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Table of contents

Some class II enzymes also have proofreading mechanisms to prevent incorrect amino acid incorporation [ 46 ]. Prokaryotic asparagine synthetase A AS-A is structurally related to class II aminoacyl-tRNA synthetases and catalyzes activation of the aspartate side-chain carboxylate 4.

These enzymes catalyze adenylation of a variety of small-molecule carboxylic acids 5. In the first two classes, this is followed by condensation with the thiol nucleophile of coenzyme A 5. The enzymes consist of a large N-terminal domain and a smaller C-terminal domain, which enclose the active site Fig.

Acyl-CoA synthetases are involved in metabolism of acetate as well as a wide range of fatty acid and other carboxylic acid substrates [ 12 ]. In contrast, NRPS adenylation domains activate amino acids and other carboxylic acid substrates during the biosynthesis of a wide range of bacterial natural products [ 15 , 16 ].


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In the third class, luciferase activates firefly d -luciferin 5. Fragmentation of this intermediate leads to formation of oxyluciferin in an excited state 5. Interestingly, luciferase can also activate the enantiomeric l -luciferin to form l -luciferyl-AMP, which condenses with CoA to form l -luciferyl-CoA, an inhibitor of the bioluminescence reaction.

The luciferase acyl-CoA synthetase activity additionally has been suggested to have a role in conversion of natural l -cysteine-derived l -luciferin to the requisite d -luciferin substrate [ 58 ]. Notably, a pair of enzymes, PtmA1 and PtmA2, which share the ANL family structure but appear to catalyze the adenylation and nucleophilic addition half-reactions separately, have been reported recently in the biosynthesis of platensimycin and platencin [ 32 ].

Biochemistry of ANL family enzymes. Cyclization of the intramolecular peroxide nucleophile forms a peroxylactone 5. Fragmentation forms excited oxyluciferin 5. E1 activating enzymes SCOPe c. This thioester intermediate then undergoes transthioesterification to the catalytic cysteine of an E2-conjugating enzyme. Most notably, E1 activating enzymes use protein substrates for both the carboxylic acid and nucleophile components.

Enantioselective Hydrolysis of Amino Acid Esters Promoted by Bis(β-cyclodextrin) Copper Complexes

E1 activating enzymes have a canyon-shaped active site with the base formed by two pseudosymmetric adenylation domains one of which is inactive and in some cases a separate heterodimeric subunit and the walls formed by a cysteine-containing domain and a ubiquitin-fold domain Fig. Biochemistry of ubiquitin-family E1 activating enzymes. The C-terminal carboxylate of Ub or a Ubl 6. Ub ubiquitin, Ubl ubiquitin-like modifier protein.

Interestingly, although E1 activating enzymes are limited to eukaryotes, structurally related enzymes have been reported in bacteria. These enzymes lack the catalytic cysteine-containing domain used in the second half-reaction by E1 enzymes and instead use external nucleophiles. Examples include the Escherichia coli molybdenum cofactor biosynthetic enzyme MoeB, which catalyzes coupling of the C terminus of MoaD to a persulfide nucleophile [ 61 ], and the thiamin biosynthetic enzyme ThiF, which catalyzes coupling of the C terminus of ThiS to a similar persulfide nucleophile [ 62 , 63 ].

Another related E. After transporter-mediated uptake into target cells, the N-terminal peptide is proteolyzed to reveal an aspartyl-adenylate-mimetic phosphoramidate 7. Intriguingly, Severinov and colleagues [ 65 ] recently discovered a Bacillus amyloliquefaciens homolog of MccB that instead catalyzes cytidylation of the C terminus of an MccA-like peptide.

Biochemistry of E. The C-terminal carboxylate of the MccA precursor peptide 7.


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MccB then catalyzes a second adenylation reaction to form a succinimide adenylate 7. Downstream installation of an O -aminopropyl group provides microcin C 7. This Trojan horse antibiotic is taken up by target cells via peptide transporters, then the N-terminal peptide is proteolyzed to form an aspartyl-phosphoramidate 7.

Extending Designed Linear Biocatalytic Cascades for Organic Synthesis

Biotin protein ligases SCOPe b. A biotin carboxylase subunit then carboxylates this biotinyl group and the carboxyl group is subsequently transferred to acetyl-CoA by a carboxyltransferase subunit to form malonyl-CoA, the key precursor in fatty acid biosynthesis.

However, the binding mode of the acyl-AMP intermediate and the active-site residues are distinct Fig. In the case of the best characterized family member, BirA, the reaction intermediate biotinyl-AMP also functions as a co-repressor in transcription, allosterically activating dimerization of BirA, leading to binding to and repression of the biotin biosynthetic operon bioO. Notably, fusion proteins of a BirA mutant that releases biotinyl-AMP prematurely have been used for proximity tagging of proteins in cells [ 33 , 34 ].

Biochemistry of biotin protein ligases. Biotin 8. In the case of the E.

Supplementary files

BCCP biotin carboxylate carrier protein. The ammonia nucleophile is often supplied by hydrolysis of the side-chain amide of a glutamine co-substrate in a glutamine amidotransferase domain of the same enzyme or by a separate subunit. Biochemistry of N-type ATP pyrophosphatases. These enzymes catalyze formation of carbamoyl-AMP intermediates, in contrast to the distinct transcarbamoylase transcarbamylase family, which uses carbamoylphosphate as an acyl donor [ 82 ].

Notably, condensation of the carbamoyl-AMP intermediate with a nucleophile in the second half-reaction is catalyzed by a separate Kae1-like domain or protein, with the adenylate intermediate thought to be shuttled between the two active sites. Biochemistry of YrdC-like carbamoyltransferases. Downstream enzymes then catalyze dehydration to a thiocyanate intermediate Another member of this family is the microbial [NiFe]-hydrogenase maturation protein HypF, which contains both YrdC-like and Kae1-like domains, as well as N-terminal acylphosphatase and Zn-finger domains [ 81 , 84 , 85 ].

