Ajoene is a garlic compound with anti‐platelet properties and, in addition, was shown to inhibit cholesterol biosynthesis by affecting 3‐hydroxy‐3‐methyl‐glutaryl coenzyme A (HMG‐CoA) reductase and late enzymatic steps of the mevalonate (MVA) pathway. MVA constitutes the precursor not only of cholesterol, but also of a number of non‐sterol isoprenoids, such as farnesyl and geranylgeranyl groups. Covalent attachment of these MVA‐derived isoprenoid groups (prenylation) is a required function of several proteins that regulate cell proliferation. We investigated the effect of ajoene on rat aortic smooth muscle cell proliferation as related to protein prenylation. Cell counting, DNA synthesis, and cell cycle analysis showed that ajoene (1–50 μ M ) interfered with the progression of the G1 phase of the cell cycle, and inhibited rat SMC proliferation. Similar to the HMG‐CoA reductase inhibitor simvastatin, ajoene inhibited cholesterol biosynthesis. However, in contrast to simvastatin, the antiproliferative effect of ajoene was not prevented by the addition of MVA, farnesol (FOH), and geranylgeraniol (GGOH). Labelling of smooth muscle cell cellular proteins with [3H]‐FOH and [3H]‐GGOH was significantly inhibited by ajoene. In vitro assays for protein farnesyltransferase (PFTase) and protein geranylgeranyltransferase type I (PGGTase‐I) confirmed that ajoene inhibits protein prenylation. High performance liquid chromatography (HPLC) and mass spectrometry analyses also demonstrated that ajoene causes a covalent modification of the cysteine SH group of a peptide substrate for protein PGGTase‐I. Altogether, our results provide evidence that ajoene interferes with the protein prenylation reaction, an effect that may contribute to its inhibition of SMC proliferation. British Journal of Pharmacology (2003) 138 , 811–818. doi: 10.1038/sj.bjp.0705126
Third world nations require immediate access to inexpensive therapeutics to counter the high mortality inflicted by malaria. Here, we report a new class of antimalarial protein farnesyltransferase (PFT) inhibitors, designed with specific emphasis on simple molecular architecture, to facilitate easy access to therapies based on this recently validated antimalarial target. This novel series of compounds represents the first Plasmodium falciparum selective PFT inhibitors reported (up to 145-fold selectivity), with lead inhibitors displaying excellent in vitro activity (IC50 < 1 nM) and toxicity to cultured parasites at low concentrations (ED50 < 100 nM). Initial studies of absorption, metabolism, and oral bioavailability are reported.
Glycoside hydrolase (GH) family 13 is among the main families of enzymes acting on starch; recently, subfamily 47 of GH13 (GH13_47) has been established. The crystal structure and function of a GH13_47 enzyme from Bacteroides ovatus has only been reported to date. This enzyme has α-amylase activity, while the GH13_47 enzymes comprise approximately 800-900 amino acid residues which are almost double those of typical α-amylases. It is important to know how different the GH13_47 enzymes are from other α-amylases. Rhodothermus marinus JCM9785, a thermophilic bacterium, possesses a gene for the GH13_47 enzyme, which is designated here as RmGH13_47A. Its structure has been predicted to be composed of seven domains: N1, N2, N3, A, B, C, and D. We constructed a plasmid encoding Gly266-Glu886, which contains the N3, A, B, and C domains and expressed the protein in Escherichia coli. The enzyme hydrolyzed starch and pullulan by a neopullulanase-type action. Additionally, the enzyme acted on maltotetraose, and saccharides with α-1,6-glucosidic linkages were observed in the products. Following the replacement of the catalytic residue Asp563 with Ala, the crystal structure of the variant D563A in complex with the enzymatic products from maltotetraose was determined; as a result, electron density for an α-1,6-branched pentasaccharide was observed in the catalytic pocket, and Ile762 and Asp763 interacted with the branched chain of the pentasaccharide. These findings suggest that RmGH13_47A is an α-amylase that prefers α-1,6-branched parts of starch to produce oligosaccharides.
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The major problems unsolved in fluorocarbon emulsions have been the long lasting retention of the substance in tissues of organs and acute shock symptom in animals receiving "coarse" emulsion with particles larger then 0.2 mum. This report offers a new, stable and sterile preparation of 25% "fine" perfluorodecalin emulsion with yolk phospholipid that is eliminated from liver, spleen and other organs within a few weeks, and whose acute and subacute toxicity is as low as perfluorotributylamine/Pluronic F68 emulsion. Effects of the perfluorodecalin emulsion thus prepared for maintaining contractile force of isolated guinea pig heart by perfusion and survival of animals receiving repeated circulatory exchange proved similar to perfluorotributylamine/Pluronic F68 emulsion.
