title: Five-Membered Cyclitol Phosphate Formation by a myo-Inositol Phosphate Synthase Orthologue in the Biosynthesis of the Carbocyclic Nucleoside Antibiotic Aristeromycin.
abstract: Aristeromycin is a unique carbocyclic nucleoside antibiotic produced by Streptomyces citricolor. In order to elucidate its intriguing carbocyclic formation, we used a genome-mining approach to identify the responsible enzyme. In silico screening with known cyclitol synthases involved in primary metabolism, such as myo-inositol-1-phosphate synthase (MIPS) and dehydroqunate synthase (DHQS), identified a unique MIPS orthologue (Ari2) encoded in the genome of S. citricolor. Heterologous expression of the gene cluster containing ari2 with a cosmid vector in Streptomyces albus resulted in the production of aristeromycin, thus indicating that the cloned DNA region (37.5 kb) with 33 open reading frames contains its biosynthetic gene cluster. We verified that Ari2 catalyzes the formation of a novel five-membered cyclitol phosphate from d-fructose 6-phosphate (F6P) with NAD+as a cofactor. This provides insight into cyclitol phosphate synthase as a member of the MIPS family of enzymes. A biosynthetic pathway to aristeromycin is proposed based on bioinformatics analysis of the gene cluster.
authors: Department of Chemistry, Tokyo Institute of Technology, 2-12-1 O-Okayama, Meguro-ku, Tokyo, 152-8551 (, Japan).
authors: Fumitaka
authors: F
authors: Kudo
authors: Department of Chemistry, Tokyo Institute of Technology, 2-12-1 O-Okayama, Meguro-ku, Tokyo, 152-8551 (, Japan).
authors: Takeshi
authors: T
authors: Tsunoda
authors: Department of Chemistry, Tokyo Institute of Technology, 2-12-1 O-Okayama, Meguro-ku, Tokyo, 152-8551 (, Japan).
authors: Makoto
authors: M
authors: Takashima
authors: Department of Chemistry, Tokyo Institute of Technology, 2-12-1 O-Okayama, Meguro-ku, Tokyo, 152-8551 (, Japan).
authors: Tadashi
authors: T
authors: Eguchi
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000096:biosynthesis / Q000737:chemistry; D000900:Anti-Bacterial Agents / Q000096:biosynthesis* / Q000737:chemistry; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D003360:Cosmids / Q000235:genetics / Q000378:metabolism; D054812:Cyclitols / Q000737:chemistry / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D005810:Multigene Family; D007296:Myo-Inositol-1-Phosphate Synthase / Q000235:genetics / Q000378:metabolism*; D009705:Nucleosides / Q000737:chemistry; D019761:Phosphorus-Oxygen Lyases / Q000235:genetics / Q000378:metabolism*; D021241:Spectrometry, Mass, Electrospray Ionization; D048372:Streptomyces coelicolor / Q000201:enzymology / Q000235:genetics
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D054812:Cyclitols; D009705:Nucleosides; C030034:aristeromycin; C020001:3-dehydroquinate synthetase; D019761:Phosphorus-Oxygen Lyases; D007296:Myo-Inositol-1-Phosphate Synthase; D000241:Adenosine
keywords: antibiotics; aristeromycin; biosynthesis; five-membered cyclitol; myo-inositol phosphate synthase