Interestingly, this enzyme uses carbamoylphosphate Siderophores are iron-chelating natural products that are used by pathogenic bacteria to acquire iron from their hosts [ 28 , 86 , 87 ]. Most are produced by hybrid NRPS-polyketide biosynthetic pathways [ 88 ]. However, some siderophores have been found to be produced by distinct pathways involving NRPS-independent siderophore synthetases [ 24 , 89 , 90 ].

The enzyme family was initially discovered in studies of the biosynthesis of aerobactin and typically catalyzes adenylation of diacid substrates or their derivatives, followed by coupling to amine or alcohol nucleophiles. These enzymes can carry out desymmetrization and macrocyclization reactions. Structural studies of AcsD, which catalyzes enantioselective adenylation of citrate The overall structure comprised three domains resembling a thumb, palm, and fingers that surround the active site Fig.

Additional NRPS-independent siderophore synthetases have been identified in biosynthetic pathways of other siderophores, including aerobactin, alcaligin, anthrachelin, legiobactin, petrobactin, staphyloferrins A and B, rhizoferrins, and vibrioferrin [ 24 , 89 , 90 ]. Several of these enzymes have been characterized structurally, including AsbB petrobactin [ 93 ], IucA and IucC aerobactin [ 94 , 95 ], and AlcC alcaligin, putative [ 96 ].

Download Enzymes Volume Iv Hydrolysis Other C N Bonds Phosphate Esters Third Edition

Biochemistry of NRPS-independent siderophore synthetases. This family typically uses diacid or monofunctionalized derivatives of diacids as substrates and couples them to alcohol or amine nucleophiles. Recently, a ninth class of adenylate-forming enzymes was discovered. The pimeloyl-CoA synthetase BioW comprises a new catalytic fold for adenylate-forming enzymes, with the active site sandwiched between a small N-terminal domain and a larger C-terminal domain [ 39 , 40 ] Fig.


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  5. It catalyzes activation of pimelate Interestingly, this enzyme has been shown to be capable of proofreading, similar to aminoacyl-tRNA synthetases, by hydrolysis of non-cognate adenylate intermediates. Biochemistry of BioW acyl-CoA synthetases. Pimelate Natural products have provided essential inspiration for the development of inhibitors of adenylate-forming enzymes.

    In particular, the sulfamoyladenosines are a small family of natural products that contain a unique sulfamate moiety Fig. The first member of this class, nucleocidin Its mechanism of action was originally proposed to involve inhibition of protein synthesis [ ], although more recent work has implicated inhibition of ubiquitin-family E1 activating enzymes as another potential mechanism [ ].

    The desfluorinated analogue AMS Another close analogue, AT A novel family member, ascamycin Interestingly, bacteria sensitive to ascamycin were found to dealanate the natural product to form AT, the presumed active species [ ]. In pioneering work, Ishida and colleagues [ ] recognized that ascamycin was also a close analogue of alanyl-AMP, the reaction intermediate formed by alanyl-tRNA synthetase. As no co-crystal structures of aminoacyl-tRNA synthetases with their cognate aminoacyl-AMP intermediates had yet been reported, they posited that the acyl sulfamate moiety could act as a stable, non-hydrolyzable bioisostere of the labile acyl phosphate.

    As a result, numerous co-crystal structures of aminoacyl-tRNA synthetases with aminoacyl-AMS inhibitors were reported vide infra. Based on this seminal discovery, the acyl-AMS inhibitor design platform has subsequently been expanded to a wide range of other adenylate-forming enzymes. As adenylate-forming enzymes typically bind their cognate acyl-AMP reaction intermediates Indeed, several research groups have used this approach effectively to target six out of the nine classes of adenylate-forming enzymes.

    Typically, the identity of the acyl group provides substantial selectivity for the targeted enzyme, while modifications to the sulfamate, ribose, and adenine motifs can be used to modulate potency, specificity, and pharmacological properties. General acyl-AMS inhibitor design platform. Acyl-AMP intermediates Initial specificity for the desired adenylate-forming enzyme is provided by the acyl group blue and additional modifications can be made in the acyl, sulfamate red , ribose, and adenine regions in analogues.

    Following the precedent set by Ishida and colleagues [ ] above, a number of class I aminoacyl-tRNA synthetases have been co-crystallized with aminoacyl-AMS analogues Notably, carbonyl-reduced aminoalkyl-AMP analogues In most class I enzymes, the carbonyl group of the aminoacyl-AMP intermediate does not interact with active-site residues, consistent with its dispensability for binding. In contrast, in class II enzymes, this carbonyl interacts with a conserved arginine side chain, consistent with the decreased affinity of the carbonyl-reduced analogues in these cases.

    Structures of aminoacyl-AMP reaction intermediates 3.

    Download Enzymes Volume Iv Hydrolysis Other C N Bonds Phosphate Esters Third Edition

    In addition to the fundamental mechanistic interest in aminoacyl-tRNA synthetases, these enzymes are implicated in a wide range of human diseases [ 2 ] and have attracted particular interest as antibacterial targets [ 25 ]. However, achieving selective inhibition of a bacterial aminoacyl-tRNA synthetase over the corresponding human enzyme presents a significant challenge. Along these lines, researchers at Cubist Pharmaceuticals found that replacement of the adenine moiety in isoleucyl-AMS with heterocyclic motifs Further, CB exhibited in vitro antibacterial activity and in vivo efficacy in a mouse model of Streptomyces pyogenes infection.