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.     

Novel mutations target distinct subgroups of medulloblastoma

Medulloblastoma is a malignant childhood brain tumour comprising four discrete subgroups. Here, to identify mutations that drive medulloblastoma, we sequenced the entire genomes of 37 tumours and matched normal blood. One-hundred and thirty-six genes harbouring somatic mutations in this discovery set were sequenced in an additional 56 medulloblastomas. Recurrent mutations were detected in 41 genes not yet implicated in medulloblastoma; several target distinct components of the epigenetic machinery in different disease subgroups, such as regulators of H3K27 and H3K4 trimethylation in subgroups 3 and 4 (for example, KDM6A and ZMYM3), and CTNNB1-associated chromatin re-modellers in WNT-subgroup tumours (for example, SMARCA4 and CREBBP). Modelling of mutations in mouse lower rhombic lip progenitors that generate WNT-subgroup tumours identified genes that maintain this cell lineage (DDX3X), as well as mutated genes that initiate (CDH1) or cooperate (PIK3CA) in tumorigenesis. These data provide important new insights into the pathogenesis of medulloblastoma subgroups and highlight targets for therapeutic development.     

A disk of dust and molecular gas around a high-mass protostar

The processes leading to the birth of low-mass stars such as our Sun have been well studied, but the formation of high-mass (over eight times the Sun's mass, M(o)) stars remains poorly understood. Recent studies suggest that high-mass stars may form through accretion of material from a circumstellar disk, in essentially the same way as low-mass stars form, rather than through the merging of several low-mass stars. There is as yet, however, no conclusive evidence. Here we report the presence of a flattened disk-like structure around a massive 15M(o) protostar in the Cepheus A region, based on observations of continuum emission from the dust and line emission from the molecular gas. The disk has a radius of about 330 astronomical units (Au) and a mass of 1 to 8 M(o). It is oriented perpendicular to, and spatially coincident with, the central embedded powerful bipolar radio jet, just as is the case with low-mass stars, from which we conclude that high-mass stars can form through accretion.