Wenjiao Diao

Unguisins, a class of structurally complex cyclic peptides featuring a γ-aminobutyric acid residue embedded in the skeleton, exhibit diverse biological activities. Here, a new unguisin K, along with three known congeners, was isolated from the marine-derived fungus Aspergillus candidus MEFC1001. The biosynthetic pathway was elucidated through gene disruption coupled with in vitro enzymatic characterization. The ugs biosynthetic gene cluster (BGC) containing ugsA and ugsB, in conjunction with an extra-clustered gene ugsC, collaborates to synthesize these unguisins. The alanine racemase (AR) UgsC catalyzes the isomerization of Ala and provides d-Ala as the starter unit for the non-ribosomal peptide synthetase (NRPS). The unique localization of ugsC outside the ugs BGC is different from previously reported unguisin-producing systems where AR genes reside within BGCs. The methyltransferase UgsB mediates a key pre-modification step by methylating phenylpyruvic acid to yield β-methylphenylpyruvate, which is subsequently incorporated as β-methylphenylalanine during NRPS assembly. This represents the first experimental evidence of the β-carbon methylation of Phe residue occurring at the precursor level rather than through post-assembly modification. The NRPS UgsA recruits a variety of amino acids for assembly and cyclization to form mature unguisins. Additionally, genome mining utilizing UgsA as a query identified homologous NRPSs in diverse fungal species, highlighting the potential for unguisin production in fungi. This study enriches the biosynthetic diversity of cyclic peptides and provides guidance for exploring unguisin-like natural products derived from fungi.

Mangrove ecosystems have attracted widespread attention because of their high salinity, muddy or sandy soil, and low pH, as well as being partly anoxic and periodically soaked by tides. Mangrove plants, soil, or sediment-derived fungi, especially the Penicillium species, possess unique metabolic pathways to produce secondary metabolites with novel structures and potent biological activities. This paper reviews the structural diversity and biological activity of secondary metabolites isolated from mangrove ecosystem-derived Penicillium species over the past 5 years (January 2020–October 2024), and 417 natural products (including 170 new compounds, among which 32 new compounds were separated under the guidance of molecular networking and the OSMAC approach) are described. The structures were divided into six major categories, including alkaloids, polyketides, terpenoids, benzene derivatives, steroids, and other classes. Among these natural products, the plausible biosynthetic pathways of 37 compounds were also proposed; 11 compounds have novel skeleton structures, and 26 compounds contain halogen atoms. A total of 126 compounds showed biological activities, such as cytotoxic, antifungal, antibacterial, anti-inflammatory, and α-glucosidase-inhibitory activities, and 11 compounds exhibited diverse biological activities. These new secondary metabolites with novel structures and potent bioactivities will continue to guide the separation or synthesis of structurally novel and biologically active compounds and will offer leading compounds for the development and innovation of pharmaceuticals and pesticides.