Abstract:Piperazic acid is a cyclic hydrazine and a non-proteinogenic amino acid found in diverse non-ribosomal peptide (NRP) and hybrid NRP–polyketide (PK) structures.
“…Piperazic acid is one of the most common N-N containing building blocks of natural products, being found in numerous natural compounds with activities ranging from antibiotics to immunosuppressants. All piperazic acid-containing molecules known to date come from Actinomycete bacteria isolated from diverse environments (Morgan et al 2019 ), but the structural and functional variety is remarkable: kutznerides, padanamides, himastatins, monamycines, polyoxypeptin and sanglifehrins, to name a few, contain piperazic acid (Fig. 7a ).…”
Section: Nmos Promoting the Formation Of N-n Bondsmentioning
confidence: 99%
“…7a ). A recent review demonstrates the versatile incorporation of piperazic acid into natural products (Morgan et al 2019 ). Fig.…”
Section: Nmos Promoting the Formation Of N-n Bondsmentioning
confidence: 99%
“…Instead, a heme-dependent protein, typically termed piperazate synthase, fuses the two nitrogen atoms in a condensation reaction, creating piperazic acid (Du et al 2017 ). The enzymatic pair is highly conserved in the gene clusters responsible for the synthesis of different piperazic acid–containing molecules (Morgan et al 2019 ).…”
Section: Nmos Promoting the Formation Of N-n Bondsmentioning
Amino groups derived from naturally abundant amino acids or (di)amines can be used as "shuttles" in nature for oxygen transfer to provide intermediates or products comprising NO functional groups such as N-hydroxy, oxazine, isoxazolidine, nitro, nitrone, oxime, C-, S-, or N-nitroso, and azoxy units. To this end, molecular oxygen is activated by flavin, heme, or metal cofactorcontaining enzymes and transferred to initially obtain N-hydroxy compounds, which can be further functionalized. In this review, we focus on flavin-dependent N-hydroxylating enzymes, which play a major role in the production of secondary metabolites, such as siderophores or antimicrobial agents. Flavoprotein monooxygenases of higher organisms (among others, in humans) can interact with nitrogen-bearing secondary metabolites or are relevant with respect to detoxification metabolism and are thus of importance to understand potential medical applications. Many enzymes that catalyze N-hydroxylation reactions have specific substrate scopes and others are rather relaxed. The subsequent conversion towards various NO or N-N comprising molecules is also described. Overall, flavin-dependent N-hydroxylating enzymes can accept amines, diamines, amino acids, amino sugars, and amino aromatic compounds and thus provide access to versatile families of compounds containing the NO motif. Natural roles as well as synthetic applications are highlighted. Key points • NO and N-N comprising natural and (semi)synthetic products are highlighted. • Flavin-based NMOs with respect to mechanism, structure, and phylogeny are reviewed. • Applications in natural product formation and synthetic approaches are provided.
