- Substrate specificity in ketosynthase domains from trans-AT polyketide synthases
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Branching out: The substrate specificity profiles for a range of ketosynthase (KS) domains from trans-AT PKSs are reported. Evidence is provided that a sterically demanding amino acid residue adjacent to the active-site Cys residue confers specificity towards non-β-methyl-branched substrates (see scheme). Copyright
- Jenner, Matthew,Frank, Sarah,Kampa, Annette,Kohlhaas, Christoph,P?plau, Petra,Briggs, Geoff S.,Piel, J?rn,Oldham, Neil J.
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- Characterization of the promiscuous: N-Acyl CoA transferase, LgoC, in legonoxamine biosynthesis
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More than 500 siderophores are known to date, but only three were identified to be aryl-containing hydroxamate siderophores, legonoxamines A and B from Streptomyces sp. MA37, and aryl ferrioxamine 2 from Micrococcus luteus KLE1011. Siderophores are produced by microorganisms to scavenge iron from the environment, thereby making this essential metal nutrient available to the microbe. We demonstrate here that LgoC from MA37 is responsible for the key aryl-hydroxamate forming step in legonoxamine biosynthesis. Biochemical characterization established that LgoC displays considerable promiscuity for the acylation between N-hydroxy-cadaverine and SNAC (N-Acetylcysteamines) thioester derivatives.
- Alrashdi, Saad,Deng, Hai,Kyeremeh, Kwaku,Maglangit, Fleurdeliz,Renault, Justine,Tong, Ming Him,Trembleau, Laurent,Victoria, Catherine,Wang, Shan
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- Postsynthetic modification of bacterial peptidoglycan using bioorthogonal n-acetylcysteamine analogs and peptidoglycan o-acetyltransferase B
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Bacteria have the natural ability to install protective postsynthetic modifications onto its bacterial peptidoglycan (PG), the coat woven into bacterial cell wall. Peptidoglycan O-acetyltransferase B (PatB) catalyzes the O-acetylation of PG in Gram (-) bacteria, which AIDS in bacterial survival, as it prevents autolysins such as lysozyme from cleaving the PG. We explored the mechanistic details of PatB's acetylation function and determined that PatB has substrate specificity for bioorthgonal short N-acetyl cysteamine (SNAc) donors. A variety of functionality including azides and alkynes were installed on tri-N-acetylglucosamine (NAG)3, a PG mimic, as well as PG isolated from various Gram (+) and Gram (-) bacterial species. The bioorthogonal modifications protect the isolated PG against lysozyme degradation in vitro. We further demonstrate that this postsynthetic modification of PG can be extended to use click chemistry to fluorescently label the mature PG in whole bacterial cells of Bacillus subtilis. Modifying PG postsynthetically can aid in the development of antibiotics and immune modulators by expanding the understanding of how PG is processed by lytic enzymes.
- Wang, Yiben,Lazor, Klare M.,DeMeester, Kristen E.,Liang, Hai,Heiss, Tyler K.,Grimes, Catherine L.
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- Structural and functional analysis of the loading acyltransferase from avermectin modular polyketide synthase
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The loading acyltransferase (AT) domains of modular polyketide synthases (PKSs) control the choice of starter units incorporated into polyketides and are therefore attractive targets for the engineering of modular PKSs. Here, we report the structural and biochemical characterizations of the loading AT from avermectin modular PKS, which accepts more than 40 carboxylic acids as alternative starter units for the biosynthesis of a series of congeners. This first structural analysis of loading ATs from modular PKSs revealed the molecular basis for the relaxed substrate specificity. Residues important for substrate binding and discrimination were predicted by modeling a substrate into the active site. A mutant with altered specificity toward a panel of synthetic substrate mimics was generated by site-directed mutagenesis of the active site residues. The hydrolysis of the N-acetylcysteamine thioesters of racemic 2-methylbutyric acid confirmed the stereospecificity of the avermectin loading AT for an S configuration at the C-2 position of the substrate. Together, these results set the stage for region-specific modification of polyketides through active site engineering of loading AT domains of modular PKSs.
- Wang, Fen,Wang, Yanjie,Ji, Junjie,Zhou, Zhan,Yu, Jingkai,Zhu, Hua,Su, Zhiguo,Zhang, Lixin,Zheng, Jianting
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p. 1017 - 1025
(2015/07/27)
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- Poly-(N,N′-dibromo-N-ethyl-benzene-1,3-disulfonamide) and N,N,N′,N′- tetrabromobenzene-1,3-disulfonamide as highly efficient catalysts, and (AC2O/SIO2) as a heterogeneous system for the acetylation of alcohols, amines, and thiols under microwave irradiation
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Chemical Equation Presented Poly-(N,N′-dibromo-N-ethyl-benzene-1,3- disulfonamide) (PBBS) and N,N,N′,N′-tetrabromobenzene-1,3- disulfonamide (TBBDA) are good activators and catalytic reagents for the acetylation of alcohols, amines, and thiols. The presented method has the advantages of mild conditions, chemoselectivity, and good to high yields, and uses noncorrosive, inexpensive, recyclable, and environmentally friendly catalysts. We have also demonstrated that combining SiO2 with microwave energy provides an efficient, fast, convenient, and easy workup procedure for the synthesis of mono- and disubstituted acetates, acetamides, and thioacetamides. Copyright Taylor & Francis Group, LLC.
