21675-61-6Relevant articles and documents
Identification of Cyclic Depsipeptides and Their Dedicated Synthetase from Hapsidospora irregularis
Zhang, Shuwei,Qiu, Yixing,Kakule, Thomas B.,Lu, Zhenyu,Xu, Fuchao,Lamb, John G.,Reilly, Christopher A.,Zheng, Yong,Sham, Shing Wo Simon,Wang, Wei,Xuan, Lijiang,Schmidt, Eric W.,Zhan, Jixun
, p. 363 - 370 (2017)
Seven cyclic depsipeptides were isolated from Hapsidospora irregularis and structurally characterized as the calcium channel blocker leualacin and six new analogues based on the NMR and HRESIMS data. These new compounds were named leualacins B-G. The absolute configurations of the amino acids and 2-hydroxyisocaproic acids were determined by recording the optical rotation values. Biological studies showed that calcium influx elicited by leualacin F in primary human lobar bronchial epithelial cells involves the TRPA1 channel. Through genome sequencing and targeted gene disruption, a noniterative nonribosomal peptide synthetase was found to be involved in the biosynthesis of leualacin. A comparison of the structures of leualacin and its analogues indicated that the A2 and A4 domains of the leualacin synthetase are substrate specific, while A1, A3, and A5 can accept alternative precursors to yield new molecules.
Near-Infrared Fluorescent Probe with Remarkable Large Stokes Shift and Favorable Water Solubility for Real-Time Tracking Leucine Aminopeptidase in Living Cells and in Vivo
Zhang, Wenda,Liu, Feiyan,Zhang, Chao,Luo, Jian-Guang,Luo, Jun,Yu, Wenying,Kong, Lingyi
, p. 12319 - 12326 (2017)
Leucine aminopeptidase (LAP) is a kind of proteolytic enzymes and associated closely with pathogenesis of cancer and liver injury. Accurate detection of LAP activity with high sensitivity and selectivity is imperative to detect its distribution and dynamic changes for understanding LAP's function and early diagnosing the disease states. However, fluorescent detection of LAP in living systems is challenging. To date, rarely fluorescent probes have been reported for imaging LAP in vivo. In this study, a novel probe (TMN-Leu) was developed by conjugating a near-infrared dicyanoisophorone derivative fluorophore with LAP activatable l-leucine amide moiety for the first time. TMN-Leu featured large Stokes shift (198 nm), favorable water solubility, ultrasensitive sensitivity (detection limit of ～0.38 ng/mL), good specificity, excellent cell membrane permeability, low toxicity, and a prominent near-infrared emission (658 nm) in response to LAP. TMN-Leu has been successfully applied to track LAP of cancer cells and normal cells, monitor LAP changes in different disease models, and rapidly evaluate LAP inhibitor in cell-based assay. Notably, this probe firstly revealed that HCT116 cells with higher LAP activity were more invasive than LAP siRNA transfected HCT116 cells, suggesting that LAP might serve as an indicator reflecting the intrinsic invasion ability of cancer cells. Finally, TMN-Leu was also employed for in vivo real-time imaging LAP in living tumor-bearing nude mice with low background interference. All together, our probe possesses potential value as a promising tool for diagnostic application, cell-based screening inhibitors and in vivo real-time tracking enzymatic activity in preclinical applications.
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Karrer et al.
, p. 211 (1925)
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Chemical and Metagenomic Studies of the Lethal Black Band Disease of Corals Reveal Two Broadly Distributed, Redox-Sensitive Mixed Polyketide/Peptide Macrocycles
Gunasekera, Sarath P.,Meyer, Julie L.,Ding, Yousong,Abboud, Khalil A.,Luo, Danmeng,Campbell, Justin E.,Angerhofer, Alexander,Goodsell, Justin L.,Raymundo, Laurie J.,Liu, Junyang,Ye, Tao,Luesch, Hendrik,Teplitski, Max,Paul, Valerie J.
