title: Metabolic coupling of two small-molecule thiols programs the biosynthesis of lincomycin A.
abstract: Low-molecular-mass thiols in organisms are well known for their redox-relevant role in protection against various endogenous and exogenous stresses. In eukaryotes and Gram-negative bacteria, the primary thiol is glutathione (GSH), a cysteinyl-containing tripeptide. In contrast, mycothiol (MSH), a cysteinyl pseudo-disaccharide, is dominant in Gram-positive actinobacteria, including antibiotic-producing actinomycetes and pathogenic mycobacteria. MSH is equivalent to GSH, either as a cofactor or as a substrate, in numerous biochemical processes, most of which have not been characterized, largely due to the dearth of information concerning MSH-dependent proteins. Actinomycetes are able to produce another thiol, ergothioneine (EGT), a histidine betaine derivative that is widely assimilated by plants and animals for variable physiological activities. The involvement of EGT in enzymatic reactions, however, lacks any precedent. Here we report that the unprecedented coupling of two bacterial thiols, MSH and EGT, has a constructive role in the biosynthesis of lincomycin A, a sulfur-containing lincosamide (C8 sugar) antibiotic that has been widely used for half a century to treat Gram-positive bacterial infections. EGT acts as a carrier to template the molecular assembly, and MSH is the sulfur donor for lincomycin maturation after thiol exchange. These thiols function through two unusual S-glycosylations that program lincosamide transfer, activation and modification, providing the first paradigm for EGT-associated biochemical processes and for the poorly understood MSH-dependent biotransformations, a newly described model that is potentially common in the incorporation of sulfur, an element essential for life and ubiquitous in living systems.
authors.affiliation: State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China.
authors.forename: Qunfei
authors.initials: Q
authors.lastname: Zhao
authors.affiliation: State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China.
authors.forename: Min
authors.initials: M
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China.
authors.forename: Dongxiao
authors.initials: D
authors.lastname: Xu
authors.affiliation: Huzhou Center of Bio-Synthetic Innovation, 1366 Hongfeng Road, Huzhou 313000, China.
authors.forename: Qinglin
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: 1] State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China [2] Huzhou Center of Bio-Synthetic Innovation, 1366 Hongfeng Road, Huzhou 313000, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Liu
mesh_terms: D000900:Anti-Bacterial Agents / Q000096:biosynthesis*; D001688:Biological Products / Q000378:metabolism; D053898:Biosynthetic Pathways / Q000235:genetics; D001711:Biotransformation; D003545:Cysteine / Q000737:chemistry / Q000378:metabolism*; D004880:Ergothioneine / Q000737:chemistry / Q000378:metabolism*; D006020:Glycopeptides / Q000737:chemistry / Q000378:metabolism*; D006031:Glycosylation; D007294:Inositol / Q000737:chemistry / Q000378:metabolism*; D008034:Lincomycin / Q000096:biosynthesis*; D055231:Lincosamides / Q000378:metabolism; D008969:Molecular Sequence Data; D013302:Streptomyces / Q000235:genetics / Q000378:metabolism*
chemical_list: D000900:Anti-Bacterial Agents; D001688:Biological Products; D006020:Glycopeptides; D055231:Lincosamides; C089265:mycothiol; D007294:Inositol; D004880:Ergothioneine; D008034:Lincomycin; D003545:Cysteine