Biosynthesis of <scp>l</scp>‐4‐Chlorokynurenine, an Antidepressant Prodrug and a Non‐Proteinogenic Amino Acid Found in Lipopeptide Antibiotics

Luhavaya, Hanna; Sigrist, Renata; Chekan, Jonathan R.; McKinnie, Shaun M. K.; Moore, Bradley S.

doi:10.1002/anie.201901571

Cited by 35 publications

(41 citation statements)

References 31 publications

(62 reference statements)

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“…Furthermore, SttH found in Streptomyces toxytricini [29] and the recently identified halogenases in Saccharomonospora sp. CNQ-490 (Tar14) [30], as well as a halogenase found through metagenomic screening of soil samples from the Anza-Borrego desert (BorH) [31] are able to chlorinate and brominate at the 6-position of this aromatic amino acid. The 5-position of the indole moiety of tryptophan can be modified by PyrH from Streptomyces rugosporus [27], SpmH from Streptomyces sp.…”

Section: Enzyme Diversity and Substrate Scopementioning

confidence: 99%

Recent Advances in Flavin-Dependent Halogenase Biocatalysis: Sourcing, Engineering, and Application

2019

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The introduction of a halogen atom into a small molecule can effectively modulate its properties, yielding bioactive substances of agrochemical and pharmaceutical interest. Consequently, the development of selective halogenation strategies is of high technological value. Besides chemical methodologies, enzymatic halogenations have received increased interest as they allow the selective installation of halogen atoms in molecular scaffolds of varying complexity under mild reaction conditions. Today, a comprehensive library of aromatic halogenases exists, and enzyme as well as reaction engineering approaches are being explored to broaden this enzyme family’s biocatalytic application range. In this review, we highlight recent developments in the sourcing, engineering, and application of flavin-dependent halogenases with a special focus on chemoenzymatic and coupled biosynthetic approaches.

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Section: Enzyme Diversity and Substrate Scopementioning

confidence: 99%

Recent Advances in Flavin-Dependent Halogenase Biocatalysis: Sourcing, Engineering, and Application

2019

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“…BorH is the fifth Trp-6-halogenase to have its structure determined, [27,28,41,42] but only the second (after Thal) to be solved with bound Trp. Clear electron density was visible in initial maps in all four chains for the substrate Trp.…”

Section: Borh Halogenates Av Ariety Of Aromatic Compounds With and Wimentioning

confidence: 99%

“…[18,[34][35][36][37][38][39] BorF (GenBank AGI62216,U niProtKB M9QXS1) is the flavin reductase in the Bor gene cluster that regenerates FADH 2 for BorH.The closestc haracterizedh omolog of BorH is Thal (70 %s equencei dentity), at ryptophan-6-halogenase involved in thienodolinb iosynthesis from Streptomycesa lbogriseolus. [24,28,40] The other characterized tryptophan-6-halogenases (Th-Hal, [41] SttH, [27] KtzR, [25] and Ta r14 [42] )s hare only 37-39 %i dentity with…”

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confidence: 99%

“…The closestc haracterizedh omolog of BorH is Thal (70 %s equencei dentity), at ryptophan-6-halogenase involved in thienodolinb iosynthesis from Streptomycesa lbogriseolus. [24,28,40] The other characterized tryptophan-6-halogenases (Th-Hal, [41] SttH, [27] KtzR, [25] and Ta r14 [42] )s hare only 37-39 %i dentity with BorH and are found in am ore distant clade along with the tryptophan-5-halogenases AbeH and PyrH ( Figure S2). BorH is more closely related to the tryptophan-7-halogenases RebH, KtzQ, and PrnAt han to the tryptophan-5-halogenases and Th-Hal, SttH and KtzR.…”

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confidence: 99%

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Structure and Activity of the Thermophilic Tryptophan‐6 Halogenase BorH