“…Piperazic acid is one of the most common N-N containing building blocks of natural products, being found in numerous natural compounds with activities ranging from antibiotics to immunosuppressants. All piperazic acid-containing molecules known to date come from Actinomycete bacteria isolated from diverse environments (Morgan et al 2019 ), but the structural and functional variety is remarkable: kutznerides, padanamides, himastatins, monamycines, polyoxypeptin and sanglifehrins, to name a few, contain piperazic acid (Fig. 7a ).…”
Section: Nmos Promoting the Formation Of N-n Bondsmentioning
confidence: 99%
“…7a ). A recent review demonstrates the versatile incorporation of piperazic acid into natural products (Morgan et al 2019 ). Fig.…”
Section: Nmos Promoting the Formation Of N-n Bondsmentioning
confidence: 99%
“…Instead, a heme-dependent protein, typically termed piperazate synthase, fuses the two nitrogen atoms in a condensation reaction, creating piperazic acid (Du et al 2017 ). The enzymatic pair is highly conserved in the gene clusters responsible for the synthesis of different piperazic acid–containing molecules (Morgan et al 2019 ).…”
Section: Nmos Promoting the Formation Of N-n Bondsmentioning
Amino groups derived from naturally abundant amino acids or (di)amines can be used as "shuttles" in nature for oxygen transfer to provide intermediates or products comprising NO functional groups such as N-hydroxy, oxazine, isoxazolidine, nitro, nitrone, oxime, C-, S-, or N-nitroso, and azoxy units. To this end, molecular oxygen is activated by flavin, heme, or metal cofactorcontaining enzymes and transferred to initially obtain N-hydroxy compounds, which can be further functionalized. In this review, we focus on flavin-dependent N-hydroxylating enzymes, which play a major role in the production of secondary metabolites, such as siderophores or antimicrobial agents. Flavoprotein monooxygenases of higher organisms (among others, in humans) can interact with nitrogen-bearing secondary metabolites or are relevant with respect to detoxification metabolism and are thus of importance to understand potential medical applications. Many enzymes that catalyze N-hydroxylation reactions have specific substrate scopes and others are rather relaxed. The subsequent conversion towards various NO or N-N comprising molecules is also described. Overall, flavin-dependent N-hydroxylating enzymes can accept amines, diamines, amino acids, amino sugars, and amino aromatic compounds and thus provide access to versatile families of compounds containing the NO motif. Natural roles as well as synthetic applications are highlighted. Key points • NO and N-N comprising natural and (semi)synthetic products are highlighted. • Flavin-based NMOs with respect to mechanism, structure, and phylogeny are reviewed. • Applications in natural product formation and synthetic approaches are provided.
“…The biosynthetic origins of piperazate-containing natural products is a young area of study 19 and our findings have important implications for biochemists studying the incorporation of these unusual amino acids into secondary metabolites. Our proposed scaffold would be only the second class of natural products bound at N1 of the piperazate (the first being the sanglifehrins) and the only class to be synthesized entirely on an NRPS assembly line.…”
In a 2016 screen of natural product extracts a new family of natural products, the cahuitamycins, was discovered and found to inhibit the formation of biofilms in the human pathogen <i>Acinetobacter baumannii</i>. The molecules contain an unusual piperazate residue that raises structure/function and biosynthesis questions and resemble iron-trafficking virulence factors from <i>A. baumannii</i>, suggesting a connection between metal homeostasis and biofilm-mediated pathogenicity. Here we disclose the first total synthesis of the reported structure of cahuitamycin A in a twelve-step longest linear sequence and 18% overall yield. Comparison of spectral data of the authentic natural product and synthetic target compound demonstrate that the reported structure is distinct from the isolated metabolite. Herein, we propose an alternative structure to reconcile our findings with the isolation report, setting the stage for future synthetic and biochemical investigations of an important class of natural products.
“…Natural products with nitrogen–nitrogen (N−N) bonds are a group of rarely isolated yet highly bioactive molecules that includes drugs and drug candidates . Unlike many natural products, the biosynthetic routes to molecules containing N−N bonds remained enigmatic until recently .…”
The formation of a N−N bond is a unique biochemical transformation, and nature employs diverse biosynthetic strategies to activate nitrogen for bond formation. Among molecules that contain a N−N bond, biosynthetic routes to diazeniumdiolates remain enigmatic. We here report the biosynthetic pathway for the diazeniumdiolate‐containing amino acid l‐alanosine. Our work reveals that the two nitrogen atoms in the diazeniumdiolate of l‐alanosine arise from glutamic acid and aspartic acid, and we clarify the early steps of the biosynthetic pathway by using both in vitro and in vivo approaches. Our work demonstrates a peptidyl‐carrier‐protein‐based mechanism for activation of the precursor l‐diaminopropionate, and we also show that nitric oxide can participate in non‐enzymatic diazeniumdiolate formation. Furthermore, we demonstrate that the gene alnA, which encodes a fusion protein with an N‐terminal cupin domain and a C‐terminal AraC‐like DNA‐binding domain, is required for alanosine biosynthesis.
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