Kenichi Matsuda

Recent studies described several different routes that facilitate nitrogen-nitrogen bond formation in natural product biosynthesis. We report herein the identification of unprecedented machinery for hydrazine formation involved in the biosynthesis of s56-p1, a dipeptide natural product with a unique hydrazone unit. The gene cassette comprising this machinery is widespread across several bacterial phyla, highlighting the overlooked potential of bacteria to synthesize hydrazine.

It has been widely accepted that cytokines play important roles in the development of organ failure in various pathophysiological conditions of critically ill patients. Various new technologies, including continuous renal replacement therapy, have been developed for the removal of causative humoral mediators in sepsis or other critical conditions. Nonselective blood purification technologies, such as hemofiltration and plasma exchange, are applied in cytokine removal technology. However, the mor

We recently revealed that a Streptomyces strain possesses the gene encoding amino group carrier protein (AmCP). AmCP is involved in the biosynthesis of a previously unidentified nonproteinogenic amino acid, (2S,6R)-diamino-(5R,7)-dihydroxy-heptanoic acid (DADH), which is a core compound for the synthesis of the dipeptide-containing novel natural product vazabitide A. We used polymerase chain reaction (PCR) screening to investigate the diversity of the biosynthetic machinery that uses AmCP; the r

SurE is a new, stand-alone thioesterase (TE) offloading the non-ribosomal peptide (NRP) assembly line found in surugamide biosynthesis. It is homologous to penicillin binding protein (PBP) and capable of cyclizing two structurally unrelated substrates derived from two different NRP assembly lines, highlighting the broad substrate tolerance of the SurE offloading cyclase.

Macrocyclization improves the pharmaceutical properties of peptides; however, regio- and chemoselective intramolecular cyclizations remain challenging. Here we developed a streamlined chemoenzymatic approach to synthesize cyclic peptides by exploiting non-ribosomal peptide (NRP) cyclases. Linear peptides linked to the resin through a <i>C</i>-terminal diol ester functionality are synthesized on a solid support, to circumvent the installation of leaving groups to the peptidic substrates in the li

Nitrogen-nitrogen bond-containing functional groups are rare, but they are found in a considerably wide class of natural products. Recent clarifications of the biosynthetic routes for such functional groups shed light onto overlooked biosynthetic genes distributed across the bacterial kingdom, highlighting the presence of yet-to-be identified natural products with peculiar functional groups. Here, the genome-mining approach targeting a unique hydrazine-forming gene led to the discovery of actino

Surugamides are a group of non-ribosomal peptides isolated from marine-derived Streptomyces. Surugamide A (1) and its closely related derivatives, surugamides B-E (2-5), are D-amino acid containing cyclic octapeptides with cathepsin B inhibitory activity. The D-isoleucine (Ile), the nonproteinogenic amino acid residue embedded in 1, is less common in natural peptides because a rare C_β-epimerization is required for its biosynthesis. Taking advantage of the synthetic route of 2 previous

Penicillin-binding protein-type thioesterases (PBP-type TEs) are a recently identified group of peptide cyclases that catalyze head-to-tail macrolactamization of nonribosomal peptides. PenA, a new member of this group, is involved in the biosyntheses of cyclic pentapeptides. In this study, we demonstrated the enzymatic activity of PenA in vitro, and analyzed its substrate scope with a series of synthetic substrates. A comparison of the reaction profiles between PenA and SurE, a representative PB

At necropsy, an 11-year-old Japanese Black cow with anemia, leukocytopenia, and progressive hind limb ataxia had marked diffuse splenomegaly and multiple masses in the thoracic vertebrae. Histologically, neoplastic erythrophagocytic histiocytes were in the splenic red pulp, vertebral masses, and blood vessels of the liver and lungs. The spinal cord was compressed by the vertebral masses. Clinicopathological, macroscopic, and histologic findings were consistent with hemophagocytic histiocytic sar

These data demonstrate the feasibility of performing total liquid ventilation in rodents. A balance must be identified where gas exchange is optimal yet hemodynamics are least affected. In the specific system studied, an inspiratory/expiratory ratio of 1:2.5 and respiratory rate of 6.8 breaths/min appeared to provide optimal gas exchange while minimizing the effects on hemodynamics.

Nitrogen-Nitrogen (N-N) bond-containing functional groups in natural products and synthetic drugs play significant roles in exerting biological activities. The mechanisms of N-N bond formation in natural organic molecules have garnered increasing attention over the decades. Recent advances have illuminated various enzymatic and nonenzymatic strategies, and our understanding of natural N-N bond construction is rapidly expanding. A group of didomain proteins with zinc-binding cupin/methionyl-tRNA

Macrocyclization of peptides reduces conformational flexibilities, potentially leading to improved drug-like properties. However, side reactions such as epimerization and oligomerization often pose synthetic challenges. Peptide-cyclizing biocatalysts in the biosynthesis of non-ribosomal peptides (NRPs) have remarkable potentials as chemoenzymatic tools to facilitate more straightforward access to complex macrocycles. This review highlights the biocatalytic potentials of NRP cyclases, especially

Macrolactamization is one of the most important peptide-modifying reactions. However, chemical macrocyclization is often hampered by several technical problems such as epimerization at the C-terminal residue, and a requirement for high dilution conditions, as well as for protective groups. In contrast, natural cyclopeptides are biosynthesized by efficient cyclases under mild conditions, suggesting these enzymes have potential as biocatalysts. However, the versatility of natural cyclases has not