- Veisi, Hojat,Ghorbani-Vaghei, Ramin,Eskandari, Hosna,Hemmati, Saba,Rezaei, Ardashir,Hajinazari, Somaye,Far, Mohammad Raoof Heidari,Entezari, Azam
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experimental part
p. 213 - 219
(2011/04/24)
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- Ketolide antibacterials
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The present invention includes compounds of the formula wherein: X is hydrogen or halide; R2is hydrogen, acyl, or a hydroxy protecting group; R6is hydrogen, hydroxyl, or —ORawherein Rais a substituted or unsubstituted moiety selected from the group consisting of C1-C10alkyl, C2-C10alkenyl, C2-C10alkynyl, aryl, heterocyclo, aryl(C1-C10)alkyl, aryl(C2-C10)alkenyl, aryl(C2-C10)alkynyl, heterocyclo(C1-C10)alkyl, heterocyclo(C2-C10)alkenyl, and heterocyclo(C2-C10)alkynyl; R13is hydrogen or a substituted or unsubstituted moiety wherein the moiety is selected from the group consisting of methyl; C3-C10alkyl, C2-C10alkenyl, C2-C10alkynyl, aryl, heterocyclo, aryl(C1-C10)alkyl, aryl(C2-C10)alkenyl, aryl(C2-C10)alkynyl, heterocyclo(C1-C10)alkyl, heterocyclo(C2-C10)alkenyl, and heterocyclo(C2-C10)alkynyl; and, R is hydrogen or a substituted or unsubstituted moiety wherein the moiety is selected from the group consisting of C1-C10alkyl, C2-C10alkenyl, C2-C10alkynyl, aryl, heterocyclo, aryl(C1-C10)alkyl, aryl(C2-C10)alkenyl, aryl(C2-C10)alkynyl, heterocyclo(C1-C10)alkyl, heterocyclo(C2-C10)alkenyl, and heterocyclo(C2-C10)alkynyl; and the pharmaceutically acceptable salts, esters and pro-drug forms thereof. These compounds possess anti-infective activity and are useful for the treatment of bacterial and protozoal infections.
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- Macrolide antiinfective agents
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The invention is directed towards antibacterial compounds. The invention concerns macrolide antibiotics useful as antiinfective agents.
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- Racemic thioesters for production of polyketides
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Facile methods for preparing diketide and triketide thioesters are disclosed. The resulting thioesters may be used as intermediates in the synthesis of desired polyketides, and may contain functional groups which ultimately reside in side chains on the resulting polyketide and thus can be used further to manipulate the polyketide so as form derivatives. The polyketides produced may also be tailored by glycosylation, hydroxylation and the like. New polyketides and their derivatives and tailored forms are thereby produced.
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- Biosynthetic Studies of Brevetoxins, Potent Neurotoxins Produced by the Dinoflagellate Gymnodinium breve
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Blooms of the dinoflegellate Gymnodinium breve (Ptychodiscus brevis) commonly known as "red tide" have led to massive fish kills, mollusk contamination, and human food intoxications along the Florida coast and the Gulf of Mexico.The toxins from G. breve responsible for these phenomena are the brevetoxins (BTX's), a group of potent neurotoxins with polycyclic trans-fused ether rings which presumably depolarize the sodium channels of the excitable membranes.BTX-B, C50H70O14, the first of these neurotoxins whose structure was elucidated, has an unprecedented structure consisting of 6/6/6/7/7/6/6/8/6/6/6 ether rings trans-fused in a ladder-like manner.Another member of these toxins, BTX-A, C49H70O13, has another remarkable structure consisting of trans-fused 5/8/6/7/9/6/6/6 ether rings.Although the carbon skeletons of BTX-B and BTX-A are different, both consist of a single carbon chain that is polyoxygenated with methyl substituent groups.This is consistent with polyketide biosynthesis, i.e., condensation of acetate units with the methyl groups originating from either S-adenosylmethionine or propionate.Labeling experiments using sodium - and acetate and methionine demonstrate that the labeling patterns of BTX-B and BTX-A are similar and that the biosynthesis of brevetoxins is not of simple polyketide origin.These labeling studies suggest that the citric acid cycle is involved in the biosynthetis of BTX-B and BTX-A, the degree of its involvement being unusually high.Furthermore, CO2 participates in a unique manner in the biosynthesis of C-1 of BTX-B and BTX-A.
- Lee, Min S.,Qin, Guo-wei,Nakanishi, Koji,Zagorski, Michael G.
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p. 6234 - 6241
(2007/10/02)
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- Steric Course of the Allylic Rearrangement Catalyzed by β-Hydroxydecanoylthioester Dehydrase. Mechanistic Implications
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β-Hydroxydecanoylthioester dehydrase, which is the pivotal enzyme in the biosynthesis of unsaturated fatty acids in anaerobic metabolism, catalyses the equilibration of thio esters of (R)-3-hydroxydecanoic acid, (E)-2-decenoic acid, and (Z)-3-decenoic acid.On the basis of evidence available to date, both two-base and one-base mechanisms of action can be envisioned for dehydrase.In an effort to distinguish between these mechanisms, the stereochemical course of the dehydrase-catalyzed allylic rearrangement has been determined.N-Acetylcysteamine (NAC) thio esters of (R)- and (S)-(E)-decanoic acid were synthesized and incubated with dehydrase.The product (Z)-3-decenoyl-NAC was derivatized, and 2H NMR analysis showed that the pro-4R hydrogen had been removed. (E)-2-Decenoyl-NAC and unlabeled (E)-2-decenoyl NAC were incubated with dehydrase in 1H2O and 2H2O, respectively.Analysis of a derivative of the resulting labeled (Z)-3-decenoyl-NAC showed that protonation had occured on the si face at substrate C-2.The overall steric course of the reaction is therefore suprafacial.The significance of this result is discussed in terms of the mechanisms of the "normal" dehydrase-catalysed reactions as well as the "suicide" inactivation of the enzyme.
- Schwab, John M.,Klassen, John B.
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p. 7217 - 7227
(2007/10/02)
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