Leinamycin

Introduction

Leinamycin is an 18-membered macrolactam produced by several species of Streptomyces atroolivaceus. This macrolactam has also been shown to exhibit antitumor properties as well as antimicrobial properties against gram-positive and gram-negative bacteria.[1] The presence of a spiro-fused 1,3-dioxo-1,2-dithiolane moiety was a unique structural property at the time of this compound’s discovery and it plays an important role in Leinamycin’s antitumor and antibacterial properties due to its ability to inhibit DNA synthesis.[2][3]

Biosynthesis

The seminal proposal for the biosynthesis of Leinamycin was published in Chemistry & Biochemistry in 2004.[4] This biosynthesis consists of a discrete and modular NRPS, AT-less PKSs, and PKS modules. NRPS-PKS assembly line dictates the loading of D-Ala to initiate biosynthesis, followed by the loading of L-Cys to the peptidyl carrier protein (PCP). The dipeptide is then cyclized and oxidized to form the thiazonyl-S-PCP intermediate. The thiazonyl intermediate is then transferred to the PKS assembly line where the backbone is elongated by six units. The leinamycin hybrid peptide-polyketide carbon backbone intermediate is then cyclized by the thioesterase domain (TE) to yield intermediate 1. Methylmalonyl-CoA then condenses at the beta-keto group of 1, yielding 2. A series of tailoring enzymes converts 2 to 4, presumably through intermediate 3 to complete the biosynthesis of Leinamycin (Figure 1).

References

  1. ↑ Kara, M; Asano, K; Kawamoto, I; Takiouchi, T; Katsumata, S; Takahashi, K-I; Nakano, H. Leinamycin, a New Antitumor Antibiotic from Streptomyces; Producing Organism, Fermentation and Isolation. J. Antibiot. (Tokyo) 1989, 42, 1768-1774.
  2. ↑ Kara, M; Saitoh, Y; Nakano, H. DNA Strand Scission by the Novel Antitumor Antibiotic Leinamycin. Biochemistry 1990, 29, 5676-5681.
  3. ↑ Asai, A; Kara, M; Kakita, S; Kanday, Y; Yoshida, M; Saito, H; Saitoh, Y. Thiol-Mediated DNA Alkylation by the Novel Antitumor Antibiotic Leinamycin. J. Am. Chem. Soc., 1996, 118, 6802-6803.
  4. ↑ Tang, G-L; Cheng, Y-Q; Shen, B. Leinamycin Biosynthesis Revealing Unprecedented Architectural Complexity for a Hybrid Polyketide Synthase and Nonribosomal Peptide Synthetase. Chemistry & Biology, 2004, 11, 33-45.
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