Browse
Submit Data
Databases
API
Help

Dataset Information

15 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Aryl Coenzyme A Ligases, a Subfamily of the Adenylate-Forming Enzyme Superfamily.

ABSTRACT: Aryl coenzyme A (CoA) ligases belong to class I of the adenylate-forming enzyme superfamily (ANL superfamily). They catalyze the formation of thioester bonds between aromatic compounds and CoA and occur in nearly all forms of life. These ligases are involved in various metabolic pathways degrading benzene, toluene, ethylbenzene, and xylene (BTEX) or polycyclic aromatic hydrocarbons (PAHs). They are often necessary to produce the central intermediate benzoyl-CoA that occurs in various anaerobic pathways. The substrate specificity is very diverse between enzymes within the same class, while the dependency on Mg²⁺, ATP, and CoA as well as oxygen insensitivity are characteristics shared by the whole enzyme class. Some organisms employ the same aryl-CoA ligase when growing aerobically and anaerobically, while others induce different enzymes depending on the environmental conditions. Aryl-CoA ligases can be divided into two major groups, benzoate:CoA ligase-like enzymes and phenylacetate:CoA ligase-like enzymes. They are widely distributed between the phylogenetic clades of the ANL superfamily and show closer relationships within the subfamilies than to other aryl-CoA ligases. This, together with residual CoA ligase activity in various other enzymes of the ANL superfamily, leads to the conclusion that CoA ligases might be the ancestral proteins from which all other ANL superfamily enzymes developed.

SUBMITTER: Arnold ME

PROVIDER: S-EPMC8388817 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

The mechanism of domain alternation in the acyl-adenylate forming ligase superfamily member 4-chlorobenzoate: coenzyme A ligase.

Project description:4-Chlorobenzoate:CoA ligase (CBL) belongs to the adenylate-forming family of enzymes that catalyze a two-step reaction to first activate a carboxylate substrate as an adenylate and then transfer the carboxylate to the pantetheine group of either coenzyme A or an acyl-carrier protein. The active site is located at the interface of a large N-terminal domain and a smaller C-terminal domain. Crystallographic structures have been determined at multiple steps along the reaction pathway and form the basis for a proposal that the C-terminal domain rotates by approximately 140 degrees between the two states that catalyze the adenylation and thioester-forming half-reactions. The domain rotation is accompanied by a change in the main chain torsional angles of Asp402, a conserved residue located at the interdomain hinge position. We have mutated the Asp402 residue to Pro in order to test the impact of reduced main chain flexibility at the putative hinge position. The crystal structure of the D402P mutant shows that the enzyme adopts the proposed adenylate-forming conformation with very little change to the overall structure. To examine the impact of this mutation on the ability of the enzyme to catalyze the complete reaction, single turnover kinetic experiments were performed. Whereas the ability of this mutant to catalyze the adenylate-forming half-reaction is reduced by approximately 3-fold, catalysis of the second half-reaction is reduced by 4 orders of magnitude. The impact of the alanine replacement of Asp402 on the thioester-forming reaction is significant, although not as dramatic as the proline mutation, and provides evidence that the Asp402 carboxylate group, through ion pair formation with N-terminal domain residue Arg400, assists in the transition to the thioester-forming conformer. Together these results support the domain alternation hypothesis.

| S-EPMC2680940 | biostudies-literature

Coenzyme F390 synthetase from Methanobacterium thermoautotrophicum Marburg belongs to the superfamily of adenylate-forming enzymes.

Project description:Depending on the reduction-oxidation state of the cell, some methanogenic bacteria synthesize or hydrolyze 8-hydroxyadenylylated coenzyme F420 (coenzyme F390). These two reactions are catalyzed by coenzyme F390 synthetase and hydrolase, respectively. To gain more insight into the mechanism of the former reaction, coenzyme F390 synthetase from Methanobacterium thermoautotrophicum Marburg was purified 89-fold from cell extract to a specific activity of 0.75 mumol.min-1.mg of protein-1. The monomeric enzyme consisted of a polypeptide with an apparent molecular mass of 41 kDa as determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. ftsA, the gene encoding coenzyme F390 synthetase, was cloned and sequenced. It encoded a protein of 377 amino acids with a predicted M(r) of 43,280. FtsA was found to be similar to domains found in the superfamily of peptide synthetases and adenylate-forming enzymes. FtsA was most similar to gramicidin S synthetase II (67% similarity in a 227-amino-acid region) and sigma-(L-alpha-aminoadipyl)-L-cysteine-D-valine synthetase (57% similarity in a 193-amino-acid region). Coenzyme F390 synthetase, however, holds an exceptional position in the superfamily of adenylate-forming enzymes in that it does not activate a carboxyl group of an amino or hydroxy acid but an aromatic hydroxyl group of coenzyme F420.

| S-EPMC177685 | biostudies-other

Adenylate-forming enzymes.

