Isopentenyl pyrophosphate (IPP) is a common precursor for the synthesis of all isoprenoids, which have important functions in living organisms. IPP is produced by the mevalonate pathway in archaea, fungi, and animals. In contrast, IPP is synthesized by a mevalonate-independent pathway in most bacteria, algae, and plant plastids. 1-Deoxy-D-xylulose 5-phosphate synthase (DXS) catalyzes the first and the rate-limiting step of the mevalonateindependent pathway and is an attractive target for the development of novel antibiotics, antimalarials, and herbicides. We report here the first structural information on DXS, from Escherichia coli and Deinococcus radiodurans, in complex with the coenzyme thiamine pyrophosphate (TPP). The structure contains three domains (I, II, and III), each of which bears homology to the equivalent domains in transketolase and the E1 subunit of pyruvate dehydrogenase. However, DXS has a novel arrangement of these domains as compared with the other enzymes, such that the active site of DXS is located at the interface of domains I and II in the same monomer, whereas that of transketolase is located at the interface of the dimer. The coenzyme TPP is mostly buried in the complex, but the C-2 atom of its thiazolium ring is exposed to a pocket that is the substrate-binding site. The structures identify residues that may have important roles in catalysis, which have been confirmed by our mutagenesis studies.Isoprenoids are an extensive class of extraordinarily diverse natural products and have important functions in all living organisms (1-4). Isopentenyl pyrophosphate (IPP) 2 is a common precursor for the synthesis of all isoprenoids. Although it has long been known that IPP can be generated from the mevalonate pathway, recent studies have revealed a mevalonate-independent pathway for IPP biosynthesis in most bacteria, algae, and plant chloroplasts (2-9). This pathway is also called the MEP pathway because 2-C-methyl-D-erythritol 4-phosphate (MEP) is its first committed precursor. Because the mevalonate-independent pathway is absent in animals, it represents a promising target for the development of novel antibiotics, antimalarials, herbicides, and other drugs. The herbicide fosmidomycin functions by inhibiting an enzyme in this pathway (10), and it also has activity against malarial infection in an animal model (11).1-Deoxy-D-xylulose 5-phosphate synthase (DXS) catalyzes the first and the rate-limiting reaction in the mevalonate-independent pathway, the condensation of glyceraldehyde 3-phosphate (GAP), and pyruvate ( Fig. 1A) (5-8, 12-15). The 1-deoxy-D-xylulose 5-phosphate product is also used for the biosynthesis of thiamine (vitamin B 1 ) and pyridoxol (vitamin B 6 ) (16,17). The dxs gene is essential for Escherichia coli, and disruption of this gene in Arabidopsis produces an albino phenotype (13, 18) because of the lack of chlorophylls and carotenoids. These studies demonstrate the crucial role of DXS in bacteria and plants. Although absent in humans, dxs and the mevalonate-independent pathwa...

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Objectives-To examine patterns of brain activation while performing a working memory task in persons with moderate to severe traumatic brain injury (TBI) and healthy controls. It is well established that working memory is an area of cognition that is especially vulnerable to disruption after TBI. Although much has been learned about the system of cerebral representation of working memory in healthy people, little is known about how this system is disrupted by TBI. Methods-Functional magnetic resonance imaging (fMRI) was used to assess brain activation during a working memory task (a modified version of the paced auditory serial addition test) in nine patients with TBI and seven healthy controls. Results-Patients with TBI were able to perform the task, but made significantly more errors than healthy controls. Cerebral activation in both groups was found in similar regions of the frontal, parietal, and temporal lobes, and resembled patterns of activation found in previous neuroimaging studies of working memory in healthy persons. However, compared with the healthy controls, the TBI group displayed a pattern of cerebral activation that was more regionally dispersed and more lateralised to the right hemisphere. Differences in lateralisation were particularly evident in the frontal lobes. Conclusions-Impairment of working memory in TBI seems to be associated with alterations in functional cerebral activity. (J Neurol Neurosurg Psychiatry 2001;71:161-168)

The estimation of free energy of binding is a key problem in structure-based design. We developed the scoring function HYDE based on a consistent description of HYdrogen bond and DEhydration energies in protein-ligand complexes. HYDE is applicable to all types of protein targets since it is not calibrated on experimental binding affinity data or protein-ligand complexes. The comprehensible atom-based score of HYDE is visualized by applying a very intuitive coloring scheme, thereby facilitating the analysis of protein-ligand complexes in the lead optimization process. In this paper, we have revised several aspects of the former version of HYDE which was described in detail previously. The revised HYDE version was already validated in large-scale redocking and screening experiments which were performed in the course of the Docking and Scoring Symposium at 241st ACS National Meeting. In this study, we additionally evaluate the ability of the revised HYDE version to predict binding affinities. On the PDBbind 2007 coreset, HYDE achieves a correlation coefficient of 0.62 between the experimental binding constants and the predicted binding energy, performing second best on this dataset compared to 17 other well-established scoring functions. Further, we show that the performance of HYDE in large-scale redocking and virtual screening experiments on the Astex diverse set and the DUD dataset respectively, is comparable to the best methods in this field.

Inhibitors of 4-hydroxyphenylpyruvate dioxygenase (HPPD) prevent plant carotenoid pigment formation, which in turn leads to chlorophyll degradation. This "bleaching" herbicide mode of action provides weed-control products for various crops, such as rice, corn, and cereals. Combinations with suitable safeners allow the full exploitation of the potential of this compound class to selectively control major weed problems, including rapidly increasing cases of resistance against other important herbicide classes.

Evidence of the relationship between childhood abuse and pain problems in adulthood has been based on cross-sectional studies using retrospective self-reports of childhood victimization. The objective of the current study was to determine whether childhood victimization increases risk for adult pain complaints, using prospective information from documented cases of child abuse and neglect. Using a prospective cohort design, cases of early childhood abuse or neglect documented between 1967 and 1971 (n = 676) and demographically matched controls (n = 520) were followed into young adulthood. The number of medically explained and unexplained pain complaints reported at follow-up (1989-1995) was examined. Assessed prospectively, physically and sexually abused and neglected individuals were not at risk for increased pain symptoms. The odds of reporting one or more unexplained pain symptoms was not associated with any childhood victimization or specific types (i.e. sexual abuse, physical abuse, or neglect). In contrast, the odds of one or more unexplained pain symptoms was significantly associated with retrospective self-reports of all specific types of childhood victimization. These findings indicate that the relationship between childhood victimization and pain symptoms in adulthood is more complex than previously thought. The common assumption that medically unexplained pain is of psychological origin should be questioned. Additional research conducting comprehensive physical examinations with victims of childhood abuse and neglect is recommended.

We developed a new empirical scoring function, HYDE, for the evaluation of protein-ligand complexes. HYDE estimates binding free energy based on two terms for dehydration and hydrogen bonding only. The essential feature of this scoring function is the integrated use of log P-derived atomic increments for the prediction of free dehydration energy and hydrogen bonding energy. Taking the dehydration of atoms within the interface into account shows that some atoms contribute favorably to the overall score, while others contribute unfavorably. For instance, hydrogen bond functions are penalized if they are dehydrated unless they can overcompensate this loss by forming a hydrogen bond with excellent geometry. The main stabilizing contribution represents the removal of apolar groups from the water: the hydrophobic effect. Initial studies using the DUD dataset show that with HYDE, there is a significant decrease in false positives, a reasonable categorization of compounds as either non-binders, weak, medium or strong binders, and in particular, there is a generally applicable and thermodynamically sensible cutoff score below which there is a high likelihood that the compound is indeed a binder.

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