Modulation of the acetylation state of histones plays a pivotal role in the regulation of gene expression. Histone deacetylases (HDACs) catalyze the removal of acetyl groups from lysines near the N termini of histones. This reaction promotes the condensation of chromatin, leading to repression of transcription. HDAC deregulation has been linked to several types of cancer, suggesting a potential use for HDAC inhibitors in oncology. Here we describe the first crystal structures of a human HDAC: the structures of human HDAC8 complexed with four structurally diverse hydroxamate inhibitors. This work sheds light on the catalytic mechanism of the HDACs, and on differences in substrate specificity across the HDAC family. The structure also suggests how phosphorylation of Ser39 affects HDAC8 activity.

In July 1995, 40 Montana residents were identified with laboratory-confirmed Escherichia coli O157:H7 infection; 52 residents had bloody diarrhea without laboratory confirmation. The median age of those with laboratory-confirmed cases was 42 years (range, 4- 86); 58% were female. Thirteen patients were hospitalized, and 1 developed hemolytic-uremic syndrome. A case-control study showed that 19 (70%) of 27 patients but only 8 (17%) of 46 controls reported eating purchased (not home-grown) leaf lettuce before illness (matched odds ratio, 25.3; 95% confidence interval, 3.9-1065.6). Pulsed-field gel electrophoresis identified a common strain among 22 of 23 isolates tested. Implicated lettuce was traced to two sources: a local Montana farm and six farms in Washington State that shipped under the same label. This outbreak highlights the increasing importance of fresh produce as a vehicle in foodborne illness. Sanitary growing and handling procedures are necessary to prevent these infections.

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Non-peptide peptidomimetics of the peptide hormone somatostatin (SRIF) were designed and synthesized, utilizing fl-D-glUCOSe as a novel scaffolding. Such compounds resemble conventional peptide analogs in that they retain critical amino acid side chains but differ in that they are devoid of both the peptide backbone and amide surrogates. Structure-activity relationships resulting from systematic deletion or modification of the side chains of 4a were consistent with expectations, with the exception that analogs 8a and 8b, lacking an indole side chain, bound to the SRIF receptor. A possible explanation for this unexpected result and its potential implications are discussed. Unexpectedly we also found that the primary amino group of Lys9 is not required for SRIF receptor binding or activation. Taken together, the results reported herein, and those described elsewhere,lJ support the validity of the concept of non-peptide scaffolding and also demonstrate that non-peptidal peptidomimetics can provide unexpected biological information not previously available from natural ligands or their peptidal analogs.

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