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41.
Dr. Elena Riva Dr. Ina Wilkening Silvia Gazzola W. M. Ariel Li Dr. Luke Smith Prof. Peter F. Leadlay Dr. Manuela Tosin 《Angewandte Chemie (International ed. in English)》2014,53(44):11944-11949
A library of functionalized chemical probes capable of reacting with ketosynthase‐bound biosynthetic intermediates was prepared and utilized to explore in vivo polyketide diversification. Fermentation of ACP mutants of S. lasaliensis in the presence of the probes generated a range of unnatural polyketide derivatives, including novel putative lasalocid A derivatives characterized by variable aryl ketone moieties and linear polyketide chains (bearing alkyne/azide handles and fluorine) flanking the polyether scaffold. By providing direct information on microorganism tolerance and enzyme processing of unnatural malonyl‐ACP analogues, as well as on the amenability of unnatural polyketides to further structural modifications, the chemical probes constitute invaluable tools for the development of novel mutasynthesis and synthetic biology. 相似文献
42.
Yu-Rong Chen Dr. Annavareddi Naresh Dr. Suh-Yuen Liang Dr. Chun-Hung Lin Dr. Rong-Jie Chein Dr. Hsiao-Ching Lin 《Angewandte Chemie (Weinheim an der Bergstrasse, Germany)》2020,132(32):13639-13643
The 1,3-enyne moiety is commonly found in cyclohexanoid natural products produced by endophytic and plant pathogenic fungi. Asperpentyn ( 1 ) is a 1,3-enyne-containing cyclohexanoid terpenoid isolated from Aspergillus and Pestalotiopsis. The genetic basis and biochemical mechanism of 1,3-enyne biosynthesis in 1 , and other natural products containing this motif, has remained enigmatic despite their potential ecological roles. Identified here is the biosynthetic gene cluster and characterization of two crucial enzymes in the biosynthesis of 1 . A P450 monooxygenase that has a dual function, to first catalyze dehydrogenation of the prenyl chain to generate a cis-diene intermediate and then serve as an acetylenase to yield an alkyne moiety, and thus the 1,3-enyne, was discovered. A UbiA prenyltransferase was also characterized and it is unusual in that it favors transferring a five-carbon prenyl chain, rather than a polyprenyl chain, to a p-hydroxybenzoic acid acceptor. 相似文献
43.
Dr. Takaaki Mitsuhashi Dr. Lena Barra Zachary Powers Volga Kojasoy Andrea Cheng Feng Yang Dr. Yoshimasa Taniguchi Dr. Takashi Kikuchi Prof. Dr. Makoto Fujita Prof. Dr. Dean J. Tantillo Prof. Dr. John A. Porco Jr Prof. Dr. Ikuro Abe 《Angewandte Chemie (Weinheim an der Bergstrasse, Germany)》2020,132(52):23980-23989
Fungal meroterpenoids are a diverse group of hybrid natural products with impressive structural complexity and high potential as drug candidates. In this work, we evaluate the promiscuity of the early structure diversity-generating step in fungal meroterpenoid biosynthetic pathways: the multibond-forming polyene cyclizations catalyzed by the yet poorly understood family of fungal meroterpenoid cyclases. In total, 12 unnatural meroterpenoids were accessed chemoenzymatically using synthetic substrates. Their complex structures were determined by 2D NMR studies as well as crystalline-sponge-based X-ray diffraction analyses. The results obtained revealed a high degree of enzyme promiscuity and experimental results which together with quantum chemical calculations provided a deeper insight into the catalytic activity of this new family of non-canonical, terpene cyclases. The knowledge obtained paves the way to design and engineer artificial pathways towards second generation meroterpenoids with valuable bioactivities based on combinatorial biosynthetic strategies. 相似文献
44.
