Lipogenesis and redox balance in nitrogen-fixing pea bacteroids

Within legume root nodules, rhizobia differentiate into bacteroids that oxidise host-derived dicarboxylic acids, which is assumed to occur via the TCA-cycle to generate NAD(P)H for reduction of N2. Metabolic flux analysis of laboratory grown Rhizobium leguminosarum showed that the flux from 13C-succinate was consistent with respiration of an obligate aerobe growing on a TCA-cycle intermediate as the sole carbon source. However, the instability of fragile pea bacteroids prevented their steady state labelling under N2-fixing conditons. Therefore, comparitive metabolomic profiling was used to compare free-living R. leguminosarum with pea bacteroids. While the TCA-cycle was shown to be essential for maximal rates of N2-fixation, pyruvate (5.5-fold down), acetyl-CoA (50-fold down), free coenzyme A (33-fold) and citrate (4.5-fold down) were much lower in bacteroids. Instead of completely oxidising acetyl-CoA, pea bacteroids channel it into both lipid and the lipid-like polymer poly-β-hydroxybutyrate (PHB), the latter via a type II PHB synthase that is only active in bacteroids. Lipogenesis may be a fundamental requirement of the redox poise of electron donation to N2 in all legume nodules. Direct reduction by NAD(P)H of the likely electron donors for nitrogenase, such as ferredoxin, is inconsistent with their redox potentials. Instead, bacteroids must balance the production of NAD(P)H from oxidation of acetyl-CoA in the TCA-cycle with its storage in PHB and lipids

Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus

A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk

Reversal of asymptomatic over-anticoagulation with oral vitamin K

No abstract available