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1.
Genome Mining of the Hitachimycin Biosynthetic Gene Cluster: Involvement of a Phenylalanine‐2,3‐aminomutase in Biosynthesis 下载免费PDF全文
Prof. Dr. Fumitaka Kudo Koichi Kawamura Asuka Uchino Dr. Akimasa Miyanaga Mario Numakura Ryuichi Takayanagi Prof. Dr. Tadashi Eguchi 《Chembiochem : a European journal of chemical biology》2015,16(6):909-914
Hitachimycin is a macrolactam antibiotic with (S)‐β‐phenylalanine (β‐Phe) at the starter position of its polyketide skeleton. To understand the incorporation mechanism of β‐Phe and the modification mechanism of the unique polyketide skeleton, the biosynthetic gene cluster for hitachimycin in Streptomyces scabrisporus was identified by genome mining. The identified gene cluster contains a putative phenylalanine‐2,3‐aminomutase (PAM), five polyketide synthases, four β‐amino‐acid‐carrying enzymes, and a characteristic amidohydrolase. A hitA knockout mutant showed no hitachimycin production, but antibiotic production was restored by feeding with (S)‐β‐Phe. We also confirmed the enzymatic activity of the HitA PAM. The results suggest that the identified gene cluster is responsible for the biosynthesis of hitachimycin. A plausible biosynthetic pathway for hitachimycin, including a unique polyketide skeletal transformation mechanism, is proposed. 相似文献
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Zhi Feng Dr. Yasushi Ogasawara Satoshi Nomura Prof. Dr. Tohru Dairi 《Chembiochem : a European journal of chemical biology》2018,19(19):2045-2048
MS‐271, produced by Streptomyces sp. M‐271, is a lasso peptide natural product comprising 21 amino acid residues with a d ‐tryptophan at its C terminus. Because lasso peptides are ribosomal peptides, the biosynthesis of MS‐271, especially the mechanism of d ‐Trp introduction, is of great interest. The MS‐271 biosynthetic gene cluster was identified by draft genome sequencing of the MS‐271 producer, and it was revealed that the precursor peptide contains all 21 amino acid residues including the C‐terminal tryptophan. This suggested that the d ‐Trp residue is introduced by epimerization. Genes for modification enzymes such as a macrolactam synthetase (mslC), precursor peptide recognition element (mslB1), cysteine protease (mslB2), disulfide oxidoreductases (mslE, mslF), and a protein of unknown function (mslH) were found in the flanking region of the precursor peptide gene. Although obvious epimerase genes were absent in the cluster, heterologous expression of the putative MS‐271 cluster in Streptomyces lividans showed that it contains all the necessary genes for MS‐271 production including a gene for a new peptide epimerase. Furthermore, a gene‐deletion experiment indicated that MslB1, ‐B2, ‐C and ‐H were indispensable for MS‐271 production and that some interactions of the biosynthetic enzymes were essential for the biosynthesis of MS‐271. 相似文献
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Sri Mulyani Dr. Ellen Egel Claudia Kittel Dr. Suada Turkanovic Wolfgang Wohlleben Prof. Roderich D. Süssmuth Prof. Karl‐Heinz van Pée Prof. 《Chembiochem : a European journal of chemical biology》2010,11(2):266-271
The putative hydrolase gene bhp from the balhimycin biosynthetic gene cluster has been cloned and overexpressed in Escherichia coli. The corresponding enzyme Bhp was purified to homogeneity by nickel‐chelating chromatography and characterized. Although Bhp has sequence similarities to hydrolases with “haloperoxidase”/perhydrolase activity, it did not show any enzymatic activity with standard “haloperoxidase”/perhydrolase substrates (e.g., monochlorodimedone and phenol red), nonspecific esterase substrates (such as p‐nitrophenyl acetate, p‐nitrophenyl phosphate and S‐thiophenyl acetate) or the model lactonase substrate dihydrocoumarin. However, Bhp could be shown to catalyse the hydrolysis of S‐β‐hydroxytyrosyl‐N‐acetyl cysteamine thioester (β‐OH‐Tyr‐SNAC) with 15 times the efficiency of S‐L ‐tyrosyl‐N‐acetyl cysteamine thioester (L ‐Tyr‐SNAC). This is in agreement with the suggestion that Bhp is involved in balhimycin biosynthesis, during which it was supposed to catalyse the hydrolysis of β‐OH‐Tyr‐S‐PCP (PCP=peptidyl carrier protein) to free β‐hydroxytyrosine (β‐OH‐Tyr) and strongly suggests that Bhp is a thioesterase with high substrate specificity for PCP‐bound β‐OH‐Tyr and not a “haloperoxidase”/perhydrolase or nonspecific esterase. 相似文献