Lingkon

Bellizzi

2019

ChemBioChem

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Flavin-dependent halogenases carry out regioselective aryl halide synthesis in aqueous solutiona ta mbient temperature and neutral pH using benign halide salts, making them attractive catalysts for green chemistry.B orHa nd BorF,t wo proteins encoded by the biosyntheticg ene clusterf or the chlorinated bisindolea lkaloid borregomycin A, are the halogenase and flavin reductase subunits of at ryptophan-6-halogenase. Quantitative conversion of l-tryptophan (Trp) to 6-chlorotryptophan could be achieved using 1.2mol %B orHa nd 2mol %B orF.T he optimal reaction temperature for Trpc hlorination is 45 8C, and the meltingt emperatures of BorH and BorF are 48 and 50 8C respectively,w hich are higher than the thermalp arameters for most other halogenases previously studied. Steady-state kinetic analysis of Trpc hlorination by BorH determined parameters of k cat = 4.42 min À1 ,a nd K M of 9.78 mm at 45 8C. BorH exhibits a broad substrate scope, chlorinating and brominatingavariety of aromatic substrates with andw ithout indole groups.C hlorination of Trpa ta100 mg scale with 52 %c rude yield, using 0.2 mol %B orH indicates that industrial scale biotransformations using BorH/BorF are feasible. The X-ray crystal structure of BorH with bound Trpp rovides additional evidence for the model that regioselectivity is determined by substrate positioning in the active site, showingC 6o fT rp juxtaposed with the catalytic Lys79 in the same binding pose previously observed in the structure of Thal.Many biologically active compounds, including natural products, [1,2] synthetic drugs, [3,4] and agricultural chemicals [5] derive potencya nd specificity from halogen atoms. Carbon-halogen bonds are also key components of many synthetic intermediates, such as aryl halidesu sed in transition metal catalyzed cross-coupling reactions. [6,7] Traditional synthetic methods for the preparationo fo rganohalogen compounds suffer from lack of regioselectivity and frequently require toxic and unsustainable reagents and solvents, though promising new "green" methods are under development. [8,9] Flavin-dependent halogenases (FDHs), which can regioselectively halogenatea romatic substrates using only halide ion and O 2 ,h avee merged as a new environmentally friendly method for aryl halide synthesis. [10][11][12][13][14][15] FDHsa re closely relatedt of lavin-dependent two-component monooxygenases [16][17][18][19] and consist of two proteins:a halogenase (which convertsO 2 and halide ion into HOCl or HOBr and water with the oxidation of FADH 2 to FAD) and a smaller flavin reductase component (which reduces FADt o FADH 2 using NADH). FDHs have been discovered in the biosynthetic pathways of bacterial and fungal natural products, where they insert chlorine or brominei nto free or acyl carrier protein-bounda romatic substrates. [20] The most extensively studied halogenases (EC 1.14.19.9, 1.14.19.58, 1.14.19.59) regioselectivity halogenate l-tryptophan on the 5, 6, or 7p ositions of the indole ring, though most have the ability to halogenate other substrates a...

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“…The first FDHs to be characterized were tryptophan halogenases (Trp halogenases; Keller et al, 2000;Yeh et al, 2005). In the following years, a variety of different halogenases were studied that can be grouped into indole halogenases (which include the Trp halogenases; Seibold et al, 2006;Heemstra & Walsh, 2008;Zeng & Zhan, 2011;Menon et al, 2016;Ma et al, 2017;Lingkon & Bellizzi, 2020;Domergue et al, 2019;Luhavaya et al, 2019), phenol halogenases (Buedenbender et al, 2009;Neumann et al, 2010;Zeng et al, 2013;Agarwal et al, 2014;Menon et al, 2017;Mori et al, 2019) and pyrrole halogenases (Hammer et al, 1997;Dorrestein et al, 2005;Yamanaka et al, 2012;Agarwal et al, 2014), depending on the classes of compounds that they halogenate.…”

Section: Introductionmentioning

confidence: 99%

Structure of apo flavin-dependent halogenase Xcc4156 hints at a reason for cofactor-soaking difficulties

Widmann

Ismail

Sewald

et al. 2020

Acta Cryst Sect D Struct Biol

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Flavin-dependent halogenases regioselectively introduce halide substituents into electron-rich substrates under mild reaction conditions. For the enzyme Xcc4156 from Xanthomonas campestris, the structure of a complex with the cofactor flavin adenine dinucleotide (FAD) and a bromide ion would be of particular interest as this enzyme exclusively brominates model substrates in vitro. Apo Xcc4156 crystals diffracted to 1.6 Å resolution. The structure revealed an open substrate-binding site lacking the loop regions that close off the active site and contribute to substrate binding in tryptophan halogenases. Therefore, Xcc4156 might accept larger substrates, possibly even peptides. Soaking of apo Xcc4156 crystals with FAD led to crumbling of the intergrown crystals. Around half of the crystals soaked with FAD did not diffract, while in the others there was no electron density for FAD. The FAD-binding loop, which changes its conformation between the apo and the FAD-bound form in related enzymes, is involved in a crystal contact in the apo Xcc4156 crystals. The conformational change that is predicted to occur upon FAD binding would disrupt this crystal contact, providing a likely explanation for the destruction of the apo crystals in the presence of FAD. Soaking with only bromide did not result in bromide bound to the catalytic halide-binding site. Simultaneous soaking with FAD and bromide damaged the crystals more severely than soaking with only FAD. Together, these latter two observations suggest that FAD and bromide bind to Xcc4156 with positive cooperativity. Thus, apo Xcc4156 crystals provide functional insight into FAD and bromide binding, even though neither the cofactor nor the halide is visible in the structure.

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Biosynthesis of l‐4‐Chlorokynurenine, an Antidepressant Prodrug and a Non‐Proteinogenic Amino Acid Found in Lipopeptide Antibiotics

Cited by 35 publications

References 31 publications

Recent Advances in Flavin-Dependent Halogenase Biocatalysis: Sourcing, Engineering, and Application

Recent Advances in Flavin-Dependent Halogenase Biocatalysis: Sourcing, Engineering, and Application

Structure and Activity of the Thermophilic Tryptophan‐6 Halogenase BorH

Structure of apo flavin-dependent halogenase Xcc4156 hints at a reason for cofactor-soaking difficulties

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