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Glutamate-alpha-ketoadipate transaminase, saccharopine reductase, and saccharopine dehydrogenase activities were demonstrated in extracts of Rhodotorula glutinis but alpha-aminoadipate reductase activity could not be measured in whole cells or in extracts. Lysine auxotroph lys1 grew in the presence of L-lysine or DL-alpha-aminoadipate and incorporated radioactivity from DL-alpha-amino-[I-14C]adipate into lysine during growth. Growing wild-type cells converted L-[U-14C]lysine into alpha-amino-[14C]adipate, suggesting both biosynthetic and degradative roles for alpha-aminoadipate. Lysine auxotrophs lys1, lys2 and lys3 of R. glutinis, unlike lysine auxotrophs of Saccharomyces cerevisiae, satisfied their growth requirement with L-pipecolate. Moreover, extracts of wild-type R. glutinis catalysed the conversion of L-pipecolate to alpha-aminoadipate-delta semialdehyde. These results suggest a biosynthetic role for L-pipecolate in R. glutinis but not in S. cerevisiae.
The glucuronic acid analogue of 1-deoxynojirimycin, 2(S)-carboxy-3(R), 4(R), 5(S)-trihydroxypiperidine, recently isolated from seeds of Baphia racemosa, is a novel specific inhibitor of human liver beta-D-glucuronidase and alpha-L-iduronidase. No other glycosidases are inhibited. The inhibition of beta-D-glucuronidase is competitive, with a Ki of 8 X 10(-5) M and is pH-dependent. This inhibitor may be useful to induce a mucopolysaccharidosis or to investigate the function of microsomal beta-D-glucuronidase.
Metabolism of L-[U-14C]lysine was studied in the human autopsy tissues and the intact monkeys through intracerebroventricular and intravenous injections. The human tissues were more active in the metabolism of L-[14C]lysine to [14C]pipecolate than the rat tissues previously reported. This metabolism was equally active in the phosphate (pH 7) and the glycyl-glycine (pH 8.6) buffers with the brain and the kidney having higher activity than the liver. Besides [14C]pipecolate, traces of [14C]saccharopine and alpha-[14C]aminoadipate were also detected in the liver incubation. Twenty-four hr after intraventricular injection of L-[14C]lysine to the monkey, substantial labeling of pipecolate and alpha-aminoadipate was observed in the brain and spinal cord, with the kidney, liver and the plasma having much reduced levels. Radioactivity levels of these two compounds were found low in the organs and plasma of the intravenously injected monkey. The urine of both monkeys contained only traces of [14C]pipecolate, even though it contained high levels of L-[14C]lysine and alpha-[14C]aminoadipate. It was concluded that L-lysine is actively metabolized to pipecolate and alpha-aminoadipate in the human and the monkey, that this reaction is most active in the brain when L-lysine is intraventricularly administered, and that in contrast to the rat, the monkey may have an effective renal reabsorption for pipecolate which is similar to the human.
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High-resolution proton nuclear magnetic resonance (1H NMR) has been used to study the conformation and dynamics of biosynthetic analogues of actinomycin D that have been substituted at one or both of the 3'-amino acids with azetidine-2-carboxylic acid, pipecolic acid, or 4-ketoproline for one or both of the prolines. The results of measurements made in organic solvents indicate that the amino acid residues on the alpha and beta pentapeptide lactone rings experience different magnetic environments in all the analogues studied. Analysis of the J alpha NH coupling constants and temperature coefficients for the valine and threonine amide protons indicates that substitution at the 3' position has little effect on the conformational and hydrogen-bonding properties of the amino acids at the 1' or 2' position. Examination of the low-field position of the H alpha proton of the 3'-amino acid reveals that the biosynthetic substitutions were made at a unique site on either the alpha or the beta pentapeptide ring and that only one conformation of proline, azetidine-2-carboxylic acid, or pipecolic acid is observed. In D2O, the dynamics of the prolines appear to differ; one remains in a preferred conformation while the other fluctuates at a rate that is intermediate on the NMR time scale. A possible relationship between the conformational and dynamic properties and the DNA binding and kinetic properties is discussed.
Acacia trees in the Negev desert and the Arava valley of Israel are suffering high levels of mortality due to water stress. Additionally, recruitment is negatively affected by bruchid beetles. We hypothesized that water-stressed trees would be less able to produce secondary defense compounds, such as the nonprotein amino acids, pipecolic acid and djenkolic acid, in their seeds to decrease seed herbivory. We further hypothesized that the high seed infestation reported is due to increased fitness of beetles infesting trees that are in a poor physiological state. Contrary to our prediction, pipecolic acid concentration was higher in water-stressed Acacia raddiana trees. We found that infestation rates and beetle fitness were higher in trees in a poor physiological state, despite the higher levels of pipecolic acid in these trees. There was a significant positive correlation between infestation level and the amounts of djenkolic acid in the seeds, indicating that the beetles may have found a means of utilizing djenkolic acid for their own benefit.
