Effect of α-Methylphenylalanine and Phenylalanine on Brain Polyribosomes and Protein Synthesis

Abstract: A chronic hyperphenylalanemia was effectively produced in developing mice by daily administrations of phenylalanine (2 mg/g body wt) and a phenylalanine hydroxylase inhibitor α-methyl-D, L-phenylalanine (0.43 mg/g body wt). The presence of α-methylphenylalanine in newborn mice inhibited 65–70% of hepatic phenylalanine hydroxylase activity within 12 h. Since this maximum inhibition persisted for 24 h or longer, decreased enzyme activity was maintained by daily administrations. Whereas concentrations of phenylalanine increased approximately 40-fold in both plasma and brain following injection of α-methylphenylalanine and phenylalanine, plasma levels of tyrosine were not altered significantly. Concomitant with changes in phenylalanine concentrations we observed the brain polyribosomes' disaggregation, which reached a maximum 3 h after injection and persisted as long as 18 h. Polyribosomes did not become refractory to as many as 10 daily injections of α-methylphenylalanine and phenylalanine. In addition to polyribosome disaggregation, chronic hyperphenylalanemia reduced the rates of polypeptide chain elongation on polyribosomes isolated from brain homogenates.     

NUTRITIONAL ASPECTS OF ANASTOMOTIC OPERATIONS—With Special Reference to the Sprue Syndrome

Necessary but radical operation which results in short-circuits between various levels of the digestive tract, with or without resections of portions of the esophagus, stomach or intestine, frequently cures the condition for which the operation was done, but leaves the patient with difficult nutritional problems. These nutritional disturbances are usually associated with inability to maintain or gain weight as a result of badly regulated movement of food material through the altered digestive tract, and by the removal or diversion of important digestive secretions, such as those elaborated by the stomach, pancreas, duodenum and small bowel.Increased intestinal rate and diminished specific gastrointestinal secretions reduce the ability of the small bowel to properly absorb food, with resulting malnutrition, deficiency disease, and at times specific avitaminosis. Inability to absorb fat and fat-soluble substances is a constant feature of these conditions. Successful treatment of the nutritional problems involves constant, prolonged overfeeding of nonbulky foods, usually given in regular, frequently administered meals of small volume. Vitamin concentrates may occasionally be of some temporary assistance but are not needed if a balanced diet is given and may cause undesirable and sometimes dangerous symptoms. The use of supplemental substances, such as liver extract and a wetting agent, such as “Tween 80,” to improve fat absorption have been demonstrated to be of value.The postoperative conditions described are fairly similar to the condition known as sprue, and it is possible that the general principles underlying the treatment of this disease apply to the entire group of post-operative nutritional disturbances alluded to.     

Azole-based inhibitors of AKT/PKB for the treatment of cancer

Through a combination of screening and structure-based rational design, we have discovered a series of N¹-(5-(heterocyclyl)-thiazol-2-yl)-3-(4-trifluoromethylphenyl)-1,2-propanediamines that were developed into potent ATP competitive inhibitors of AKT. Studies of linker strand-binding adenine isosteres identified SAR trends in potency and selectivity that were consistent with binding interactions observed in structures of the inhibitors bound to AKT1 and to the counter-screening target PKA. One compound was shown to have acceptable pharmacokinetic properties and to be a potent inhibitor of AKT signaling and of in vivo xenograft tumor growth in a preclinical model of glioblastoma.     

Increased urinary excretion of free N-acetylneuraminic acid in thirteen patients with Salla disease

Thirteen severely retarded patients with Salla disease, a new type of lysosomal storage disorder, have been studied biochemically. All patients excreted approximately ten times more free sialic acid than normal individuals. The isolated sialic acid was characterized by paper chromatography, thin-layer chromatography, optical rotation, 13C and 1H nuclear magnetic resonance spectroscopy, and mass spectrometry of its permethylated derivative. The results clearly indicated that the excreted sialic acid was identical to N-acetylneuraminic acid. The main sialylated trisaccharide present in the urine of the patients was identified as 3'-sialyllactose by sugar and methylation analysis. The excreted amounts were found to be within normal range.     

Atmospheric Production of Glycolaldehyde Under Hazy Prebiotic Conditions

The early Earth’s atmosphere, with extremely low levels of molecular oxygen and an appreciable abiotic flux of methane, could have been a source of organic compounds necessary for prebiotic chemistry. Here, we investigate the formation of a key RNA precursor, glycolaldehyde (2-hydroxyacetaldehyde, or GA) using a 1-dimensional photochemical model. Maximum atmospheric production of GA occurs when the CH₄:CO₂ ratio is close to 0.02. The total atmospheric production rate of GA remains small, only 1×10⁷ mol yr^???1. Somewhat greater amounts of GA production, up to 2 × 10⁸ mol yr^???1, could have been provided by the formose reaction or by direct delivery from space. Even with these additional production mechanisms, open ocean GA concentrations would have remained at or below ~1 μM, much smaller than the 1–2 M concentrations required for prebiotic synthesis routes like those proposed by Powner et al. (Nature 459:239–242, 2009). Additional production or concentration mechanisms for GA, or alternative formation mechanisms for RNA, are needed, if this was indeed how life originated on the early Earth.