Phenylalanine <i>meta</i>‐Hydroxylase: A Single Residue Mediates Mechanistic Control of Aromatic Amino Acid Hydroxylation

Grüschow, Sabine; Sadler, Joanna C.; Sharratt, Peter; Goss, Rebecca J. M.

doi:10.1002/cbic.201900320

Cited by 6 publications

(3 citation statements)

References 30 publications

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“…Between June and October of 2019, additional papers describing pathways to free-standing α-amino acids have appeared in the biosynthetic literature. For interested readers, these references are cited here without further description. − …”

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confidence: 99%

Biosynthetic Pathways to Nonproteinogenic α-Amino Acids

2019

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Natural nonproteinogenic amino acids vastly outnumber the well-known 22 proteinogenic amino acids. Such amino acids are generated in specialized metabolic pathways. In these pathways, diverse biosynthetic transformations, ranging from isomerizations to the stereospecific functionalization of C–H bonds, are employed to generate structural diversity. The resulting nonproteinogenic amino acids can be integrated into more complex natural products. Here we review recently discovered biosynthetic routes to freestanding nonproteinogenic α-amino acids, with an emphasis on work reported between 2013 and mid-2019.

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Biosynthetic Pathways to Nonproteinogenic α-Amino Acids

2019

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“…The UPAs include the pacidamycins, [1] napsamycins, [2] sansanmycins, [3,4] mureidomycins [5,6] tunicamycins [7] and liposidomycins [8] . These structurally similar and biosynthetically intriguing compounds employ series of previously unprecedented and rare enzymatic steps in their assemblies [9–11] . Napsamycins, pacidamycin 4 N ( 2 ) and sansanmycin F ( 4 ) [11] all contain a bicyclic amino acid, 6‐hydroxy‐1,2,3,4‐tetrahydro‐3‐isoquinoline carboxylic acid (TIC), or its 1‐methyl, or 1,1‐dimethyl analogue at the N terminus of the pseudo‐tetrapeptide backbone (Figure 1).…”

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SynBio‐SynChem Approaches to Diversifying the Pacidamycins through the Exploitation of an Observed Pictet‐Spengler Reaction

et al. 2021

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A nonenzymatic Pictet‐Spengler reaction has been postulated to give rise to a subset of naturally occurring uridyl peptide antibiotics (UPAs). Here, using a combination of strain engineering and synthetic chemistry, we demonstrate that Pictet‐Spengler chemistry may be employed to generate even greater diversity in the UPAs. We use an engineered strain to afford access to meta‐tyrosine containing pacidamycin 4. Pictet‐Spengler diversification of this compound using a small series of aryl‐aldehydes was achieved with some derivatives affording remarkable diastereomeric control.

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“…The formation of m-tyrosine catalyzed by a phenylalanine mhydroxylase was reported in Streptomyces coeruleorubidus. 14 However, a meta hydroxylation of cyclopenin to cyclopenol was demonstrated in the later 1970s with a crude enzyme extract from Penicillum cyclopium. 15,16 This controversial ambiguity encouraged us to investigate the biosynthesis of 6 and especially the hydroxylation step, because a meta hydroxylation at a monoalkylated benzene ring has rarely been reported previously.…”

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Biosynthesis of Viridicatol in Penicillium palitans Implies a Cytochrome P450-Mediated meta Hydroxylation at a Monoalkylated Benzene Ring

et al. 2021

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Cyclopenol (1) and viridicatol (6) with m-hydroxyl groups were isolated from a culture of Penicillium palitans. Genome mining and heterologous expression in Aspergillus nidulans led to the identification of their biosynthetic gene cluster and the cytochrome P450 enzyme VdoD responsible for the meta hydroxylation. Precursor feeding experiments into vdoD transformant proved the conversion of cyclopenin (2) to 1, which then undergoes a spontaneous or VdoA-catalyzed rearrangement to 6. A direct conversion of viridicatin (5) to 6 by VdoD was not detected.

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Phenylalanine meta‐Hydroxylase: A Single Residue Mediates Mechanistic Control of Aromatic Amino Acid Hydroxylation

Abstract: Scheme4.Twop utative mechanismsofd eprotonation following meta-hydroxylation of Phe by WT Phe3H. A) Direct deprotonation or B) stereospecific NIH shift followed by stereospecific deprotonation to restore aromaticity wouldb othaccount for the observed loss of one of the deuterium labels.

Cited by 6 publications

References 30 publications

Biosynthetic Pathways to Nonproteinogenic α-Amino Acids

Biosynthetic Pathways to Nonproteinogenic α-Amino Acids

SynBio‐SynChem Approaches to Diversifying the Pacidamycins through the Exploitation of an Observed Pictet‐Spengler Reaction

Biosynthesis of Viridicatol in Penicillium palitans Implies a Cytochrome P450-Mediated meta Hydroxylation at a Monoalkylated Benzene Ring

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