Project description:Thioesters, amides, and esters are common chemical building blocks in a wide array of natural products. The formation of these bonds can be catalyzed in a variety of ways. For chemists, the use of an activating group is a common strategy and adenylate enzymes are exemplars of this approach. Adenylating enzymes activate the otherwise unreactive carboxylic acid by transforming the normal hydroxyl leaving group into adenosine monophosphate. Recently there have been a number of studies of such enzymes and in this review we suggest a new classification scheme. The review highlights the diversity in enzyme fold, active site architecture, and metal coordination that has evolved to catalyze this particular reaction.

| S-EPMC3313645 | biostudies-literature

Structures of Mycobacterium tuberculosis FadD10 protein reveal a new type of adenylate-forming enzyme.

Project description:Mycobacterium tuberculosis has a group of 34 FadD proteins that belong to the adenylate-forming superfamily. They are classified as either fatty acyl-AMP ligases (FAALs) or fatty acyl-CoA ligases based on sequence analysis. FadD10, involved in the synthesis of a virulence-related lipopeptide, was mis-annotated as a fatty acyl-CoA ligase; however, it is in fact a FAAL that transfers fatty acids to an acyl carrier protein (Rv0100). In this study, we have determined the structures of FadD10 in both the apo-form and the complexed form with dodecanoyl-AMP, where we see for the first time an adenylate-forming enzyme that does not adopt a closed conformation for catalysis. Indeed, this novel conformation of FadD10, facilitated by its unique inter-domain and intermolecular interactions, is critical for the enzyme to carry out the acyl transfer onto Rv0100 rather than coenzyme A. This contradicts the existing model of FAALs that rely on an insertion motif for the acyltransferase specificity and thus makes FadD10 a new type of FAAL. We have also characterized the fatty acid preference of FadD10 through biological and structural analyses, and the data indicate long chain saturated fatty acids as the biological substrates of the enzyme.

| S-EPMC3689989 | biostudies-literature

Unprecedented acetoacetyl-coenzyme A synthesizing enzyme of the thiolase superfamily involved in the mevalonate pathway.

Project description:Acetoacetyl-CoA is the precursor of 3-hydroxy-3-methylglutaryl (HMG)-CoA in the mevalonate pathway, which is essential for terpenoid backbone biosynthesis. Acetoacetyl-CoA is also the precursor of poly-beta-hydroxybutyrate, a polymer belonging to the polyester class produced by microorganisms. The de novo synthesis of acetoacetyl-CoA is usually catalyzed by acetoacetyl-CoA thiolase via a thioester-dependent Claisen condensation reaction between two molecules of acetyl-CoA. Here, we report that nphT7, found in the mevalonate pathway gene cluster from a soil-isolated Streptomyces sp. strain, encodes an unusual acetoacetyl-CoA synthesizing enzyme. The recombinant enzyme overexpressed in Escherichia coli catalyzes a single condensation of acetyl-CoA and malonyl-CoA to give acetoacetyl-CoA and CoA. Replacement of malonyl-CoA with malonyl-(acyl carrier protein) resulted in loss of the condensation activity. No acetoacetyl-CoA synthesizing activity was detected through the condensation of two molecules of acetyl-CoA. Based on these properties of NphT7, we propose to name this unusual enzyme of the thiolase superfamily acetoacetyl-CoA synthase. Coexpression of nphT7 with the HMG-CoA synthase gene and the HMG-CoA reductase gene in a heterologous host allowed 3.5-fold higher production of mevalonate than when only the HMG-CoA synthase and HMG-CoA reductase genes were expressed. This result suggests that nphT7 can be used to significantly increase the concentration of acetoacetyl-CoA in cells, eventually leading to the production of useful terpenoids and poly-beta-hydroxybutyrate.

| S-EPMC2895072 | biostudies-literature

Structure-Based Design, Synthesis, and Biological Evaluation of Non-Acyl Sulfamate Inhibitors of the Adenylate-Forming Enzyme MenE.

Project description:N-Acyl sulfamoyladenosines (acyl-AMS) have been used extensively to inhibit adenylate-forming enzymes that are involved in a wide range of biological processes. These acyl-AMS inhibitors are nonhydrolyzable mimics of the cognate acyl adenylate intermediates that are bound tightly by adenylate-forming enzymes. However, the anionic acyl sulfamate moiety presents a pharmacological liability that may be detrimental to cell permeability and pharmacokinetic profiles. We have previously developed the acyl sulfamate OSB-AMS (1) as a potent inhibitor of the adenylate-forming enzyme MenE, an o-succinylbenzoate-CoA (OSB-CoA) synthetase that is required for bacterial menaquinone biosynthesis. Herein, we report the use of computational docking to develop novel, non-acyl sulfamate inhibitors of MenE. A m-phenyl ether-linked analogue (5) was found to be the most potent inhibitor (IC50 = 8 ?M; Kd = 244 nM), and its X-ray co-crystal structure was determined to characterize its binding mode in comparison to the computational prediction. This work provides a framework for the development of potent non-acyl sulfamate inhibitors of other adenylate-forming enzymes in the future.

| S-EPMC6653581 | biostudies-literature

Targeting adenylate-forming enzymes with designed sulfonyladenosine inhibitors.

