8GYJ

Crystal structure of Fic25 complexed with PLP-(5S,6S)-N2-acetyl-DADH adduct from Streptomyces ficellus

Summary for 8GYJ

• Entry DOI: 10.2210/pdb8gyj/pdb
• Descriptor: DegT/DnrJ/EryC1/StrS family aminotransferase, GLYCEROL, IMIDAZOLE, ... (5 entities in total)
• Functional Keywords: sugar aminotransferase, dadh, biosythetic protein, biosynthetic protein
• Biological source: Streptomyces ficellus
• Total number of polymer chains: 2
• Total formula weight: 95237.90

Authors

Kurosawa, S.,Yoshida, A.,Tomita, T.,Nishiyama, M. (deposition date: 2022-09-22, release date: 2023-02-22, Last modification date: 2023-11-29)

Primary citation

Kurosawa, S.,Okamura, H.,Yoshida, A.,Tomita, T.,Sone, Y.,Hasebe, F.,Shinada, T.,Takikawa, H.,Kosono, S.,Nishiyama, M.
Mechanisms of Sugar Aminotransferase-like Enzymes to Synthesize Stereoisomers of Non-proteinogenic Amino Acids in Natural Product Biosynthesis.
Acs Chem.Biol., 18:385-395, 2023

PubMed Abstract: (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 (6) and (6) configurations, respectively. The crystal structure of the Fic25 complex with a PLP-(6)--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 (6) and (6) 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.

PubMed: 36669120
DOI: 10.1021/acschembio.2c00823

Experimental method

X-RAY DIFFRACTION (1.82 Å)