, p. 111 - 121 (2019)
Black band disease (BBD), a lethal, polymicrobial disease consortium dominated by the cyanobacterium Roseofilum reptotaenium, kills many species of corals worldwide. To uncover chemical signals or cytotoxins that could be important in proliferation of Roseofilum and the BBD layer, we examined the secondary metabolites present in geographically diverse collections of BBD from Caribbean and Pacific coral reefs. Looekeyolide A (1), a 20-membered macrocyclic compound formed by a 16-carbon polyketide chain, 2-deamino-2-hydroxymethionine, and d-leucine, and its autoxidation product looekeyolide B (2) were extracted as major compounds (～1 mg g-1 dry wt) from more than a dozen field-collected BBD samples. Looekeyolides A and B were also produced by a nonaxenic R. reptotaenium culture under laboratory conditions at similar concentrations. R. reptotaenium genomes that were constructed from four different metagenomic data sets contained a unique nonribosomal peptide/polyketide biosynthetic cluster that is likely responsible for the biosynthesis of the looekeyolides. Looekeyolide A, which readily oxidizes to looekeyolide B, may play a biological role in reducing H2O2 and other reactive oxygen species that could occur in the BBD layer as it overgrows and destroys coral tissue.
Isolation and characterization of two novel antibacterial cyclic hexapeptides from streptomyces alboflavus 313
Ji, Zhiqin,Qiao, Gang,Wei, Shaopeng,Fan, Lixia,Wu, Wenjun
, p. 1567 - 1578 (2012)
Two novel cyclic hexapeptides, designated NW-G08 (1) and NW-G09 (2), were isolated from the fermentation broth of Streptomyces alboflavus 313. Their structures were elucidated on the basis of extensive spectroscopic analysis, MS experiments, and chemical
Mechanochemical Racemization of L-Leucine
Ikekawa, Akiko,Hayakawa, Sohachiro
, p. 889 - 890 (1984)
On treating a ball-milled mixture of L-leucine and such diluents as silicone dioxide in hydrochloric acid, a part of L-leucine was transformed into D-leucine.
Development of a multi-enzymatic desymmetrization and its application for the biosynthesis of L-norvaline from DL-norvaline
Qi, Yunlong,Yang, Taowei,Zhou, Junping,Zheng, Junxian,Xu, Meijuan,Zhang, Xian,Rao, Zhiming,Yang, Shang-Tian
, p. 104 - 109 (2017)
Perindopril is an effective antihypertensive drug in strong demand used to treat hypertension. L-norvaline is a vital intermediate of Perindopril production mainly produced by chemical synthesis with low purity. We developed an environmentally friendly method to produce L-norvaline with high purity based on a desymmetrization process. D-Norvaline was oxidized to the corresponding keto acid by D-amino acid oxidase from the substrate DL-norvaline. Asymmetric hydrogenation of the keto acid to L-norvaline was carried out by leucine dehydrogenase with concomitant oxidation of NADH to NAD+. A NADH regeneration system was introduced by overexpressing a formate dehydrogenase. The unwanted H2O2by-product generated during D-norvaline oxidation was removed by adding catalase. A total of 54.09?g/L of L-norvaline was achieved, with an enantiomeric excess over 99% under optimal conditions, with a 96.7% conversion rate. Our desymmetrization method provides an environmental friendly strategy for the production of enantiomerically pure L-norvaline in the pharmaceutical industry.
Single-step fluorescent probes to detect decrotonylation activity of HDACs through intramolecular reactions
Xie, Yusheng,Yang, Liu,Chen, Qingxin,Zhang, Jie,Feng, Ling,Chen, Jian Lin,Hao, Quan,Zhang, Liang,Sun, Hongyan
, (2021)
Lysine crotonylation plays vital roles in gene transcription and cellular metabolism. Nevertheless, methods for dissecting the molecular mechanisms of decrotonyaltion remains limited. So far, there is no single-step fluorescent method developed for enzymatic decrotonylation activity detection. The major difficulty is that the aliphatic crotonylated lysine doesn't allow π-conjugation to a fluorophore and decrotonylation can not modulate the electronic state directly. Herein, we have designed and synthesized two activity-based single-step fluorogenic probes KTcr-I and KTcr-II for detecting enzymatic decrotonylation activity. These two probes can be recognized by histone deacetylases and undergo intramolecular nucleophilic exchange reaction to generate fluorescence signal. Notably, peptide sequence-dependent effect was observed. KTcr-I can be recognized by Sirt2 more effectively, while KTcr-II with LGKcr peptide sequence preferentially reacted with HDAC3. Compared to other methods of studying enzymatic decrotonylation activity, our single-step fluorescent method has a number of advantages, such as facileness, high sensitivity, cheap facility and little material consumed. We envision that the probes developed in this study will provide useful tools to screen inhibitors which suppress the decrotonylation activity of HDACs. Such probes will be useful for further delineating the roles of decrotonylation enzyme and aid in biomarker identification and drug discovery.
