Mechanisms of Sugar Aminotransferase-like Enzymes to Synthesize Stereoisomers of Non-proteinogenic Amino Acids in Natural Product Biosynthesis

• Published in: ACS chemical biology Vol. 18; no. 2; pp. 385 - 395
• Main Authors: Kurosawa, Sumire, Okamura, Hironori, Yoshida, Ayako, Tomita, Takeo, Sone, Yusuke, Hasebe, Fumihito, Shinada, Tetsuro, Takikawa, Hirosato, Kosono, Saori, Nishiyama, Makoto
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 17-02-2023
• Subjects: Amino Acids - chemistry; Biological Products; Hexanes; Stereoisomerism; Sugars; Transaminases - metabolism
• ISSN: 1554-8929; 1554-8937
• DOI: 10.1021/acschembio.2c00823

(2,6)-Diamino-(5,7)-dihydroxyheptanoic acid (DADH), a non-proteinogenic amino acid, is converted to 1-azabicyclo[3.1.0]­hexane ring-containing amino acids that are subsequently incorporated into ficellomycin and vazabitide A. The present study revealed that the sugar aminotransferase-like enzymes Fic25 and Vzb9, with a high amino acid sequence identity (56%) to each other, synthesized stereoisomers of DADH with (6S) and (6R) configurations, respectively. The crystal structure of the Fic25 complex with a PLP-(6S)–N 2-acetyl-DADH adduct indicated that Asn45 and Gln197 (Asn205 and Ala53 in Vzb9) were located at positions that affected the stereochemistry of DADH being synthesized. A modeling study suggested that amino acid substitutions between Fic25 and Vzb9 allowed the enzymes to bind to the substrate with almost 180° rotation in the C5–C7 portions of the DADH molecules, accompanied by a concomitant shift in their C1–C4 portions. In support of this result, the replacement of two corresponding residues in Fic25 and Vzb9 increased (6R) and (6S) stereoselectivities, respectively. The different stereochemistry at C6 of DADH resulted in a different stereochemistry/orientation of the aziridine portion of the 1-azabicyclo[3.1.0]­hexane ring, which plays a crucial role in biological activity, between ficellomycin and vazabitide A. A phylogenic analysis suggested that Fic25 and Vzb9 evolved from sugar aminotransferases to produce unusual building blocks for expanding the structural diversity of secondary metabolites.