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Dr. Yee Hwee Lim Dr. Fong Tian Wong Wan Lin Yeo Dr. Kuan Chieh Ching Yi Wee Lim Elena Heng Shuwen Chen De‐Juin Tsai Dr. Tsai‐Ling Lauderdale Dr. Kak‐Shan Shia Dr. Ying Swan Ho Dr. Shawn Hoon Dr. Ee Lui Ang Dr. Mingzi M. Zhang Prof. Dr. Huimin Zhao 《Chembiochem : a European journal of chemical biology》2018,19(16):1716-1719
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Sphinganine‐Like Biogenesis of (E)‐1‐Nitropentadec‐1‐ene in Termite Soldiers of the Genus Prorhinotermes 下载免费PDF全文
Dr. Anna Jirošová Dr. Pavel Majer Andrej Jančařík Klára Dolejšová Dr. Richard Tykva Dr. Jan Šobotník Dr. Pavel Jiroš Dr. Robert Hanus 《Chembiochem : a European journal of chemical biology》2014,15(4):533-536
In 1974, (E)‐1‐nitropentadec‐1‐ene, a strong lipophilic contact poison of soldiers of the termite genus Prorhinotermes, was the first‐described insect‐produced nitro compound. However, its biosynthesis remained unknown. In the present study, we tested the hypothesis that (E)‐1‐nitropentadec‐1‐ene biosynthesis originates with condensation of amino acids with tetradecanoic acid. By using in vivo experiments with radiolabeled and deuterium‐labeled putative precursors, we show that (E)‐1‐nitropentadec‐1‐ene is synthesized by the soldiers from glycine or L ‐serine and tetradecanoic acid. We propose and discuss three possible biosynthetic pathways. 相似文献
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Özlem Erol Till F. Schäberle Dr. Alexander Schmitz Shwan Rachid Dr. Cristian Gurgui Dr. Mustafa El Omari Friederike Lohr Stefan Kehraus Dr. Jörn Piel Prof. Dr. Rolf Müller Prof. Dr. Gabriele M. König Prof. Dr. 《Chembiochem : a European journal of chemical biology》2010,11(9):1253-1265
Corallopyronin A is a myxobacterial compound with potent antibacterial activity. Feeding experiments with labelled precursors resulted in the deduction of all biosynthetic building blocks for corallopyronin A and revealed an unusual feature of this metabolite: its biosynthesis from two chains, one solely PKS‐derived and the other NRPS/PKS‐derived. The starter molecule is believed to be carbonic acid or its monomethyl ester. The putative corallopyronin A biosynthetic gene cluster is a trans‐AT‐type mixed PKS/NRPS gene cluster, containing a β‐branching cassette. Striking features of this gene cluster are a NRPS‐like adenylation domain that is part of a PKS‐type module and is believed to be responsible for glycine incorporation, as well as split modules with individual domains occurring on different genes. It is suggested that CorB is a trans‐acting ketosynthase and it is proposed that it catalyses the Claisen condensation responsible for the interconnection of the two chains. Additionally, the stereochemistry of corallopyronin A was deduced by a combination of a modified Mosher's method and ozonolysis with subsequent chiral GC analyses. 相似文献
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Makoto Hibi Takuya Kasahara Takashi Kawashima Hiroko Yajima Shoko Kozono Sergey V. Smirnov Tomohiro Kodera Masakazu Sugiyama Sakayu Shimizu Kenzo Yokozeki Jun Ogawa 《Advanced Synthesis \u0026amp; Catalysis》2015,357(4):767-774
A novel enzymatic production system of optically pure β‐hydroxy α‐amino acids was developed. Two enzymes were used for the system: an N‐succinyl L ‐amino acid β‐hydroxylase (SadA) belonging to the iron(II)/α‐ketoglutarate‐dependent dioxygenase superfamily and an N‐succinyl L ‐amino acid desuccinylase (LasA). The genes encoding the two enzymes are part of a gene set responsible for the biosynthesis of peptidyl compounds found in the Burkholderia ambifaria AMMD genome. SadA stereoselectively hydroxylated several N‐succinyl aliphatic L ‐amino acids and produced N‐succinyl β‐hydroxy L ‐amino acids, such as N‐succinyl‐L ‐β‐hydroxyvaline, N‐succinyl‐L ‐threonine, (2S,3R)‐N‐succinyl‐L ‐β‐hydroxyisoleucine, and N‐succinyl‐L ‐threo‐β‐hydroxyleucine. LasA catalyzed the desuccinylation of various N‐succinyl‐L ‐amino acids. Surprisingly, LasA is the first amide bond‐forming enzyme belonging to the amidohydrolase superfamily, and has succinylation activity towards the amino group of L ‐leucine. By combining SadA and LasA in a preparative scale production using N‐succinyl‐L ‐leucine as substrate, 2.3 mmol of L ‐threo‐β‐hydroxyleucine were successfully produced with 93% conversion and over 99% of diastereomeric excess. Consequently, the new production system described in this study has advantages in optical purity and reaction efficiency for application in the mass production of several β‐hydroxy α‐amino acids.
