Volume 8 Issue 11, November 2012

A gain of function in the cancer-associated mutant of isocitrate dehydrogenase inspired protein engineering of Saccharomyces cerevisiae homoisocitrate dehydrogenase to create a 2-hydroxyadipate dehydrogenase. This neoactivity yields chirally pure (R)-2-hydroxyadipic acid, a synthetic precursor to the industrially valuable adipic acid used in pharmaceuticals and synthetic polymers.

The first direct chemical inhibitor of a key histone-methylating enzyme provides a new tool to alter epigenetic states and genome expression profiles in normal and cancer cells.

A metabolic route including a RubisCO-like protein links polyamine metabolism with isoprenoid biosynthesis in the photosynthetic bacterium Rhodospirillum rubrum. Methanethiol is released in the pathway but is recaptured in the form of methionine, and thus methylthioadenosine, previously regarded as something of a byproduct of polyamine biosynthesis, is converted to two major cell components.

A new approach for rational enzyme design uses gain-of-function cancer mutations to guide homologous mutations in homoisocitrate dehydrogenase, yielding a biocatalytic path to (R)-2-hydroxyadipate, a precursor for the major commodity chemical adipic acid.

EZH2 is a protein methyltransferase component of the polycomb repressive complex 2 (PRC2) that installs the H3K27me3 chromatin mark. EPZ005687 inhibits EZH2 function and H3K27 trimethylation in cells and selectively kills lymphoma cells that require EZH2 for proliferation.

A small molecule that disrupts interaction between Nur77 and LKB1 leads to LKB1 exit from the nucleus to activate cytoplasmic AMPK and, ultimately, reduces blood glucose and insulin in diabetic mice.

A systems-pharmacology approach reveals that the combined off-target activity of two kinase inhibitors that impedes MAPK signaling to decrease expression of Myc target genes increases apoptosis in CML cells containing gatekeeper mutations in BCR-ABL.

Mass spectrometric profiling has revealed S-geranylation as a new tRNA modification and identified SelU as the tailoring enzyme in bacterial cells. Nucleotide S-geranylation was found in the anticodon of several tRNAs and regulates translational frameshifting and codon usage.

A compound derived from a structure-based screen binds to an allosteric site that includes residues of both the helicase and protease domains of HCV NS3, stabilizing an inactive conformation and inhibiting viral replication.

Combined omics techniques lead to the functional assignment of four enzymes involved in a new methionine salvage pathway linking polyamine metabolism with isoprenoid biosynthesis. This reaction sequence involves a homolog of nature's most abundant protein, the CO₂-fixing enzyme RubisCO.

The use of abbreviated pathway constructs leads to trapping of a series of cobalamin intermediates, allowing assignment of the full biosynthetic pathway and defining the roles of CobL as a dual-function methyltransferase and CobE as a likely carrier protein, perhaps facilitating metabolic channeling.

Ferritin controls iron concentrations by storing Fe(III), but the mechanism by which Fe(II) is bound and trafficked into the protein core after oxidation remains controversial. Spectroscopic methods in combination with labeling and competition assays now define a mechanism conserved from archaea to humans.