Biomedical subjects

Sarah E Chobot

Publications and source records attributed to Sarah E Chobot.

3 recordsLinked to original sources

PubMed2006

Electron tunneling chains of mitochondria.

The single, simple concept that natural selection adjusts distances between redox cofactors goes a long way towards encompassing natural electron transfer protein design. Distances are short or long as required to direct or insulate promiscuously tunneling single electrons. Along a chain, distances are usually 14 A or less. Shorter distances are needed to allow climbing of added energetic barriers at paired-electron catalytic centers in which substrate and the required number of cofactors form a compact cluster. When there is a short-circuit danger, distances between shorting centers are relatively long. Distances much longer than 14 A will support only very slow electron tunneling, but could act as high impedance signals useful in regulation. Tunneling simulations of the respiratory complexes provide clear illustrations of this simple engineering.

Animals↗

PubMed2005

Chemogenomic profiling on a genome-wide scale using reverse-engineered gene networks.

A major challenge in drug discovery is to distinguish the molecular targets of a bioactive compound from the hundreds to thousands of additional gene products that respond indirectly to changes in the activity of the targets. Here, we present an integrated computational-experimental approach for computing the likelihood that gene products and associated pathways are targets of a compound. This is achieved by filtering the mRNA expression profile of compound-exposed cells using a reverse-engineered model of the cell's gene regulatory network. We apply the method to a set of 515 whole-genome yeast expression profiles resulting from a variety of treatments (compounds, knockouts and induced expression), and correctly enrich for the known targets and associated pathways in the majority of compounds examined. We demonstrate our approach with PTSB, a growth inhibitory compound with a previously unknown mode of action, by predicting and validating thioredoxin and thioredoxin reductase as its target.

Algorithms↗

PubMed2004

A distinctive electrocatalytic response from the cytochrome c peroxidase of nitrosomonas europaea.

Here the cytochrome c peroxidase (CcP) from Nitrosomonas europaea is examined using the technique of catalytic protein film voltammetry. Submonolayers of the bacterial diheme enzyme at a pyrolytic graphite edge electrode give catalytic, reductive signals in the presence of the substrate hydrogen peroxide. The resulting waveshapes indicate that CcP is bound non-covalently in a highly active configuration. The native enzyme has been shown to possess two heme groups of low and high potential (L and H, -260 and +450 mV versus hydrogen, respectively), and here we find that the catalytic waves of the N. europaea enzyme have a midpoint potential of >500 mV and a shape that corresponds to a 1-electron process. The signals increase in magnitude with hydrogen peroxide concentration, revealing Michaelis-Menten kinetics and K(m) = 55 microm. The midpoint potentials shift with substrate concentration, indicating the electrochemically active species observed in our data corresponds to a catalytic species. The potentials also shift with respect to pH, and the pH dependence is interpreted in terms of a two pK(a) model for proton binding. Together the data show that the electrochemistry of the N. europaea cytochrome c peroxidase is unlike other peroxidases studied to date, including other bacterial enzymes. This is discussed in terms of a catalytic model for the N. europaea enzyme and compared with other cytochrome c peroxidases.

Cytochrome-c Peroxidase↗