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Characterization of Heronamide Biosynthesis Reveals a Tailoring Hydroxylase and Indicates Migrated Double Bonds 下载免费PDF全文
Dr. Yiguang Zhu Dr. Wenjun Zhang Yaolong Chen Dr. Chengshan Yuan Haibo Zhang Dr. Guangtao Zhang Liang Ma Dr. Qingbo Zhang Dr. Xinpeng Tian Prof. Dr. Si Zhang Prof. Dr. Changsheng Zhang 《Chembiochem : a European journal of chemical biology》2015,16(14):2086-2093
Heronamides belong to a growing family of β‐amino acid polyketide macrolactams (βPMs) with an unsaturated side chain. The biosynthetic gene cluster for heronamide F was identified from the deep‐sea‐derived Streptomyces sp. SCSIO 03032. The involvement of the gene cluster in heronamide biosynthesis was confirmed by the functional characterization of the P450 enzyme HerO as an 8‐hydroxylase for tailoring heronamide biosynthesis. The presence of migrated double bonds in the conjugated diene‐containing side chain of heronamides was confirmed by feeding experiments with labeled small carboxylic acid molecules. This study is the first demonstration of migrated double bonds in βPMs with an unsaturated side chain. 相似文献
10.
NAD+‐Dependent Dehydrogenase PctP and Pyridoxal 5′‐Phosphate Dependent Aminotransferase PctC Catalyze the First Postglycosylation Modification of the Sugar Intermediate in Pactamycin Biosynthesis 下载免费PDF全文
Dr. Akane Hirayama Jinmiao Chu Ena Goto Dr. Fumitaka Kudo Prof. Dr. Tadashi Eguchi 《Chembiochem : a European journal of chemical biology》2018,19(2):126-130
The unique five‐membered aminocyclitol core of the antitumor antibiotic pactamycin originates from d ‐glucose, so unprecedented enzymatic modifications of the sugar intermediate are involved in the biosynthesis. However, the order of the modification reactions remains elusive. Herein, we examined the timing of introduction of an amino group into certain sugar‐derived intermediates by using recombinant enzymes that were encoded in the pactamycin biosynthesis gene cluster. We found that the NAD+‐dependent alcohol dehydrogenase PctP and pyridoxal 5′‐phosphate dependent aminotransferase PctC converted N‐acetyl‐d ‐glucosaminyl‐3‐aminoacetophonone into 3′‐amino‐3′‐deoxy‐N‐acetyl‐d ‐glucosaminyl‐3‐aminoacetophenone. Further, N‐acetyl‐d ‐glucosaminyl‐3‐aminophenyl‐β‐oxopropanoic acid ethyl ester was converted into the corresponding 3′‐amino derivative. However, PctP did not oxidize most of the tested d ‐glucose derivatives, including UDP‐GlcNAc. Thus, modification of the GlcNAc moiety in pactamycin biosynthesis appears to occur after the glycosylation of aniline derivatives. 相似文献
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Biosynthetic Gene Cluster for Surugamide A Encompasses an Unrelated Decapeptide,Surugamide F 下载免费PDF全文
Akihiro Ninomiya Prof. Yohei Katsuyama Prof. Takefumi Kuranaga Masayuki Miyazaki Dr. Yuichi Nogi Prof. Shigeru Okada Prof. Toshiyuki Wakimoto Prof. Yasuo Ohnishi Prof. Shigeki Matsunaga Prof. Kentaro Takada 《Chembiochem : a European journal of chemical biology》2016,17(18):1709-1712
Genome mining is a powerful method for finding novel secondary metabolites. In our study on the biosynthetic gene cluster for the cyclic octapeptides surugamides A–E (inhibitors of cathepsin B), we found a putative gene cluster consisting of four successive non‐ribosomal peptide synthetase (NRPS) genes, surA, surB, surC, and surD. Prediction of amino acid sequence based on the NRPSs and gene inactivation revealed that surugamides A–E are produced by two NRPS genes, surA and surD, which were separated by two NRPS genes, surB and surC. The latter genes are responsible for the biosynthesis of an unrelated peptide, surugamide F. The pattern of intercalation observed in the sur genes is unprecedented. The structure of surugamide F, a linear decapeptide containing one 3‐amino‐2‐methylpropionic acid (AMPA) residue, was determined by spectroscopic methods and was confirmed by solid‐phase peptide synthesis. 相似文献
12.
