title: Chemical intervention in bacterial lignin degradation pathways: Development of selective inhibitors for intradiol and extradiol catechol dioxygenases.
abstract: Bacterial lignin degradation could be used to generate aromatic chemicals from the renewable resource lignin, provided that the breakdown pathways can be manipulated. In this study, selective inhibitors of enzymatic steps in bacterial degradation pathways were developed and tested for their effects upon lignin degradation. Screening of a collection of hydroxamic acid metallo-oxygenase inhibitors against two catechol dioxygenase enzymes, protocatechuate 3,4-dioxygenase (3,4-PCD) and 2,3-dihydroxyphenylpropionate 1,2-dioxygenase (MhpB), resulted in the identification of selective inhibitors D13 for 3,4-PCD (IC50 15μM) and D3 for MhpB (IC50 110μM). Application of D13 to Rhodococcus jostii RHA1 in minimal media containing ferulic acid led to the appearance of metabolic precursor protocatechuic acid at low concentration. Application of 1mM disulfiram, an inhibitor of mammalian aldehyde dehydrogenase, to R. jostii RHA1, gave rise to 4-carboxymuconolactone on the β-ketoadipate pathway, whereas in Pseudomonas fluorescens Pf-5 disulfiram treatment gave rise to a metabolite found to be glycine betaine aldehyde.
authors.affiliation: Department of Chemistry, University of Warwick, Coventry CV4 7AL, UK.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Sainsbury
authors.affiliation: Department of Chemistry, University of Warwick, Coventry CV4 7AL, UK.
authors.forename: Yelena
authors.initials: Y
authors.lastname: Mineyeva
authors.affiliation: Department of Chemistry, University of Warwick, Coventry CV4 7AL, UK.
authors.forename: Zoe
authors.initials: Z
authors.lastname: Mycroft
authors.affiliation: Department of Chemistry, University of Warwick, Coventry CV4 7AL, UK. Electronic address: T.D.Bugg@warwick.ac.uk.
authors.forename: Timothy D H
authors.initials: TD
authors.lastname: Bugg
mesh_terms: D065086:Acetaldehyde Dehydrogenase Inhibitors / Q000494:pharmacology; D049308:Dioxygenases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004221:Disulfiram / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D005285:Fermentation / Q000187:drug effects; D006877:Hydroxamic Acids / Q000737:chemistry / Q000494:pharmacology*; D062385:Hydroxybenzoates / Q000378:metabolism; D008031:Lignin / Q000378:metabolism*; D011520:Protocatechuate-3,4-Dioxygenase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011551:Pseudomonas fluorescens / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D012240:Rhodococcus / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D014233:Tricarboxylic Acids / Q000378:metabolism
chemical_list: D065086:Acetaldehyde Dehydrogenase Inhibitors; D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D062385:Hydroxybenzoates; D014233:Tricarboxylic Acids; C005968:carboxymuconolactone; C009091:protocatechuic acid; D008031:Lignin; D049308:Dioxygenases; C083582:3-carboxyethylcatechol 2,3-dioxygenase; D011520:Protocatechuate-3,4-Dioxygenase; D004221:Disulfiram
keywords: Aldehyde dehydrogenase; Catechol dioxygenase; Disulfiram; Enzyme inhibition; Hydroxamic acid; Lignin valorization