Kinetic study on stability of Schiff base of pyridoxal 5'-phosphate and leucine in water media with cationic surfactants
Vazquez,Munoz,Donoso,Garcia-Blanco
, p. 1029 - 1038 (1992)
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Functional significance of Glu-77 and Tyr-137 within the active site of isoaspartyl dipeptidase
Marti-Arbona, Ricardo,Thoden, James B.,Holden, Hazel M.,Raushel, Frank M.
, p. 448 - 458 (2005)
Isoaspartyl dipeptidase (IAD) is a binuclear metalloenzyme and a member of the amidohydrolase superfamily. This enzyme catalyzes the hydrolytic cleavage of β-aspartyl dipeptides. The pH-rate profiles for the hydrolysis of β-Asp-Leu indicates that catalysis is dependent on the ionization of two groups; one that ionizes at a pH ～6 and the other ～9. The group that must be ionized for catalysis is directly dependent on the identity of the metal ion bound to the active site. This result is consistent with the ionization of the hydroxide that bridges the two divalent cations. In addition to the residues that interact directly with the divalent cations there are two other residues that are highly conserved and found within the active site: Glu-77 and Tyr-137. Mutation of Tyr-137 to phenylalanine reduced the rate of catalysis by three orders of magnitude. The three dimensional X-ray structure of the Y137F mutant did not show any significant conformation changes relative to the three dimensional structure of the wild-type enzyme. The positioning of the side-chain phenolic group of Tyr-137 in the active site of IAD is consistent with the stabilization of the tetrahedral adduct concomitant with nucleophilic attack by the hydroxide that bridges the two divalent cations. Mutation of Glu-77 resulted in the reduction of catalytic activity by five orders of magnitude. The three dimensional structure of the E77Q mutant did not show any significant conformational changes in the mutant relative to the three dimensional structure of the wild-type enzyme. The positioning of the side-chain carboxylate of Glu-77 is consistent with the formation of an ion pair interaction with the free α-amino group of the substrate.
Recreating the natural evolutionary trend in key microdomains provides an effective strategy for engineering of a thermomicrobial N-demethylase
Gu, Zhenghua,Guo, Zitao,Shao, Jun,Shen, Chen,Shi, Yi,Tang, Mengwei,Xin, Yu,Zhang, Liang
, (2022/03/09)
N-demethylases have been reported to remove the methyl groups on primary or secondary amines, which could further affect the properties and functions of biomacromolecules or chemical compounds; however, the substrate scope and the robustness of N-demethylases have not been systematically investigated. Here we report the recreation of natural evolution in key microdomains of the Thermomicrobium roseum sarcosine oxidase (TrSOX), an N-demethylase with marked stability (melting temperature over 100 C) and enantioselectivity, for enhanced substrate scope and catalytic efficiency on -C-N-bonds. We obtained the structure of TrSOX by crystallization and X-ray diffraction (XRD) for the initial framework. The natural evolution in the nonconserved residues of key microdomains—including the catalytic loop, coenzyme pocket, substrate pocket, and entrance site—was then identified using ancestral sequence reconstruction (ASR), and the substitutions that accrued during natural evolution were recreated by site-directed mutagenesis. The single and double substitution variants catalyzed the N-demethylation of N-methyl-L-amino acids up to 1800- and 6000-fold faster than the wild type, respectively. Additionally, these single substitution variants catalyzed the terminal N-demethylation of non-amino-acid compounds and the oxidation of the main chain -C-N- bond to a -C=N- bond in the nitrogen-containing heterocycle. Notably, these variants retained the enantioselectivity and stability of the initial framework. We conclude that the variants of TrSOX are of great potential use in N-methyl enantiomer resolution, main-chain Schiff base synthesis, and alkaloid modification or degradation.
Decarboxylative Radical Addition to Methylideneoxazolidinones for Stereocontrolled Synthesis of Selectively Protected Diamino Diacids
Annadate, Ritesh,Beadle, Jonathan,Hsiao, Yu-Ting,Pascoe, Cameron,Vederas, John C.
supporting information, p. 7270 - 7273 (2021/10/01)
Syntheses of stereochemically pure and selectively protected diamino diacids can be achieved by redox decarboxylation of distal N-hydroxyphthalimide esters of protected aspartic, glutamic or α-aminoadipic acids via radical addition to methylideneoxazolidinones. The products are useful for solid-supported syntheses of robust bioactive carbocyclic peptide analogs. Yields of reactive primary radical addition are superior to those of more stabilized radicals, and the reaction fails if the alkylideneoxazolidinone has a methyl substituent on its terminus (i.e., 13a/13b).