Identification and Characterization of the Streptazone E Biosynthetic Gene Cluster in Streptomyces sp. MSC090213JE08 下载免费PDF全文
Shoto Ohno Dr. Yohei Katsuyama Yuka Tajima Dr. Miho Izumikawa Dr. Motoki Takagi Dr. Manabu Fujie Dr. Noriyuki Satoh Dr. Kazuo Shin‐ya Dr. Yasuo Ohnishi 《Chembiochem : a European journal of chemical biology》2015,16(16):2385-2391
Streptazone derivatives isolated from Streptomyces species are piperidine alkaloids with a cyclopenta[b]pyridine scaffold. Previous studies indicated that these compounds are polyketides, but the biosynthetic enzymes responsible for their synthesis are unknown. Here, we have identified the streptazone E biosynthetic gene cluster in Streptomyces sp. MSC090213JE08, which encodes a modular type I PKS and tailoring enzymes that include an aminotransferase, three oxidoreductases, and two putative cyclases. The functions of the six tailoring enzymes were analyzed by gene disruption, and two putative biosynthetic intermediates that accumulated in particular mutants were structurally elucidated. On the basis of these results, we propose a pathway for the biosynthesis of streptazone E in which the two putative cyclases of the nuclear transport factor 2–like superfamily are responsible for C?C bond formation coupled with epoxide ring opening to give the five‐membered ring of streptazone E. 相似文献
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Bian Wu Wiktor Szymanski Dr. Piet Wietzes Stefaan de Wildeman Dr. Gerrit J. Poelarends Dr. Ben L. Feringa Prof. Dr. Dick B. Janssen Prof. Dr. 《Chembiochem : a European journal of chemical biology》2009,10(2):338-344
The phenylalanine aminomutase (PAM) from Taxus chinensis catalyses the conversion of α‐phenylalanine to β‐phenylalanine, an important step in the biosynthesis of the N‐benzoyl phenylisoserinoyl side‐chain of the anticancer drug taxol. Mechanistic studies on PAM have suggested that (E)‐cinnamic acid is an intermediate in the mutase reaction and that it can be released from the enzyme's active site. Here we describe a novel synthetic strategy that is based on the finding that ring‐substituted (E)‐cinnamic acids can serve as a substrate in PAM‐catalysed ammonia addition reactions for the biocatalytic production of several important β‐amino acids. The enzyme has a broad substrate range and a high enantioselectivity with cinnamic acid derivatives; this allows the synthesis of several non‐natural aromatic α‐ and β‐amino acids in excellent enantiomeric excess (ee >99 %). The internal 5‐methylene‐3,5‐dihydroimidazol‐4‐one (MIO) cofactor is essential for the PAM‐catalysed amination reactions. The regioselectivity of amination reactions was influenced by the nature of the ring substituent. 相似文献
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Biosynthesis of Hygrocins,Antitumor Naphthoquinone Ansamycins Produced by Streptomyces sp. LZ35 下载免费PDF全文
Dr. Shanren Li Dr. Haoxin Wang Dr. Yaoyao Li Jingjing Deng Dr. Chunhua Lu Yan Shen Prof. Dr. Yuemao Shen 《Chembiochem : a European journal of chemical biology》2014,15(1):94-102
Hygrocins are naphthoquinone ansamycins with significant antitumor activities. Here, we report the identification and characterization of the hygrocin biosynthetic gene cluster (hgc) in Streptomyces sp. LZ35. A biosynthetic pathway is proposed based on bioinformatics analysis of the hgc genes and intermediates accumulated in selected gene disruption mutants. One of the steps during the biosynthesis of hygrocins is a Baeyer–Villiger oxidation between C5 and C6, catalyzed by luciferase‐like monooxygenase homologue Hgc3. Hgc3 represents the founding member of a previously uncharacterized family of enzymes acting as Baeyer–Villiger monooxygenases. 相似文献
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Epimerization at C‐3′′ in Butirosin Biosynthesis by an NAD+‐Dependent Dehydrogenase BtrE and an NADPH‐Dependent Reductase BtrF 下载免费PDF全文
Ryohei Takeishi Prof. Dr. Fumitaka Kudo Mario Numakura Prof. Dr. Tadashi Eguchi 《Chembiochem : a European journal of chemical biology》2015,16(3):487-495
