K-26, a novel inhibitor of angiotensin I converting enzyme produced by an Actinomycete K-26.

Yamato, Masayuki; Koguchi, Toshiro; Okachi, Ryo; Yamada, Kôji; Nakayama, Kiyoshi; Kase, Hiroshi; Karasawa, Akira; Shuto, Katsuichi

doi:10.7164/antibiotics.39.44

Cited by 52 publications

(30 citation statements)

References 20 publications

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“…Hydrolysis of the C -terminal peptide linkage of dehydrophos would result in an enamine that is expected to hydrolyze to methyl acetylphosphonate, which is a structural analog of pyruvate and could inhibit pyruvate utilizing enzymes. On the other hand, the reactive vinyl phosphonate moiety in dehydrophos may inhibit a cellular process directly, analogous to the activity of the phosphonotripeptide K-26 (vide infra) that inhibits angiotensin converting enzyme without the requirement of hydrolysis (134). Future studies should shed light onto these questions.…”

Section: Dehydrophosmentioning

confidence: 99%

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Biosynthesis of Phosphonic and Phosphinic Acid Natural Products

Metcalf

Donk

2009

Annu. Rev. Biochem.

301

299

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Natural products containing carbon-phosphorus bonds (phosphonic and phosphinic acids) have found widespread use in medicine and agriculture. Recent years have seen a renewed interest in the biochemistry and biology of these compounds with the cloning of the biosynthetic gene clusters for several family members. This review discusses the commonalities and differences in the molecular logic that lies behind the biosynthesis of these compounds. The current knowledge regarding the metabolic pathways and enzymes involved in the production of a number of natural products, including the approved antibiotic fosfomycin, the widely used herbicide phosphinothricin, and the clinical candidate for treatment of malaria FR900098, is presented. Many of the enzymes involved in the biosynthesis of these compounds catalyze chemically and biologically unprecedented transformations and a wealth of new biochemistry has been revealed through their study. These studies have also suggested new strategies for natural product discovery. metcalf@uiuc.edu, vddonk@uiuc.edu. Summary Points •Phosphonates and phosphinates function by mimicking phosphate esters or anhydrides or carboxylate groups in enzyme substrates. As such, a large number of enzymes can be potential targets of this class of compounds.• The number of unprecedented reactions involved in the biosynthesis of fosfomycin, phosphinothricin, and FR900098 is an indication of the wealth of novel biochemistry used in the biosynthesis of this class of compounds.• Phosphoenolpyruvate (PEP) mutase catalyzes the C-P bond-forming step in all naturally occurring phosphonates for which the gene clusters are currently known. Hence, degenerate primers for PEPM can be used for the discovery of new phosphonate encoding gene clusters and hence new natural products.• Given the current commercial use of phosphonates and phosphinates in medicine and agriculture, discovery of new naturally occurring compounds beyond the twenty or so currently known structures may provide an important untapped source of new products for human use. Future issues• Based on the large number of metabolic processes that can be targeted with phosphonates, numerous phosphonate and phosphinate containing natural products likely remain to be discovered. Future studies will confirm or refute this hypothesis.• The fundamentally new radical-SAM strategy for methylation of unactivated carbon centers must be confirmed or disproven by in vitro studies.• The molecular logic that dictates epoxidation by HppE and C-C bond cleavage in HEPD is not understood and requires further investigation. Fine-tuning the activities of these enzymes may result in useful catalysts for synthetic purposes.• What is the cellular target of dehydrophos?• What alternative strategies are used in Nature to install a C-P bond that do not rely on the PEP mutase-like reaction?

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Section: Dehydrophosmentioning

confidence: 99%

“…The compound is a potent inhibitor and shows promise in the treatment of high blood pressure (134). K-26 contains a phosphonate analog of tyrosine as its C-terminal residue that is shared in several analogs produced by Actinomadura strains (135, 136) (Figure 1).…”

Section: K-26mentioning

confidence: 99%

Biosynthesis of Phosphonic and Phosphinic Acid Natural Products

Metcalf

Donk

2009

Annu. Rev. Biochem.

301

299

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“…Fosfomycin (phosphonomycin) [19,8], bialaphos (SF-1293, phosphinothricin tripeptide, PTT) [1,41], phosalacine [45,46], trialaphos [28], dehydrophos (A53868) [24], FR-900098 [43], fosmidomycin [44], the plumbemycins [47,49,48], SF-2312 [60], and fosfonochlorin [58] were originally isolated by assaying inhibition of bacterial growth. Inhibition of fungal growth was used in isolation of the fosfazinomycins [18,42] and the rhizocticins [51], while inhibition of angiotensin converting enzyme (ACE) activity was used in discovery of I5B2 [29] and K-26 [65], and prevention of seed germination in the discovery of phosphonothrixin [33,57]. …”

Section: The Discovery Of Phosphonate Natural Product Antibioticsmentioning

confidence: 99%

Genomics-enabled discovery of phosphonate natural products and their biosynthetic pathways

Doroghazi

Metcalf

2014

Journal of Industrial Microbiology and Biotechnology

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Phosphonate natural products have proven to be a rich source of useful pharmaceutical, agricultural and biotechnology products, whereas study of their biosynthetic pathways has revealed numerous intriguing enzymes that catalyze unprecedented biochemistry. Here we review the history of phosphonate natural product discovery, highlighting technological advances that have played a key role in the recent advances in their discovery. Central to these developments has been the application of genomics, which allowed discovery and development of a global phosphonate metabolic framework to guide research efforts. This framework suggests that the future of phosphonate natural products remains bright, with many new compounds and pathways yet to be discovered.

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“…1,2 Examples of naturally occurring phosphonates with established bioactivity include the industrially relevant herbicide phosphinothricin (PT); 3 antimalarials FR-900098 and fosmidomycin; 4 antimicrobials such as fosfomycin, 5 dehydrophos, 6 and the plumbemycins; 7 the antifungal rhizocticins; 8 and antihypertensive peptides K-4 9 and K-26. 10 …”

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confidence: 99%

Cyanohydrin Phosphonate Natural Product from Streptomyces regensis

Cioni

Doroghazi

et al. 2014

J. Nat. Prod.

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Streptomyces regensis strain WC-3744 was identified as a potential phosphonic acid producer in a large-scale screen of microorganisms for the presence of the pepM gene, which encodes the key phosphonate biosynthetic enzyme phosphoenolpyruvate phosphonomutase. 31P NMR revealed the presence of several unidentified phosphonates in spent medium after growth of S. regensis. These compounds were purified and structurally characterized via extensive 1D and 2D NMR spectroscopic and mass spectrometric analyses. Three new phosphonic acid metabolites, whose structures were confirmed by comparison to chemically synthesized standards, were observed: (2-acetamidoethyl)phosphonic acid (1), (2-acetamido-1-hydroxyethyl)phosphonic (3), and a novel cyanohydrin-containing phosphonate, (cyano(hydroxy)methyl)phosphonic acid (4). The gene cluster responsible for synthesis of these molecules was also identified from the draft genome sequence of S. regensis, laying the groundwork for future investigations into the metabolic pathway leading to this unusual natural product.

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K-26, a novel inhibitor of angiotensin I converting enzyme produced by an Actinomycete K-26.

Cited by 52 publications

References 20 publications

Biosynthesis of Phosphonic and Phosphinic Acid Natural Products

Biosynthesis of Phosphonic and Phosphinic Acid Natural Products

Genomics-enabled discovery of phosphonate natural products and their biosynthetic pathways

Cyanohydrin Phosphonate Natural Product from Streptomyces regensis

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