The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder

Kinetic and Spectroscopic Studies of N694C Lipoxygenase: A Probe of the Substrate Activation Mechanism of a Nonheme Ferric Enzyme

Lipoxygenases (LOs) comprise a class of substrate activating mononuclear nonheme iron enzymes which catalyze the hydroperoxidation of unsaturated fatty acids. A commonly proposed mechanism for LO catalysis involves H-atom abstraction by an FeIII-OH- site, best described as a proton coupled electron transfer (PCET) process, followed by direct reaction of O2 with the resulting substrate radical to yield product. An alternative mechanism that has also been discussed involves the abstraction of a proton from the substrate by the FeIII-OH leading to a -organoiron intermediate, where the subsequent bond insertion of dioxygen into the C-Fe bond completes the reaction. H-atom abstraction is favored by a high E of the FeII/FeIII couple and high pKa of water bound to the ferrous state, while an organoiron mechanism would be favored by a low E (to keep the site oxidized) and a high pKa of water bound to the ferric state (to deprotonate the substrate). A first coordination sphere mutant of soybean LO (N694C) has been prepared and characterized by near-infrared circular dichroism (CD) and variable-temperature, variable-field (VTVH) magnetic circular dichroism (MCD) spectroscopies (FeII site), as well as UV/vis absorption, UV/vis CD, and electron paramagnetic resonance (EPR) spectroscopies (FeIII site). These studies suggest that N694C has a lowered E of the FeII/FeIII couple and a raised pKa of water bound to the ferric site relative to wild type soybean lipoxygenase-1 (WT sLO-1) which would favor the organoiron mechanism. However, the observation in N694C of a significant deuterium isotope effect, anaerobic reduction of iron by substrate, and a substantial decrease in kcat (~3000-fold) support H-atom abstraction as the relevant substrate-activation mechanism in sLO-1

Geometric structure determination of N694C lipoxygenase: a comparative near-edge X-ray absorption spectroscopy and extended X-ray absorption fine structure study

The mononuclear nonheme iron active site of N694C soybean lipoxygenase (sLO1) has been investigated in the resting ferrous form using a combination of Fe-K-pre-edge, near-edge (using the minuit X-ray absorption near-edge full multiple-scattering approach), and extended X-ray absorption fine structure (EXAFS) methods. The results indicate that the active site is six-coordinate (6C) with a large perturbation in the first-shell bond distances in comparison to the more ordered octahedral site in wild-type sLO1. Upon mutation of the asparigine to cystiene, the short Fe-O interaction with asparigine is replaced by a weak Fe-(H₂O), which leads to a distorted 6C site with an effective 5C ligand field. In addition, it is shown that near-edge multiple scattering analysis can give important three-dimensional structural information, which usually cannot be accessed using EXAFS analysis. It is further shown that; relative to EXAFS, near-edge analysis is more sensitive to partial coordination numbers and can be potentially used as a tool for structure determination in a mixture of chemical species