Results are reported on equilibrium and kinetic experiments probing the DNA binding properties of a series of actinomycin analogues differing at the 3'-amino acid position. While the parent compound, actinomycin D, contains proline at this position on both pentapeptide lactone rings, the analogues under consideration here contain either azetidine-2-carboxylic acid, pipecolic acid, or 4-ketoproline on one or both pentapeptide rings. This study extends our earlier results on doubly substituted analogues [Shafer, R.H., Burnett, R. R., & Mirau, P.A. (1980) Nucleic Acids Res. 8, 1121]. DNA binding constants were determined from Scatchard plots constructed from visible absorption data and covered the range of (0.3-9) X 10(6) M-1 for the whole series of analogues. The thermal denaturation temperature of calf-thymus DNA was increased by 3-17 degrees C. DNA dissociation kinetics, along with enthalpies and entropies of activation, were also determined. The time constant for the slowest dissociation process ranged from 278 to 10 900 s. The strongest DNA binding analogue, in terms of the largest binding constant, the largest increase in DNA thermal denaturation temperature, and the slowest DNA dissociation rate, was actinomycin V, which has 4-ketoproline in the beta peptide ring, while the weakest DNA binding analogue has pipecolic acid on both peptide rings. Evidence is presented for one peptide ring exerting a greater influence than the other in the interaction with DNA. Also, the possible role of cis-trans isomerization about one or two peptide bonds in determining the slow DNA binding kinetics is discussed.
The structures of neoefrapeptins A to N, peptides with insecticidal activity, were elucidated. They showed a close similarity to efrapeptin. However, all neoefrapeptins contained the very rare amino acid 1-amino-cyclopropane-carboxylic acid and some of them also contained (2S,3S)-3-methylproline. The neoefrapeptins are the first case, in which these amino acids are found as building blocks for linear peptides. They were identified by comparison of the silylated hydrolyzate to reference material by GC/MS (EI-mode). The sequence was elucidated using mass spectrometry (ESI+ mode). Full scan spectra showed two fragments in high yield, even under mild ionization conditions. MS/MS spectra of these two fragments yielded fragment rich spectra from which the sequence of the compounds was determined almost completely. The proteolytic cleavage with the proteinase papain yielded products that allowed to prove the rest of the sequence and the identity of the C-terminus to efrapeptin. The proteolytic cleavage products allowed furthermore to determine the position of the isobaric amino acids, pipecolic acid and 3-methylproline in neoefrapeptin F, as well as the location of R-isovaline and S-isovaline. Papain digestion was such established as a tool for structure elucidation of peptides rich in alpha,alpha-dialkylated amino acids. CD spectra suggested a 3(10) helical structure for neoefrapeptins A and F.
A 5-year-old boy with panperoxisomal dysfunction is described. Clinical features included hypotonia, areflexia, and ataxia. Cognition, vision, hearing, and hepatic function were normal. A panel of peroxisomal markers, including very-long-chain fatty acids, phytanic acid, pipecolic acid, and catalase compartmentalization, were abnormal. This is a uniquely benign syndrome of disordered peroxisome biogenesis.
Seeds from Sophora secundiflora were extracted into three major fractions: lipids, alkaloids, and amino acids. Most of the lipid material was composed of steroid esters. These esters were hydrolyzed, and the fatty acid compositions were determined. The major alkaloid component was cytisine, with N-methylcytisine, anagyrine, and the fatty acid compositions were determined. The major alkaloid component was cytisine, with N-methylcytisine, anagyrine, and termopsine in lower concentration. The major free ninhydrin-positive compound was gamma-glutamyltyrosine. In addition to several common amino acids, pipecolic acid and 4-hydroxypipecolic acid were identified. Both the amino acid fraction and the alkaloid fractions caused minor pharmacological disorder when injected into rats. However, when both fractions were simultaneously administered, they were lethal.
A preterm (gestational age 34 weeks), small for gestational age infant (birth weight less than P2,3) is described. Because of unexplained slightly disturbed liver function tests at age 2 months, extensive metabolic examinations were performed. Elevated blood levels of very long-chain fatty acids, pipecolic acid and abnormal levels of bile acid intermediates were detected, suggesting a peroxisomal disorder. The plasmalogen content of erythrocytes was decreased. Morphologically distinct peroxisomes were absent in the liver. In fibroblasts an accumulation of very long-chain fatty acids, decreased activity of acyl-CoA:dihydroxyacetone phosphate acyltransferase and impaired de novo biosynthesis of plasmalogens was found. In summary, a mild variant of the classical cerebro-hepato-renal syndrome of Zellweger was found without the characteristic clinical facial signs.