A heme-dependent enzyme forms the nitrogen–nitrogen bond in piperazate

Du, Yi‐Ling; He, Haiyan; Higgins, M.A.; Ryan, Katherine S.

doi:10.1038/nchembio.2411

Cited by 121 publications

(150 citation statements)

References 28 publications

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“…[ 1 ] Understanding how these groups are installed can reveal useful enzymatic transformations and facilitate the discovery of new bioactive compounds. [ 1 , 3 ] …”

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confidence: 99%

“…[1] Understanding how these groups are installed can reveal useful enzymatic transformations and facilitate the discovery of new bioactive compounds. [1,3] Oxyvinylglycines are au nique family of NAAs featuring ac ore vinyl ether and av ariety of alkoxy substituents ( Figure 1A). This family acts as mechanism-based inhibitors of the eliminase subgroup of pyridoxal phosphate (PLP)dependent enzymes by forming astable adduct with enzymebound PLP.…”

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confidence: 99%

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In Vitro Biosynthesis of the Nonproteinogenic Amino Acid Methoxyvinylglycine

2018

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Oxyvinylglycines are a family of nonproteinogenic amino acids featuring an essential vinyl ether conferring mechanism-based inhibition of pyridoxal phosphate enzymes. The gene clusters for a few oxyvinylglycines are known, yet the biosynthetic origin of the vinyl ether is elusive. The in vitro biosynthesis of methoxyvinylglycine or l-2-amino-4-methoxy-trans-3-butenoic acid (AMB) is reported. It is shown that AMB is made from glutamate as an alanyl-AMB dipeptide and the rationale is provided for the N-term Ala. Using a chemical capture method, the order and timing of the modifications on non-ribosomal peptide synthetase (NRPS)-bound substrates was determined, including a cryptic hydroxylation of the Glu β-carbon. Eliminating this hydroxy group likely generates a key α,β-dehydroamino acid intermediate that facilitates decarboxylation. This work sheds light on vinyl ether biosynthesis and uncovers new NRPS chemistry.

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“…[ 1 ] Understanding how these groups are installed can reveal useful enzymatic transformations and facilitate the discovery of new bioactive compounds. [ 1 , 3 ] …”

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confidence: 99%

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confidence: 99%

In Vitro Biosynthesis of the Nonproteinogenic Amino Acid Methoxyvinylglycine

2018

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“…[1] These compounds have been isolated from differents ources, including bacteria, fungi, and plants.Despitee xtensive studies on the genetic and biochemical basis of naturalp roduct biosynthesis over the past three decades, the biochemical routes leading to enzymatic NÀNb ond formation are only startingt ob er evealed. [2][3][4][5][6][7][8][9][10][11][12][13][14] We recently reported ah eme-dependent piperazate synthase responsible for NÀNc yclization to give piperazic acid, ab uilding block for many nonribosomal peptide (NRP) or NRP-polyketide hybrid…”

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confidence: 99%

The biosynthetic gene cluster of the C-nucleoside antibiotic pyrazomycin with a rare pyrazole moiety

Zhao¹,

Yao²,

Rothchild³

et al. 2019

Preprint

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Pyrazomycin is ar are C-nucleoside antibiotic containing an aturally occurring pyrazole ring, the biosynthetic origin of which has remained obscure for decades. In this study we report the identification of the gene cluster responsible for pyrazomycin biosynthesis in Streptomycesc andidus NRRL 3601, revealing that the StrR-family regulator PyrR is the cluster-situatedt ranscriptional activator governing pyrazomycin biosynthesis. Furthermore, our results from in vivo reconstitution and stableisotope feeding experiments provides upport for the hypothesis that PyrN is an ew nitrogen-nitrogenb ond-forming enzyme that catalyzes the linkageo ft he e-NH 2 nitrogen atom of l-N 6 -OH-lysine and the a-NH 2 nitrogen atom of l-glutamic acid. This study lays the foundation for further genetic and biochemicalc haracterization of pyrazomycin pathway enzymes involved in constructing the characteristic pyrazolering.Natural products containing nitrogen-nitrogen (NÀN) bonds are ag roup of specialized metabolites with diverses tructures and av ariety of biological activities. [1] These compounds have been isolated from differents ources, including bacteria, fungi, and plants.Despitee xtensive studies on the genetic and biochemical basis of naturalp roduct biosynthesis over the past three decades, the biochemical routes leading to enzymatic NÀNb ond formation are only startingt ob er evealed. [2][3][4][5][6][7][8][9][10][11][12][13][14] We recently reported ah eme-dependent piperazate synthase responsible for NÀNc yclization to give piperazic acid, ab uilding block for many nonribosomal peptide (NRP) or NRP-polyketide hybrid

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“…One chemical logic involves the activation of one nitrogen atom to a more electrophilic species followed by intramolecular addition to a second nucleophilic nitrogen. As an example, N5 of ornithine is hydroxylated by a flavin‐dependent enzyme (KtzI) before N−N bond formation promoted by a heme enzyme (KtzT, Figure S1 in the Supporting Information) . Similarly, N 6 ‐hydroxylysine is conjugated to glycine followed by intramolecular nucleophilic attack from the glycine amino group catalyzed by a fusion protein (Spb40) consisting of a cupin and a methionyl‐tRNA synthetase‐like protein (Figure S1) …”

Section: Figurementioning

confidence: 99%

Identifying the Biosynthetic Gene Cluster for Triacsins with an N‐Hydroxytriazene Moiety

et al. 2019

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Triacsins are a family of natural products having in common an N‐hydroxytriazene moiety not found in any other known secondary metabolites. Though many studies have examined the biological activity of triacsins in lipid metabolism, their biosynthesis has remained unknown. Here we report the identification of the triacsin biosynthetic gene cluster in Streptomyces aureofaciens ATCC 31442. Bioinformatic analysis of the gene cluster led to the discovery of the tacrolimus producer Streptomyces tsukubaensis NRRL 18488 as a new triacsin producer. In addition to targeted gene disruption to identify necessary genes for triacsin production, stable isotope feeding was performed in vivo to advance the understanding of N‐hydroxytriazene biosynthesis.

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A heme-dependent enzyme forms the nitrogen–nitrogen bond in piperazate

Cited by 121 publications

References 28 publications

In Vitro Biosynthesis of the Nonproteinogenic Amino Acid Methoxyvinylglycine

In Vitro Biosynthesis of the Nonproteinogenic Amino Acid Methoxyvinylglycine

The biosynthetic gene cluster of the C-nucleoside antibiotic pyrazomycin with a rare pyrazole moiety

Identifying the Biosynthetic Gene Cluster for Triacsins with an N‐Hydroxytriazene Moiety

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