A photochemical cascade process is reported affording complex pentacyclic scaffolds in high yields from readily available substrates. Flow processing provided reaction control and scalability to generate gram quantities of these intriguing for further studies.

During endoplasmic reticulum-associated degradation (ERAD), misfolded lumenal and membrane proteins in the ER are recognized by the transmembrane Hrd1 ubiquitin ligase complex and retrotranslocated to the cytosol for ubiquitination and degradation. Although substrates are believed to be delivered to the proteasome only after the ATPase Cdc48p/p97 acts, there is limited knowledge about how the H...

Proteases are candidate biomarkers and therapeutic targets for many diseases. Sensitive and robust techniques are needed to quantify proteolytic activities within the complex biological milieu. We hypothesized that a combinatorial protease substrate library could be used effectively to identify similarities and differences between serum and bronchoalveolar lavage fluid (BALF), two body fluids t...

PARP1 is the main sensor of single- and double-strand breaks in DNA and, in building chains of poly(ADP-ribose), promotes the recruitment of many downstream signaling and effector proteins involved in the DNA damage response (DDR). We show a robust physical interaction between PARP1 and the replication fork protein TIMELESS, distinct from the known TIMELESS-TIPIN complex, which activates the in...

Histone acetyltransferases (HATs) and histone deacetylases (HDACs) conduct many critical functions through nonhistone substrates in metazoans, but only chromatin-associated nonhistone substrates are known in Saccharomyces cerevisiae. Using yeast proteome microarrays, we identified and validated many nonchromatin substrates of the essential nucleosome acetyltransferase of H4 (NuA4) complex. Amon...

The organochlorine insecticide methoxychlor (mxc) is an established reproductive toxicant that affects other systems including the central nervous system (CNS), possibly by mechanisms involving oxidative stress. This study tested the hypothesis that mxc inhibits brain mitochondrial respiration, resulting in increased production of reactive oxygen species (ROS). Oxygen electrode measurements of ...

We recently identified ERdj3 as a component of unassembled immunoglobulin (Ig) heavy chain:BiP complexes. ERdj3 also associates with a number of other protein substrates, including unfolded light chains, a nonsecreted Ig light chain mutant, and the VSV-G ts045 mutant at the nonpermissive temperature. We produced an ERdj3 mutant that was unable to stimulate BiP's ATPase activity in vitro or to b...

Hrd1p and Doa10p organize factors used for the recognition, ubiquitination, and extraction of substrates. Indeed, Hrd1p provides the direct physical link between recognition events in the ER lumen and ubiquitination and extraction activities in the cytosol (Carvalho et al., 2006; Denic et al., 2006; Gauss et al., 2006). However, many pressing questions remain. Left out of the discussion is a se...

Over the past 50 years, more than 15 pharmaceuticals derived from marine organisms have come to market. Most of these filter-feeding invertebrates that contain a high proportion microbial symbionts. Microbiology and molecular genetic studies shown many drug-like compounds are produced by symbiont. The enzymes produce promiscuous meaning they can process diverse range related substrates, making ...