Butirosin is an aminoglycoside antibiotic consisting two epimers at C‐3′′ of ribostamycin/xylostasin with a unique 4‐amino‐2‐hydroxybutyrate moiety at C‐1 of the aminocyclitol 2‐deoxystreptamine (2DOS). To date, most of the enzymes encoded in the biosynthetic gene cluster for butirosin, from the producing strain Bacillus circulans, have been characterized. A few unknown functional proteins, including nicotinamide adenine dinucleotide cofactor‐dependent dehydrogenase/reductase (BtrE and BtrF), are supposed to be involved in the epimerization at C‐3′′ of butirosin B/ribostamycin but remain to be characterized. Herein, the conversion of ribostamycin to xylsostasin by BtrE and BtrF in the presence of NAD+ and NADPH was demonstrated. BtrE oxidized the C‐3′′ of ribostamycin with NAD+ to yield 3′′‐oxoribostamycin. BtrF then reduced the generated 3′′‐oxoribostamycin with NADPH to produce xylostasin. This reaction step was the last piece of butirosin biosynthesis to be described. 相似文献
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Jacob C. Carlson J. L. Fortman Dr. Yojiro Anzai Dr. Shengying Li Douglas A. Burr Dr. David H. Sherman Prof. 《Chembiochem : a European journal of chemical biology》2010,11(4):564-572
The structurally intriguing bicyclic ketal moiety of tirandamycin is common to several acyl‐tetramic acid antibiotics, and is a key determinant of biological activity. We have identified the tirandamycin biosynthetic gene cluster from the environmental marine isolate Streptomyces sp. 307–9, thus providing the first genetic insight into the biosynthesis of this natural product scaffold. Sequence analysis revealed a hybrid polyketide synthase–nonribosomal peptide synthetase gene cluster with a colinear domain organization, which is entirely consistent with the core structure of the tirandamycins. We also identified genes within the cluster that encode candidate tailoring enzymes for elaboration and modification of the bicyclic ketal system. Disruption of tamI, which encodes a presumed cytochrome P450, led to a mutant strain deficient in production of late stage tirandamycins that instead accumulated tirandamycin C, an intermediate devoid of any post assembly‐line oxidative modifications. 相似文献
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Targeting an Aromatic Hotspot in Plasmodium falciparum 1‐Deoxy‐d‐xylulose‐5‐phosphate Reductoisomerase with β‐Arylpropyl Analogues of Fosmidomycin 下载免费PDF全文
Dr. Sanjeewani Sooriyaarachchi René Chofor Martijn D. P. Risseeuw Terese Bergfors Dr. Jenny Pouyez Dr. Cynthia S. Dowd Dr. Louis Maes Dr. Johan Wouters Dr. T. Alwyn Jones Dr. Serge Van Calenbergh Dr. Sherry L. Mowbray 《ChemMedChem》2016,11(18):2024-2036
Blocking the 2‐C‐methyl‐d ‐erythrithol‐4‐phosphate pathway for isoprenoid biosynthesis offers new ways to inhibit the growth of Plasmodium spp. Fosmidomycin [(3‐(N‐hydroxyformamido)propyl)phosphonic acid, 1 ] and its acetyl homologue FR‐900098 [(3‐(N‐hydroxyacetamido)propyl)phosphonic acid, 2 ] potently inhibit 1‐deoxy‐d ‐xylulose‐5‐phosphate reductoisomerase (Dxr), a key enzyme in this biosynthetic pathway. Arylpropyl substituents were introduced at the β‐position of the hydroxamate analogue of 2 to study changes in lipophilicity, as well as electronic and steric properties. The potency of several new compounds on the P. falciparum enzyme approaches that of 1 and 2 . Activities against the enzyme and parasite correlate well, supporting the mode of action. Seven X‐ray structures show that all of the new arylpropyl substituents displace a key tryptophan residue of the active‐site flap, which had made favorable interactions with 1 and 2 . Plasticity of the flap allows substituents to be accommodated in many ways; in most cases, the flap is largely disordered. Compounds can be separated into two classes based on whether the substituent on the aromatic ring is at the meta or para position. Generally, meta‐substituted compounds are better inhibitors, and in both classes, smaller size is linked to better potency. 相似文献
