Mechanistic studies on trans-2,3-dihydro-2,3-dihydroxybenzoate dehydrogenase (Ent A) in the biosynthesis of the iron chelator enterobactin

Sakaitani, Masahiro; Rusnak, Frank; Quinn, Nina; Tu, Cheng; Frigo, Timothy B.; Berchtold, Glenn A.; Walsh, Christopher T.

doi:10.1021/bi00481a006

Cited by 44 publications

(20 citation statements)

References 42 publications

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“…Dehydrogenases with these stereochemical preferences are well known (27,36,38,39). Figure 8 (E4) describes the reduction of NAD ϩ and oxidation of an alcohol formed by dihydrodiol dehydrogenases; i.e., the hydrogen transfer occurs from the Re face of the alcohol to the Si face of NAD, giving (4S)-NADH (1,32).…”

Section: Discussionmentioning

confidence: 99%

Stereochemical course of two arene-cis-diol dehydrogenases specifically induced in Pseudomonas putida

et al. 1997

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Catabolism of nonphenolic arenes is frequently initiated by dioxygenases, yielding single isomer products with two adjacent hydroxylated asymmetric centers. The next enzymic reaction dehydrogenates these cyclic cis-diols, with aromatization yielding catechols for ring cleavage. H was transferred from both the 2-and 3-C atoms of (2S,3R)-p-toluate-2,3-dihydrodiol with specifically deuterated species in approximately equal amounts; and (iii) the unexpected lack of stereo-and regioselectivity of p-toluate-2,3-diol dehydrogenase was supported by kinetic isotope effect studies.Most nonhydroxylated arenes biodegraded by bacteria are dihydroxylated initially, in NADH-dependent reactions, to give cis-1,2-diol cyclohexadiene intermediates (10,(12)(13)(14)17). The second reaction of these catabolic pathways is usually an NADdependent dehydrogenation with concomitant rearomatization of the ring to give a catechol. The seminal work of Gibson (11) established this central, and apparently sole, preserve of bacterial evolution; cis-1,2-diol formation in other biological kingdoms has not yet been described.These dihydroxylation and dehydrogenation systems pose several questions of enzyme stereospecificity. Two asymmetric centers are formed in a single initial reaction, and they are destroyed in the next catabolic reaction by dehydrogenation to catechols. There are therefore two possible stereochemical questions to address for each reaction, to describe the diastereochemistry of these enzymic reactions. (i) Which hydrogen of NADH (4R or 4S) is transferred for the dihydroxylation? (ii) Which atom in the diol product receives hydrogen (H ϩ or H Ϫ )? For the successive dehydrogenation reactions, the inverse questions require solution. (iii) To which face of the nicotinamide ring of NAD ϩ is hydride ion transferred? (iv) From which C center of the dihydrodiol is hydride transferred to give NADH. In this paper we provide answers to questions ii, iii, and iv.Previously we have shown that the flavoprotein hydroxylases for orcinol, resorcinol, and 3-hydroxybenzoate (4-and 6-hydroxylases) donate the (4S) proton from NADH, by 3 H and 2 H isotope experiments (30, 37). You et al. (38) confirmed these results by proton nuclear magnetic resonance (NMR) experiments with five enzymes that we provided. A recent study by Schläfli et al. (34), using the tritium method to discriminate the (4S) and (4R) protons in NADH, examined the stereospecificity of hydride (tritide) transfer by the flavin cytochrome reductases of several arene-cis-1,2-dihydroxylases. There appears to be a consistency, since the examined enzymes of class I, e.g., phthalate dioxygenase and 2-chlorobenzoate dioxygenase, used the (4S)-3

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Section: Discussionmentioning

confidence: 99%

Stereochemical course of two arene-cis-diol dehydrogenases specifically induced in Pseudomonas putida

et al. 1997

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“…EntB forms a homodimer, and the dimerization takes place via the isochorismatase domain. The last step in DHB synthesis is catalyzed by a 2,3-dihydro-DHB dehydrogenase, a member of the shortchain oxidoreductase enzyme family, which oxidizes the EntB product into the aromatic catechol DHB using NAD ϩ as a cofactor (289). The crystal structure of the E. coli 2,3-dihydro-DHB dehydrogenase EntA revealed a homotetramer formation (Fig.…”

