Enzymic activation and transfer of fatty acids as acyl-adenylates in mycobacteria

The metabolic repertoire in nature is augmented by generating hybrid metabolites from a limited set of gene products. In mycobacteria, several unique complex lipids are produced by the combined action of fatty acid synthases and polyketide synthases (PKSs), although it is not clear how the covalently sequestered biosynthetic intermediates are transferred from one enzymatic complex to another. Here we show that some of the 36 annotated fadD genes, located adjacent to the PKS genes in the Mycobacterium tuberculosis genome, constitute a new class of long-chain fatty acyl-AMP ligases (FAALs). These proteins activate long-chain fatty acids as acyl-adenylates, which are then transferred to the multifunctional PKSs for further chain extension. This mode of activation and transfer of fatty acids is contrary to the previously described universal mechanism involving the formation of acyl-coenzyme A thioesters. Similar mechanisms may operate in the biosynthesis of other lipid-containing metabolites and could have implications in engineering novel hybrid products.     

Eosinophils in the pathogenesis of allergic airways disease

Eosinophils are traditionally thought to form part of the innate immune response against parasitic helminths acting through the release of cytotoxic granule proteins. However, they are also a central feature in asthma. From their development in the bone marrow to their recruitment to the lung via chemokines and cytokines, they form an important component of the inflammatory milieu observed in the asthmatic lung following allergen challenge. A wealth of studies has been performed in both patients with asthma and in mouse models of allergic pulmonary inflammation to delineate the role of eosinophils in the allergic response. Although the long-standing association between eosinophils and the induction of airway hyper-responsiveness remains controversial, recent studies have shown that eosinophils may also promote airway remodelling. In addition, emerging evidence suggests that the eosinophil may also serve to modulate the immune response. Here we review the highly co-ordinated nature of eosinophil development and trafficking and the evolution of the eosinophil as a multi-factoral leukocyte with diverse functions in asthma. Received 6 December 2006; received after revision 11 January 2007; accepted 15 February 2007