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Very little is known about cortical development in the first years of life, a time of rapid cognitive development and risk for neurodevelopmental disorders. We studied regional cortical and subcortical gray matter volume growth in a group of 72 children who underwent magnetic resonance scanning after birth and at ages 1 and 2 years using a novel longitudinal registration/parcellation approach. Overall, cortical gray matter volumes increased substantially (106%) in the first year of life and less so in the second year (18%). We found marked regional differences in developmental rates, with primary motor and sensory cortices growing slower in the first year of life with association cortices growing more rapidly. In the second year of life, primary sensory regions continued to grow more slowly, while frontal and parietal regions developed relatively more quickly. The hippocampus grew less than other subcortical structures such as the amygdala and thalamus in the first year of life. It is likely that these patterns of regional gray matter growth reflect maturation and development of underlying function, as they are consistent with cognitive and functional development in the first years of life.

Orotidine 5 -phosphate decarboxylase produces the largest rate enhancement that has been reported for any enzyme. The crystal structure of the recombinant Saccharomyces cerevisiae enzyme has been determined in the absence and presence of the proposed transition state analog 6-hydroxyuridine 5 -phosphate, at a resolution of 2.1 Å and 2.4 Å, respectively. Orotidine 5 -phosphate decarboxylase folds as a TIM-barrel with the ligand binding site near the open end of the barrel. The binding of 6-hydroxyuridine 5 -phosphate is accompanied by protein loop movements that envelop the ligand almost completely, forming numerous favorable interactions with the phosphoryl group, the ribofuranosyl group, and the pyrimidine ring. Lysine-93 appears to be anchored in such a way as to optimize electrostatic interactions with developing negative charge at C-6 of the pyrimidine ring, and to donate the proton that replaces the carboxylate group at C-6 of the product. In addition, H-bonds from the active site to O-2 and O-4 help to delocalize negative charge in the transition state. Interactions between the enzyme and the phosphoribosyl group anchor the pyrimidine within the active site, helping to explain the phosphoribosyl group's remarkably large contribution to catalysis despite its distance from the site of decarboxylation.O rotidine 5Ј-phosphate decarboxylase (ODCase) (EC 4.1.1.23) is responsible for de novo synthesis of uridine 5Ј-phosphate, an essential precursor of RNA and DNA. In neutral solution, orotidine 5Ј-monophosphate (OMP) undergoes spontaneous decarboxylation to uridine 5Ј-phosphate with a half-time of 78 million years (1). At the ODCase active site, the same reaction proceeds with a half-time of 18 msec (2). Comparison of k cat ͞K m with k non indicates that ODCase surpasses other enzymes in its proficiency ʈ as a catalyst, achieving a remarkable affinity for the altered substrate in the transition state (1). In addition to surmounting this formidable kinetic barrier, the ODCase reaction is of special interest in view of its lack of precedent in biological chemistry. The substrate is devoid of an effective repository for the negative charge that is generated at C-6 when CO 2 is eliminated, yet the enzyme functions without metals or other cofactors. Enzymatic decarboxylation of OMP is also remarkable in the importance (for catalysis) of a seemingly irrelevant part of the substrate. By its presence, the 5Ј-phosphoryl group contributes a factor of Ϸ10 8 -fold to k cat ͞K m , in spite of its considerable distance from the site of chemical transformation of the substrate (3). As a first step toward understanding these unusual properties, we have investigated the crystal structure of recombinant Saccharomyces cerevisiae ODCase alone and in complex with a postulated transition state analogue, 6-hydroxyuridine 5Ј-phosphate (BMP) (K i ϭ 9 ϫ 10 Ϫ12 M (4)]. Materials and MethodsRecombinant yeast ODCase was expressed in Escherichia coli SS6130 (pBGM88) and was purified as described (5). Crystals of the native enzyme were grown a...

The repositioning of efavirenz within the drug binding pocket of the mutant RT, together with conformational rearrangements in the protein, could represent a general mechanism whereby certain second-generation non-nucleoside inhibitors are able to reduce the effect of drug-resistance mutations on binding potency.

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