Dihydrofolate reductase: A potential drug target in trypanosomes and leishmania

Dihydrofolate reductase has successfully been used as a drug target in the area of anti-cancer, anti-bacterial and anti-malarial chemotherapy. Little has been done to evaluate it as a drug target for treatment of the trypanosomiases and leishmaniasis. A crystal structure of Leishmania major dihydrofolate reductase has been published. In this paper, we describe the modelling of Trypanosoma cruzi and Trypanosoma brucei dihydrofolate reductases based on this crystal structure. These structures and models have been used in the comparison of protozoan, bacterial and human enzymes in order to highlight the different features that can be used in the design of selective anti-protozoan agents. Comparison has been made between residues present in the active site, the accessibility of these residues, charge distribution in the active site, and the shape and size of the active sites. Whilst there is a high degree of similarity between protozoan, human and bacterial dihydrofolate reductase active sites, there are differences that provide potential for selective drug design. In particular, we have identified a set of residues which may be important for selective drug design and identified a larger binding pocket in the protozoan than the human and bacterial enzymes.     

Structured discharges in high frequency plasmas

Experiments are described in which structured discharges, including stationary and moving striations, were observed in 4 MHz rf plasmas generated using two solenoidal coil configurations. The structured plasmas which formed in the vicinity of the solenoidal coils were not quenched when elaborate precautions were taken to shield the capacitive electric fields. Measurements of the rf power input to the plasma and the resistance reflected by the plasma into the drive circuit showed no discontinuous change during the formation or disappearance of the structured discharges surrounding the solenoidal coils. Observations of striated rf discharges reported by other investigators are reviewed. Arguments are given to support the conclusion that the striation-like structures observed in rf plasmas and the moving striations observed in dc plasmas are part of the same general family.Much of the work described in this paper was supported by the Air Force Office of Scientific Research. One of us (RCW) received partial support from Contract DAAA 13-68-C-0033 and Grant NSF GK-24150.     

Regular elements in sandwich semigroups of binary relations

This note gives a counterexample to a published characterization of regular elements in sandwich semigroups of binary relations. The method of that paper is used to characterize those elements having a right identity. A characterization of regular elements is obtained following the approach of Schein.     

Mass excesses of 79As, 81As,and 80Ge

Accurate mass measurements for the nuclides ⁷⁹As, ⁸¹As, and ⁸⁰Ge have been measured. Good agreement has been found for ⁷⁹As and ⁸¹As with the Garvey-Kelson transverse mass relation and with several mass model predictions. The agreement for ⁸⁰Ge is not as satisfactory and presents a challenge for understanding mass values far off the line of stability.     

Electrical detection of amine ligation to a metalloporphyrin via a hybrid SOI-MOSFET

A close-packed monolayer of zinc 5,10,15,20-tetrakis(3-carboxyphenyl)porphyrin has been prepared and deposited on the thin native oxide covering the surface of an SOI-MOSFET (silicon-on-insulator metal-oxide-semiconductor field effect transistor) using Langmuir-Blodgett techniques. When the device is exposed to amine vapors in a nitrogen atmosphere, the amine coordinates to the zinc atom. The resulting change in electron distribution within the porphyrin leads to a large change in the drain current of the transistor, biased via a back gate. This change is sensitive to both the amount of amine present and the base strength of the amine. Only very small changes in drain current were observed with a monolayer of free base porphyrin or palmitic acid. After exposure to high pyridine concentrations, the device response saturates, but partially recovers after overnight exposure to flowing nitrogen gas. Interestingly, the device response is instantaneously reset by exposure to visible light, suggesting that photode-ligation occurs. An electrical model for the hybrid device that describes its response to ligand binding in terms of a change in the work function of the porphyrin monolayer has been developed. A transistor response to a few hundred attomoles of bound pyridine can be readily detected. This extreme sensitivity, coupled with the ability to reset the device using light, suggests that such systems might be useful as sensors.     

Evolution of enzymes and pathways for the biosynthesis of cofactors

The evolution of metabolic pathways is discussed with reference to the biosynthesis of a number of vitamins and cofactors. Retrograde and patchwork models are highlighted and their relevance to our knowledge of pathway processes and enzymes is examined. Pathway complexity is explained in terms of the acquisition of broad specificity enzymes.