Summary Plasmodium falciparum, the primary cause of deaths from malaria, is a purine auxotroph and relies on hypoxanthine salvage from the host purine pool. Purine starvation as an antimalarial target has been validated by inhibition of purine nucleoside phosphorylase. Hypoxanthine depletion kills Plasmodium falciparum in cell culture and in Aotus monkey infections. Hypoxanthine-guanine-xanthine phosphoribosyltransferase (HGXPRT) from P. falciparum is required for hypoxanthine salvage by forming inosine 5′-monophosphate, a branchpoint for all purine nucleotide synthesis in the parasite. Here we present a new class of HGXPRT inhibitors, the acyclic Immucillin phosphonates (AIPs), and cell permeable AIP prodrugs. The AIPs are simple, potent, selective and biologically stable inhibitors. The AIP prodrugs block proliferation of cultured parasites by inhibiting the incorporation of hypoxanthine into the parasite nucleotide pool and validates HGXPRT as a target in malaria.

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The pathogenic protozoa responsible for malaria lack enzymes for the de novo synthesis of purines and rely on purine salvage from the host. In Plasmodium falciparum (Pf), hypoxanthine-guanine-xanthine phosphoribosyltransferase (HGXPRT) converts hypoxanthine to inosine monophosphate and is essential for purine salvage making the enzyme an anti-malarial drug target. We have synthesized a number of simple acyclic aza-C- nucleosides and shown that some are potent inhibitors of Pf HGXPRT while showing excellent selectivity for the Pf versus the human enzyme.

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Mercury (Hg) has been increasing in some marine birds in the Canadian Arctic over the past several decades. To evaluate the potential reproductive impact of Hg exposure, eggs of two species of arctic-breeding seabirds, the thick-billed murre and arctic tern, were dosed with graded concentrations of methylmercury (MeHg) and artificially incubated in the laboratory to determine species differences in sensitivity. Based on the dose-response curves, the median lethal concentrations (LC(50)) for thick-billed murre and arctic tern embryos were 0.48 and 0.95 μg g(-1) Hg on a wet-weight (ww) basis, respectively. Compared with published LC(50) values for other avian species, the murres and terns had a medium sensitivity to MeHg exposure. LC(50) values were also calculated for the actual Hg concentration measured in the embryos, that is, the maternally-deposited Hg plus the injected MeHg dose. This increased the LC(50) values to 0.56 μg g(-1) Hg ww in the thick-billed murre and to 1.10 μg g(-1) Hg ww in the arctic tern. Although muscarinic acetylcholine and N-methyl-D-aspartic acid glutamate receptor levels have been correlated with increasing Hg concentrations in brains of adult birds, no significant associations were found in brain tissue of the murre or tern embryos. The incidence of gross external anatomical deformities was 4.3 % in the murre embryos and 3.6 % in the tern embryos. However, given that the eggs were taken from wild populations, it is unlikely that the deformities observed in this study were due to MeHg exposure alone.

Both glutamate and gamma-aminobutyric acid (GABA) are involved in pituitary hormone release in fish. Glutamate serves 2 purposes, both as a neurotransmitter and as a precursor for GABA synthesis. Glutamate can be catabolized to GABA by the actions of 2 distinct but related enzymes, glutamate decarboxylase 65 (GAD65) and GAD67. They derive from 2 different genes that likely arose from an early gene duplication prior to the emergence of teleosts more than 400 million years ago. There is good evidence for the involvement of GABA in luteinizing hormone (LH) release in fish. The mechanism of GABA action to stimulate LH release appears to be a combination of effects on GnRH release, potentiation of gonadotropin hormone-releasing hormone (GnRH) action, and in some cases directly at the LH cell. These actions appear to be dependent on such factors as sex or sex steroid levels, and there may also be species differences. Nevertheless, the stimulatory effects of GABA on LH are present in at least 4 fish species. In contrast, convincing data for the inhibitory effects of GABA on LH release have only been observed in 1 fish species. The sites and mechanisms of action of amino acid neurotransmitters on LH release have yet to be fully characterized. Both 130N-methyl-D-aspartic acid (NMDA) and S-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) type glutamate receptors are likely to have important roles. We suggest that it is a receptor similar to the GABA(A) type which mediates the effects of GABA on LH release in fish, at least partially acting on the GnRH neuron, but likely directly acting at the gonadotroph as well. GABA may also be involved in regulating the release of other pituitary hormones in fish, namely follicle stimulating hormone (FSH = GTH-I), prolactin, and growth hormone. Based on the findings described in this review, a working model for the involvement of glutamate and GABA in the regulation of LH release in teleost fish is proposed.

This study investigated the influence of mustelid anal-gland compounds in suppressing feeding by snowshoe hares on coniferous tree seedlings. Pen and field bioassays indicated that 3-propyl-1,2-dithiolane from the stoat (Mustela erminea), and secondarily, 2,2-dimethylthietane from the mink (M. vison) had a very negative effect on feeding behavior of hares. The major component of stoat anal gland secretions, 2-propylthietane, and the related compounds, thietane and 2-methylthietane, were not effective. 3,3-Dimethyl-1,2-dithiolane from the least weasel (M. nivalis) and ferret (M. putorius) and di-n-propyldisulfide (acyclic analog of 3-propyl-1,2-dithiolane) similarly did not affect hare feeding. 3-Propyl-1,2-dithiolane and 2,2-dimethylthietane (also found inM. erminea) may act as interspecific chemical signals which induce a fear or avoidance response in hares. Such compounds have outstanding potential as area repellents to reduce crop and livestock depredations. Our study reports one of the first practical utilizations of mammalian semiochemicals in crop protection and wildlife management.

Background: Human and malaria orotate phosphoribosyltransferases (OPRTs) in the de novo pyrimidine biosynthesis pathway are characterized by ribocation transition states with fully dissociated leaving orotate groups. Results: Transition state analogues with varied ribocation substitutions, different linkers, and distinct leaving groups exhibited nanomolar binding affinities for the OPRT enzymes. Conclusion: Components crucial for inhibitor binding to the OPRT active sites have been identified, and powerful inhibitors were characterized. Significance: Transition state analogues of OPRTs provide new insights into the nature of potential antimalarials and anticancer agents.