Total Synthesis of the Nonribosomal Peptide Surugamide B and Identification of a New Offloading Cyclase Family

Abstract

The cathepsin B inhibitor surugamide B (2), along with structurally related derivatives (A and C–E), has previously been isolated from the marine actinomycete Streptomyces sp. JAMM992. The biosynthetic genes are unexpectedly part of a cluster of four non‐ribosomal peptide synthetase (NRPS) genes, two of which are responsible for the biosynthesis of the additional linear decapeptide surugamide F. However, the thioesterase domain required for the later stage of the biosynthesis of the cyclic peptides surugamides A–E is not present in any module architecture of the surugamide NRPSs. Herein, we report the first total synthesis of surugamide B (2) through the macrocyclization at the biomimetic position, which not only alleviated the Cα epimerization in the macrolactamization process, but also efficiently provided 2 in 34 % yield for 18 steps. Furthermore, both the chemical and enzymatic studies with the biosynthetic precursor mimics revealed that the stand‐alone enzyme SurE, which belongs to the penicillin‐binding protein family, is responsible for macrocyclization of the tethered octapeptidyl intermediate.

Chlorinated metabolites from Streptomyces sp. highlight the role of biosynthetic mosaics and superclusters in the evolution of chemical diversity

“…Interestingly, sve also contains an analogue of DsaJ, a peptide cyclase required for the cyclisation of hexapeptides, such as desotamide 72 and ullungmycin, 73 and octapeptides, such as surugamide. [74][75][76] The presence of both a thioesterase domain and a peptide cyclase is apparently redundant and requires further investigation.…”

Discovery of Acyl-Surugamide A2 from Marine Streptomyces albidoflavus RKJM-0023—A New Cyclic Nonribosomal Peptide Containing an N-ε-acetyl-L-lysine Residue

“…Major MS2 fragments of acyl-surugamide A2, their predicted fragment sequence, the equivalent fragment mass for surugamide A [1,21], and the mass difference of the fragments. The biosynthetic gene cluster of a NRP can also be used to determine the amino acid order of cyclic-NRPs [1,5]. To date, all core surugamides follow the LDLDLLDD amino acid configuration sequence [1][2][3]5,29] as well as the core AA order cyclo-[IAIIKIFL] with possible substitutions of L-Ile-1, L-Ile-2, or L-Ile-4 for Val [1,3,14].…”

“…The biosynthetic gene cluster of a NRP can also be used to determine the amino acid order of cyclic-NRPs [1,5]. To date, all core surugamides follow the LDLDLLDD amino acid configuration sequence [1][2][3]5,29] as well as the core AA order cyclo-[IAIIKIFL] with possible substitutions of L-Ile-1, L-Ile-2, or L-Ile-4 for Val [1,3,14]. The genome of S. albidoflavus RKJM-0023 was sequenced using PacBio RSII sequencing [30] and 1.5 × 10 6 resulting reads were assembled into two contigs representing a 7,031,575 bp genome (GenBank accession CP133227) and a 90,910 bp plasmid (GenBank accession CP133227) [31].…”

“…The surugamide family includes several core members, the surugamides A-E [1] and G-J [3], albucyclone A-F [3] and acyl-surugamide A [3]. Several other natural products can be included in the surugamide family when extending the family to other cyclic peptides that are cyclized by the same type of unique standalone β-lactamase superfamily cyclase enzyme [4,5]. These related natural products are the surugamide F-F2 [4], cyclosurugamide F [4], desotamides [6,7], wollamides [8], ulleungmycins [9], and noursamycins/curacomycins [10,11].…”

Recent Progress in Solid‐Phase Total Synthesis of Naturally Occurring Small Peptides

“…In 2018, Wakimoto and co‐workers reported the first total synthesis of surugamide B (Scheme 34). [115] Fmoc‐ d ‐Leu‐loaded 2‐chlorotrityl resin ( 228 ) was subjected to a standard SPPS with the use of DIC/Oxyma as the coupling reagents, affording the resin‐bounded linear peptide 229 . The linear peptide precursor, arising from the cleavage from the resin with the treatment of HFIP/DCM to keep the Boc intact, underwent macrocyclization at the biomimetic position (between d ‐Leu and l ‐Ile) to give 230 , of which the final deprotection gave surugamide B under acidic conditions.…”