Section: General Steps Of Siderophore Pathwaysmentioning

confidence: 99%

Siderophore-Based Iron Acquisition and Pathogen Control

Miethke

Marahiel

2007

Microbiol Mol Biol Rev

1,442

1,302

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SUMMARY High-affinity iron acquisition is mediated by siderophore-dependent pathways in the majority of pathogenic and nonpathogenic bacteria and fungi. Considerable progress has been made in characterizing and understanding mechanisms of siderophore synthesis, secretion, iron scavenging, and siderophore-delivered iron uptake and its release. The regulation of siderophore pathways reveals multilayer networks at the transcriptional and posttranscriptional levels. Due to the key role of many siderophores during virulence, coevolution led to sophisticated strategies of siderophore neutralization by mammals and (re)utilization by bacterial pathogens. Surprisingly, hosts also developed essential siderophore-based iron delivery and cell conversion pathways, which are of interest for diagnostic and therapeutic studies. In the last decades, natural and synthetic compounds have gained attention as potential therapeutics for iron-dependent treatment of infections and further diseases. Promising results for pathogen inhibition were obtained with various siderophore-antibiotic conjugates acting as “Trojan horse” toxins and siderophore pathway inhibitors. In this article, general aspects of siderophore-mediated iron acquisition, recent findings regarding iron-related pathogen-host interactions, and current strategies for iron-dependent pathogen control will be reviewed. Further concepts including the inhibition of novel siderophore pathway targets are discussed.

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“…141, 145 The isochorismate is then hydrolyzed by the isochorismatase domain of the bifunctional EntB to produce 2,3-dihydro-2,3-dihydroxybenzoate ( 6 ) and pyruvate, 146 which is then converted to DHB by the activity of the short-chain dehydrogenase/reductase protein EntA. 136, 147 …”

Section: Klebsiella Pneumoniaementioning

confidence: 99%

Nonribosomal peptide synthetase biosynthetic clusters of ESKAPE pathogens

Gulick

2017

Nat. Prod. Rep.

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Overview Natural products are important secondary metabolites produced by bacterial and fungal species that play important roles in cellular growth and signaling, nutrient acquisition, intra- and interspecies communication, and virulence. A subset of natural products is produced by nonribosomal peptide synthetases (NRPSs), a family of large, modular enzymes that function in an assembly line fashion. Because of the pharmaceutical activity of many NRPS products, much effort has gone into the exploration of their biosynthetic pathways and the diverse products they make. Many interesting NRPS pathways have been identified and characterized from both terrestrial and marine bacterial sources. Recently, several NRPS pathways in human commensal bacterial species have been identified that produce molecules with antibiotic activity, suggesting another source of interesting NRPS pathways may be the commensal and pathogenic bacteria that live on the human body. The ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp.) have been identified as a significant cause of human bacterial infections that are frequently multidrug resistant. The emerging resistance profile of these organisms has prompted calls from multiple international agencies to identify novel antibacterial targets and develop new approaches to treat infections from ESKAPE pathogens. Each of these species contains several NRPS biosynthetic gene clusters. While some have been well characterized and produce known natural products with important biological roles in microbial physiology, others have yet to be investigated. This review catalogs the NRPS pathways of ESKAPE pathogens. The exploration of novel NRPS products may lead to a better understanding of the chemical communication used by human pathogens and potentially to the discovery of novel therapeutic approaches.

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Mechanistic studies on trans-2,3-dihydro-2,3-dihydroxybenzoate dehydrogenase (Ent A) in the biosynthesis of the iron chelator enterobactin

Cited by 44 publications

References 42 publications

Stereochemical course of two arene-cis-diol dehydrogenases specifically induced in Pseudomonas putida

Stereochemical course of two arene-cis-diol dehydrogenases specifically induced in Pseudomonas putida

Siderophore-Based Iron Acquisition and Pathogen Control

Nonribosomal peptide synthetase biosynthetic clusters of ESKAPE pathogens

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