Guifa Zhai Wenyan Wang Dr. Wei Xu Guo Sun Chaoqun Hu Xiangming Wu Zisong Cong Liang Deng Yanrong Shi Prof. Dr. Peter F. Leadlay Prof. Dr. Heng Song Prof. Dr. Kui Hong Prof. Dr. Zixin Deng Prof. Dr. Yuhui Sun 《Angewandte Chemie (Weinheim an der Bergstrasse, Germany)》2020,132(50):22926-22930
The colinearity of canonical modular polyketide synthases, which creates a direct link between multienzyme structure and the chemical structure of the biosynthetic end-product, has become a cornerstone of knowledge-based genome mining. Herein, we report genetic and enzymatic evidence for the remarkable role of an enoylreductase in the polyketide synthase for azalomycin F biosynthesis. This internal enoylreductase domain, previously identified as acting only in the second of two chain extension cycles on an initial iterative module, is shown to also catalyze enoylreduction in trans within the next module. The mechanism for this rare deviation from colinearity appears to involve direct cross-modular interaction of the reductase with the longer acyl chain, rather than back transfer of the substrate into the iterative module, suggesting an additional and surprising plasticity in natural PKS assembly-line catalysis. 相似文献
45.
Shusuke Sato Fumitaka Kudo Michel Rohmer Tadashi Eguchi 《Angewandte Chemie (International ed. in English)》2020,59(1):237-241
Adenosylhopane is a crucial intermediate in the biosynthesis of bacteriohopanepolyols, which are widespread prokaryotic membrane lipids. Herein, it is demonstrated that reconstituted HpnH, a putative radical S‐adenosyl‐l ‐methionine (SAM) enzyme, commonly encoded in the hopanoid biosynthetic gene cluster, converts diploptene into adenosylhopane in the presence of SAM, flavodoxin, flavodoxin reductase, and NADPH. NMR spectra of the enzymatic reaction product were identical to those of synthetic (22R)‐adenosylhopane, indicating that HpnH catalyzes stereoselective C?C formation between C29 of diploptene and C5′ of 5′‐deoxyadenosine. Further, the HpnH reaction in D2O‐containing buffer revealed that a D atom was incorporated at the C22 position of adenosylhopane. Based on these results, we propose a radical addition reaction mechanism catalyzed by HpnH for the formation of the C35 bacteriohopane skeleton. 相似文献
46.
Wenjuan Ji Xinjian Ji Qi Zhang Dhanaraju Mandalapu Zixin Deng Wei Ding Peng Sun Qi Zhang 《Angewandte Chemie (International ed. in English)》2020,59(23):8880-8884
Sulfur‐based homolytic substitution (SH reaction) plays an important role in synthetic chemistry, yet whether such a reaction could occur on the positively charged sulfonium compounds remains unknown. In the study of the anaerobic coproporphyrinogen III oxidase HemN, a radical S‐adenosyl‐l ‐methionine (SAM) enzyme involved in heme biosynthesis, we observed the production of di‐(5′‐deoxyadenosyl)methylsulfonium, which supports a deoxyadenosyl (dAdo) radical‐mediated SH reaction on the sulfonium center of SAM. The sulfonium‐based SH reactions were then investigated in detail by density functional theory calculations and model reactions, which showed that this type of reactions is thermodynamically favorable and kinetically competent. These findings represent the first report of sulfonium‐based SH reactions, which could be useful in synthetic chemistry. Our study also demonstrates the remarkable catalytic promiscuity of the radical SAM superfamily enzymes. 相似文献
47.
Microbial biosynthesis of hydrocarbon from CO2 reduction driven by electron uptake process from the cathodic electrode has gained intensive attention in terms of potential industrial application. However, a lack of a model system for detailed studies on the mechanism of the CO2 reduction hinders the improvement in efficiency for microbial electrosynthesis. Here, we examined the mechanism of microbial CO2 reduction at the cathode by a well‐described microbe for extracellular electron uptake, Shewanella oneidensis MR‐1, capable of reducing gaseous CO2 to produce formic acid. Using whole‐cell electrochemical assay, we observed stable cathodic current production at ?0.65 V vs Ag/AgCl KCl sat. associated with the introduction of CO2. The observed cathodic current was enhanced by the addition of 4 μM riboflavin, which specifically accelerates the electron uptake process of MR‐1 by the interaction to its outer‐membrane c‐type cytochromes. The significant impact of an uncoupler agent and a mutant strain of MR‐1 lacking sole F‐type ATPase suggested the importance of proton import to the cytoplasm for the cathodic CO2 reduction. The present data suggest that MR‐1 potentially serves as a model system for microbial electrosynthesis from CO2. 相似文献
48.