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A Tryptophan 6‐Halogenase and an Amidotransferase Are Involved in Thienodolin Biosynthesis 下载免费PDF全文
Dr. Daniela Milbredt Dr. Eugenio P. Patallo Prof. Karl‐Heinz van Pée 《Chembiochem : a European journal of chemical biology》2014,15(7):1011-1020
The biosynthetic gene cluster for the plant growth‐regulating compound thienodolin was identified in and cloned from the producer organism Streptomyces albogriseolus MJ286‐76F7. Sequence analysis of a 27 kb DNA region revealed the presence of 21 ORFs, 14 of which are involved in thienodolin biosynthesis. Three insertional inactivation mutants were generated in the sequenced region to analyze their involvement in thienodolin biosynthesis and to functionally characterize specific genes. The gene inactivation experiments together with enzyme assays with enzymes obtained by heterologous expression and feeding studies showed that the first step in thienodolin biosynthesis is catalyzed by a tryptophan 6‐halogenase and that the last step is the formation of a carboxylic amide group catalyzed by an amidotransferase. The results led to a hypothetical model for thienodolin biosynthesis. 相似文献
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A Membrane‐Bound Prenyltransferase Catalyzes the O‐Prenylation of 1,6‐Dihydroxyphenazine in the Marine Bacterium Streptomyces sp. CNQ‐509 下载免费PDF全文
Philipp Zeyhle Judith S. Bauer Marco Steimle Franziska Leipoldt Manuela Rösch Prof. Dr. Jörn Kalinowski Prof. Dr. Harald Gross Prof. Dr. Lutz Heide 《Chembiochem : a European journal of chemical biology》2014,15(16):2385-2392
Streptomyces sp. CNQ‐509 produces the rare O‐prenylated phenazines marinophenazines A and B. To identify the enzyme catalyzing the O‐prenyl transfer in marinophenazine biosynthesis, we sequenced the genome of S. sp. CNQ‐509. This led to the identification of two genomic loci harboring putative phenazine biosynthesis genes. The first locus contains orthologues for all seven genes involved in phenazine‐1‐carboxylic acid biosynthesis in pseudomonads. The second locus contains two known phenazine biosynthesis genes and a putative prenyltransferase gene termed cnqPT1. cnqPT1 codes for a membrane protein with sequence similarity to the prenyltransferase UbiA of ubiquinone biosynthesis. The enzyme CnqPT1 was identified as a 1,6‐dihydroxyphenazine geranyltransferase, which catalyzes the C?O bond formation between C‐1 of the geranyl moiety and O‐6 of the phenazine scaffold. CnqPT1 is the first example of a prenyltransferase catalyzing O‐prenyl transfer to a phenazine. 相似文献
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Identification of the First Diphenyl Ether Gene Cluster for Pestheic Acid Biosynthesis in Plant Endophyte Pestalotiopsis fici 下载免费PDF全文
Xinxin Xu Dr. Ling Liu Dr. Fan Zhang Dr. Wenzhao Wang Jinyang Li Prof. Liangdong Guo Prof. Yongsheng Che Prof. Gang Liu 《Chembiochem : a European journal of chemical biology》2014,15(2):284-292
The diphenyl ether pestheic acid was isolated from the endophytic fungus Pestalotiopsis fici, which is proposed to be the biosynthetic precursor of the unique chloropupukeananes. The pestheic acid biosynthetic gene (pta) cluster was identified in the fungus through genome scanning. Sequence analysis revealed that this gene cluster encodes a nonreducing polyketide synthase, a number of modification enzymes, and three regulators. Gene disruption and intermediate analysis demonstrated that the biosynthesis proceeded through formation of the polyketide backbone, cyclization of a polyketo acid to a benzophenone, chlorination, and formation of the diphenyl ether skeleton through oxidation and hydrolyzation. A dihydrogeodin oxidase gene, ptaE, was essential for diphenyl ether formation, and ptaM encoded a flavin‐dependent halogenase catalyzing chlorination in the biosynthesis. Identification of the pta cluster laid the foundation to decipher the genetic and biochemical mechanisms involved in the pathway. 相似文献