Project description:Adenylate-forming enzymes are a mechanistic superfamily that are involved in diverse biochemical pathways. They catalyze ATP-dependent activation of carboxylic acid substrates as reactive acyl adenylate (acyl-AMP) intermediates and subsequent coupling to various nucleophiles to generate ester, thioester, and amide products. Inspired by natural products, acyl sulfonyladenosines (acyl-AMS) that mimic the tightly bound acyl-AMP reaction intermediates have been developed as potent inhibitors of adenylate-forming enzymes. This simple yet powerful inhibitor design platform has provided a wide range of biological probes as well as several therapeutic lead compounds. Herein, we provide an overview of the nine structural classes of adenylate-forming enzymes and examples of acyl-AMS inhibitors that have been developed for each.

| S-EPMC6594144 | biostudies-literature

Functional and phylogenetic divergence of fungal adenylate-forming reductases.

Project description:A key step in fungal L-lysine biosynthesis is catalyzed by adenylate-forming L-α-aminoadipic acid reductases, organized in domains for adenylation, thiolation, and the reduction step. However, the genomes of numerous ascomycetes and basidiomycetes contain an unexpectedly large number of additional genes encoding similar but functionally distinct enzymes. Here, we describe the functional in vitro characterization of four reductases which were heterologously produced in Escherichia coli. The Ceriporiopsis subvermispora serine reductase Nps1 features a terminal ferredoxin-NADP+ reductase (FNR) domain and thus belongs to a hitherto undescribed class of fungal multidomain enzymes. The second major class is characterized by the canonical terminal short-chain dehydrogenase/reductase domain and represented by Ceriporiopsis subvermispora Nps3 as the first biochemically characterized L-α-aminoadipic acid reductase of basidiomycete origin. Aspergillus flavus l-tyrosine reductases LnaA and LnbA are members of a distinct phylogenetic clade. Phylogenetic analysis supports the view that fungal adenylate-forming reductases are more diverse than previously recognized and belong to four distinct classes.

| S-EPMC4178688 | biostudies-literature

Biochemical and structural characterization of bisubstrate inhibitors of BasE, the self-standing nonribosomal peptide synthetase adenylate-forming enzyme of acinetobactin synthesis.

Project description:The human pathogen Acinetobacter baumannii produces a siderophore called acinetobactin that is derived from one molecule each of threonine, histidine, and 2,3-dihydroxybenzoic acid (DHB). The activity of several nonribosomal peptide synthetase (NRPS) enzymes is used to combine the building blocks into the final molecule. The acinetobactin synthesis pathway initiates with a self-standing adenylation enzyme, BasE, that activates the DHB molecule and covalently transfers it to the pantetheine cofactor of an aryl-carrier protein of BasF, a strategy that is shared with many siderophore-producing NRPS clusters. In this reaction, DHB reacts with ATP to form the aryl adenylate and pyrophosphate. In a second partial reaction, the DHB is transferred to the carrier protein. Inhibitors of BasE and related enzymes have been identified that prevent growth of bacteria on iron-limiting media. Recently, a new inhibitor of BasE has been identified via high-throughput screening using a fluorescence polarization displacement assay. We present here biochemical and structural studies to examine the binding mode of this inhibitor. The kinetics of the wild-type BasE enzyme is shown, and inhibition studies demonstrate that the new compound exhibits competitive inhibition against both ATP and 2,3-dihydroxybenzoate. Structural examination of BasE bound to this inhibitor illustrates a novel binding mode in which the phenyl moiety partially fills the enzyme pantetheine binding tunnel. Structures of rationally designed bisubstrate inhibitors are also presented.

| S-EPMC2964879 | biostudies-literature

A new subfamily of conotoxins belonging to the A-superfamily.

Project description:Two novel conotoxins from vermivorous cone snails Conus pulicarius and Conus tessulatus, designated as Pu14.1 and ts14a, were identified by cDNA cloning and peptide purification, respectively. The signal sequence of Pu14.1 is identical to that of ?-conotoxins, while its predicted mature peptide, pu14a, shares high sequence similarity with ts14a, with only one residue different in their first intercysteine loop, which contains 10 residues and is rich in proline. Both pu14a and ts14a contain four separate cysteines in framework 14 (C-C-C-C). Peptide pu14a was chemically synthesized, air oxidized, and the connectivity of its two disulfide bonds was determined to be C1-C3, C2-C4, which is the same as found in ?-conotoxins. The synthetic pu14a induced a sleeping symptom in mice and was toxic to freshwater goldfish upon intramuscular injection. Using the Xenopus oocyte heterologous expression system, 1?M of pu14a demonstrated to inhibit the rat neuronal ?3?2-containing as well as the mouse neuromuscular ?1?1?? subtypes of nicotinic acetylcholine receptors, and then rapidly dissociated from the receptors. However, this toxin had no inhibitory effect on potassium channels in mouse superior cervical ganglion neurons. According to the identical signal sequence to ?-conotoxins, the unique cysteine framework and molecular target of pu14a, we propose that pu14a and ts14a may represent a novel subfamily in the A-superfamily, designated as ?1-conotoxins.

| S-EPMC3721517 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data