Chunhua Zhao Shan Yan Qin Li Hucheng Zhu Zhiyu Zhong Ying Ye Zixin Deng Yonghui Zhang 《Angewandte Chemie (International ed. in English)》2020,59(24):9478-9484
While halogenated nucleosides are used as common anticancer and antiviral drugs, naturally occurring halogenated nucleosides are rare. Adechlorin (ade) is a 2′‐chloro nucleoside natural product first identified from Actinomadura sp. ATCC 39365. However, the installation of chlorine in the ade biosynthetic pathway remains elusive. Reported herein is a Fe2+‐α‐ketoglutarate halogenase AdeV that can install a chlorine atom at the C2′ position of 2′‐deoxyadenosine monophosphate to afford 2′‐chloro‐2′‐deoxyadenosine monophosphate. Furthermore, 2′,3′‐dideoxyadenosine‐5′‐monophosphate and 2′‐deoxyinosine‐5′‐monophosphate can also be converted, albeit 20‐fold and 2‐fold, respectively, less efficiently relative to the conversion of 2′‐deoxyadenosine monophosphate. AdeV represents the first example of a Fe2+‐α‐ketoglutarate‐dependent halogenase that converts nucleotides into chlorinated analogues. 相似文献
49.
Dr. Reiko Ueoka Dr. Roy A. Meoded Alejandro Gran‐Scheuch Dr. Agneya Bhushan Prof. Dr. Marco W. Fraaije Prof. Dr. Jörn Piel 《Angewandte Chemie (International ed. in English)》2020,59(20):7761-7765
Bacterial trans‐acyltransferase polyketide synthases (trans‐AT PKSs) are multimodular megaenzymes that biosynthesize many bioactive natural products. They contain a remarkable range of domains and module types that introduce different substituents into growing polyketide chains. As one such modification, we recently reported Baeyer–Villiger‐type oxygen insertion into nascent polyketide backbones, thereby generating malonyl thioester intermediates. In this work, genome mining focusing on architecturally diverse oxidation modules in trans‐AT PKSs led us to the culturable plant symbiont Gynuella sunshinyii, which harbors two distinct modules in one orphan PKS. The PKS product was revealed to be lobatamide A, a potent cytotoxin previously only known from a marine tunicate. Biochemical studies show that one module generates glycolyl thioester intermediates, while the other is proposed to be involved in oxime formation. The data suggest varied roles of oxygenation modules in the biosynthesis of polyketide scaffolds and support the importance of trans‐AT PKSs in the specialized metabolism of symbiotic bacteria. 相似文献
50.
Carsten Kegler Helge B. Bode 《Angewandte Chemie (International ed. in English)》2020,59(32):13463-13467
The interaction in multisubunit non‐ribosomal peptide synthetases (NRPSs) is mediated by docking domains that ensure the correct subunit‐to‐subunit interaction. We introduced natural docking domains into the three‐module xefoampeptide synthetase (XfpS) to create two to three artificial NRPS XfpS subunits. The enzymatic performance of the split biosynthesis was measured by absolute quantification of the products by HPLC‐ESI‐MS. The connecting role of the docking domains was probed by deleting integral parts of them. The peptide production data was compared to soluble protein amounts of the NRPS using SDS‐PAGE. Reduced peptide synthesis was not a result of reduced soluble NRPS concentration but a consequence of the deletion of vital docking domain parts. Splitting the xefoampeptide biosynthesis polypeptide by introducing docking domains was feasible and resulted in higher amounts of product in one of the two tested split‐module cases compared to the full‐length wild‐type enzyme. 相似文献