title: In vitro kinetic study of the squalestatin tetraketide synthase dehydratase reveals the stereochemical course of a fungal highly reducing polyketide synthase.
abstract: Six potential diketide substrates for the squalestatin tetraketide synthase (SQTKS) dehydratase (DH) domain were synthesised as N-acetyl cysteamine thiolesters (SNAC) and tested in kinetic assays as substrates with an isolated DH domain. 3R-3-hydroxybutyryl SNAC 3R-16 was turned over by the enzyme, but its enantiomer was not. Of the four 2-methyl substrates only 2R,3R-2-methyl-3-hydroxybutyryl SNAC 2R,3R-8 was a substrate. Combined with stereochemical information from the isolated SQTKS enoyl reductase (ER) domain, our results provide a near complete stereochemical description of the first cycle of beta-modification reactions of a fungal highly reducing polyketide synthase (HR-PKS). The results emphasise the close relationship between fungal HR-PKS and vertebrate fatty acid synthases (vFAS).
authors.affiliation: School of Chemistry, University of Bristol, Cantock's Close, Bristol, BS8 1TS, UK.
authors.forename: Emma
authors.initials: E
authors.lastname: Liddle
authors.forename: Alan
authors.initials: A
authors.lastname: Scott
authors.forename: Li-Chen
authors.initials: LC
authors.lastname: Han
authors.forename: David
authors.initials: D
authors.lastname: Ivison
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Simpson
authors.forename: Christine L
authors.initials: CL
authors.lastname: Willis
authors.forename: Russell J
authors.initials: RJ
authors.lastname: Cox
mesh_terms: D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000737:chemistry* / Q000378:metabolism; D003512:Cyclohexanones / Q000737:chemistry* / Q000378:metabolism; D004187:Disaccharides / Q000737:chemistry* / Q000378:metabolism; D005658:Fungi / Q000201:enzymology*; D006836:Hydro-Lyases / Q000378:metabolism*; D007700:Kinetics; D015394:Molecular Structure; D048630:Polyketide Synthases / Q000378:metabolism*; D013237:Stereoisomerism; D014233:Tricarboxylic Acids / Q000737:chemistry* / Q000378:metabolism
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D003512:Cyclohexanones; D004187:Disaccharides; D014233:Tricarboxylic Acids; C413265:tetraketide; C075117:squalestatin 1; D048630:Polyketide Synthases; D006836:Hydro-Lyases