• respective extension module is precisely that needed to generate the full-length linear precursor of ebelactone with the exception that the ketoreductase of module 3 is predicted to be active but is not required for the production of authentic ebelactone. Such skipping of a single, apparently active domain

• the known structure of ebelactone A. The only discrepancy is that the ketoreductase domain in module 3 is predicted to be active but is not needed to produce ebelactone. Proposed model for iteration of module 1 of AzlA1 in azalomycin biosynthesis. The 4-guanidinobutyryl starter is loaded onto the

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

• ) domains as well as ketoreductase (KR), dehydratase (DH), enoyl reductase (ER) and thioesterase (TE) domains [6][8]. The PKS intermediates remain tethered to the megaenzyme via a thioester linkage during the whole process. Among these domains, only TE domains participate in cyclisation reactions as part of

• (3HAD). Enzymes of this family catalyse the dehydration of L-3-hydroxyacyl-CoA during β-oxidation of fatty acids. In this case, it acts as a ketoreductase that installs the secondary hydroxy group in 39. The catalytic mechanism has been proposed using a homologous 3HAD from the human heart as a model

Biosynthesis of α-pyrones

• Till F. Schäberle

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

• reduced by further enzymes involved. In fatty acid biosynthesis usually a complete reductive cycle takes place, i.e., a ketoreductase (KR) generates a hydroxy group, a dehydratase (DH) reduces to an alkene double bond, and an enoyl reductase (ER) yields a completely saturated acyl-backbone. These

• elongated by a butyrate moiety. Subsequently three further elongation steps, this time using malonate as extender units, follow. This results in the incorporation of acetate units via Claisen-condensation reactions. The reductive domains, i.e., ketoreductase (KR) and dehydration (DH) domains, present in the

• given. The ACP-tethered nascent chain gets elongated by the incorporation of acetate units. The corresponding reductive domains (ketoreductase, KR; and dehydratase, DH) reduce the β-keto group to a cis double bond. The chain is then released from the assembly line through pyrone ring formation catalyzed

Cuevaenes C–E: Three new triene carboxylic derivatives from Streptomyces sp. LZ35ΔgdmAI

• Jing-Jing Deng,
• Chun-Hua Lu,
• Yao-Yao Li,
• Shan-Ren Li and
• Yue-Mao Shen

Beilstein J. Org. Chem. 2014, 10, 858–862, doi:10.3762/bjoc.10.82

• bond. A previous study indicated that the double-bond geometry is determined by the stereochemistry of Ketoreductase (KR)-catalyzed ketoreduction [9]. By multiple sequence alignment of modular PKS KR domains we identified an Asp residue in the KR5 domain of cuevaenes PKS (Supporting Information File 1

Synthesis of complex intermediates for the study of a dehydratase from borrelidin biosynthesis

• Frank Hahn,
• Nadine Kandziora,
• Steffen Friedrich and
• Peter F. Leadlay

Beilstein J. Org. Chem. 2014, 10, 634–640, doi:10.3762/bjoc.10.55

• position 12 in 1 is installed by the dehydratase of polyketide synthase (PKS) module 3 (BorDH3). Characteristic residues in the active site of the preceding ketoreductase point towards a 3D configuration of the BorDH3 precursor 3 [10][11]. Furthermore, we have shown in a previous study that BorDH3

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

• -aminosalicylate, antCD encode the hybrid NRPS/PKS machinery and antE and antM encode a crotonyl-CoA reductase and a discrete ketoreductase, respectively. The antB and antO genes encode tailoring enzymes and antA encodes an extracytoplasmic function (ECF) RNA polymerase σ factor named σAntA. The additional genes

• ketoreductase, AntM catalyses the stereoselective reduction of the β-keto group, which precedes AntDTE – promoted regiospecific macrolactonisation and release of the nine-membered dilactone. Sandy et al. heterologously produced and purified AntCDEFGM and used building monomers anthranilate, L-threonine

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

• . The reaction between the ACP-bound malonyl and the KS-bound acetyl group under decarboxylation conditions results in the formation of acetoacetyl-S~ACP by release of the KS. A three-step reductive process involving the subsequent actions of a ketoreductase (KR), a dehydratase (DH), and an enoyl

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

• incorporated in the product [21]. Characteristic features of the pathway further include an adenylation/ketoreductase didomain for the generation of α-hydroxy acids following activation of leucine [57]. The pathway also features an FAD-dependent halogenase [57] and the CYP450 epoxidase CrpE [58]. Peptides

• domain; PCP: Peptidyl carrier protein; MT: Methyltransferase; E: Epimerase; AT: Acyltransferase; ACP: Acyl carrier protein; KS: Ketosynthase; KR: Ketoreductase; DH: Dehydratase; ER: Enoyl reductase; TE: Thioesterase. Structures of NRPS and PKS products in freshwater cyanobacteria. A) Synthesis of the