title: Staphylococcus aureus haem biosynthesis: characterisation of the enzymes involved in final steps of the pathway.
abstract: Haem is a life supporting molecule that is ubiquitous in all major kingdoms. In Staphylococcus aureus, the importance of haem is highlighted by the presence of systems both for the exogenous acquisition and endogenous synthesis of this prosthetic group. In this work, we show that in S. aureus the formation of haem involves the conversion of coproporphyrinogen III into coproporphyrin III by coproporphyrin synthase HemY, insertion of iron into coproporphyrin III via ferrochelatase HemH, and oxidative decarboxylation of Fe-coproporphyrin III into protohaem IX by Fe-coproporphyrin oxidase/dehydrogenase HemQ. Together, this route represents a transitional pathway between the classic pathway and the more recently acknowledged alternative biosynthesis machinery. The role of the haem biosynthetic pathway in the survival of the bacterium was investigated by testing for inhibitors of HemY. Analogues of acifluorfen are shown to inhibit the flavin-containing HemY, highlighting this protein as a suitable target for the development of drugs against S. aureus. Moreover, the presence of a transitional pathway for haem biosynthesis within many Gram positive pathogenic bacteria suggests that this route has the potential not only for the design of antimicrobials but also for the selective discrimination between bacteria operating different routes to the biosynthesis of haem.
authors.affiliation: Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa, Avenida da República (EAN), 2780-157, Oeiras, Portugal.
authors.forename: Susana A L
authors.initials: SA
authors.lastname: Lobo
authors.affiliation: School of Biosciences, University of Kent, Giles Lane, Canterbury, Kent, CT2 7NJ, UK.
authors.forename: Alan
authors.initials: A
authors.lastname: Scott
authors.affiliation: Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa, Avenida da República (EAN), 2780-157, Oeiras, Portugal.
authors.forename: Marco A M
authors.initials: MA
authors.lastname: Videira
authors.affiliation: Pfizer Global Research and Development, Sandwich, Kent, UK.
authors.forename: David
authors.initials: D
authors.lastname: Winpenny
authors.affiliation: Pfizer Global Research and Development, Sandwich, Kent, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Gardner
authors.affiliation: Pfizer Global Research and Development, Sandwich, Kent, UK.
authors.forename: Mike J
authors.initials: MJ
authors.lastname: Palmer
authors.affiliation: School of Biosciences, University of Kent, Giles Lane, Canterbury, Kent, CT2 7NJ, UK.
authors.forename: Susanne
authors.initials: S
authors.lastname: Schroeder
authors.affiliation: School of Biosciences, University of Kent, Giles Lane, Canterbury, Kent, CT2 7NJ, UK.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Lawrence
authors.affiliation: Pfizer Global Research and Development, Sandwich, Kent, UK.
authors.forename: Tanya
authors.initials: T
authors.lastname: Parkinson
authors.affiliation: School of Biosciences, University of Kent, Giles Lane, Canterbury, Kent, CT2 7NJ, UK.
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Warren
authors.affiliation: Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa, Avenida da República (EAN), 2780-157, Oeiras, Portugal.
authors.forename: Lígia M
authors.initials: LM
authors.lastname: Saraiva
mesh_terms: D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D053898:Biosynthetic Pathways / Q000235:genetics*; D004791:Enzyme Inhibitors / Q000378:metabolism; D004798:Enzymes / Q000235:genetics / Q000378:metabolism; D006418:Heme / Q000096:biosynthesis*; D050296:Microbial Viability; D013211:Staphylococcus aureus / Q000235:genetics* / Q000378:metabolism*
chemical_list: D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D004798:Enzymes; D006418:Heme