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PubMed1979

Role of pipecolic acid in the biosynthesis of lysine in Rhodotorula glutinis.

The role of pipecolic acid in the biosynthesis of lysine was investigated in Rhodotorula glutinis, an aerobic red yeast. Supplementation of pipecolic acid in the minimal medium supported the growth of mutants lys2, lys3, and lys5; alpha-aminoadipic acid supported the growth of lys5; but neither alpha-aminoadipic acid nor pipecolic acid supported the growth of mutants MNNG42 and MNNG37. During the growth of the appropriate mutants, pipecolic acid was removed from the growth medium and the intracellular pool. In tracer experiments, radioactivity from [(14)C]pipecolic acid was selectively incorporated into the cellular lysine of lys5 and the wild-type strain. l-Pipecolic acid-dependent enzyme activity did not require any cofactor and was inhibited by mercuric chloride and potassium cyanide. This activity was present in the wild-type strain and all of the mutants tested and was repressed in mutant lys5 when grown in the presence of higher concentration of lysine. The reaction product of pipecolic acid was converted to saccharopine by lys5 enzyme in the presence of glutamate and reduced nicotin-amide adenine dinucleotide phosphate. Mutant MNNG37 lacked the saccharopine dehydrogenase activity, indicating that this step is involved in the conversion of alpha-aminoadipic acid and pipecolic acid to lysine. Mutants MNNG37 and MNNG42 accumulated a p-dimethylaminobenzaldehyde-reacting product in the culture supernatant and in the intracellular pool. Chromatographic properties of the p-dimethylaminobenzaldehyde adduct and that of the pipecolic acid-dependent reaction product were similar. The reaction product and the accumulation product were characterized on the basis of mass and absorption spectra as alpha-aminoadipic-semialdehyde, which in solution remains in equilibrium with Delta(1)-piperideine-6-carboxylic acid. Since alpha-aminoadipic-semialdehyde is a known intermediate of the alpha-aminoadipic acid pathway for the biosynthesis of lysine, it is concluded that pipecolic acid is converted to lysine in R. glutinis via alpha-aminoadipic-semialdehyde and saccharopine.

2-Aminoadipic Acid↗
PubMed1998

Epoxide derivatives of pipecolic acid and proline are inhibitors of pipecolate oxidase.

The cis-4,5-epoxide derivative of L-pipecolic acid (2S,4S,5R-epoxypipecolic acid, cis-3) was synthesized and found to serve as an excellent substrate for L-pipecolate oxidase (L-PO) and also to cause time-dependent, irreversible inactivation of the enzyme. Data are presented showing this compound is a mechanism-based inhibitor of L-PO, whereas 2S,3R,4S-epoxyproline acts as a reversible inhibitor.

Drug Design↗
PubMed1981

Comparison of synaptosomal and glial uptake of pipecolic acid and GABA in rat brain.

The active uptake of [3H]pipecolic acid increased with incubation time and its uptake at 3 min was half of that at 20 min. On the other hand, a ratio (pellet/medium) of [3H]pipecolic acid uptake into glial cell-enriched fractions, was much less (0.4 - 0.6) than that of [14C]GABA (25.8 - 74.1). GABA, 10(-4) M, and pipecolic acid, 10(-4) M, produced a significant inhibitor of [3H]pipecolic acid uptake into P2 fractions. Pipecolic acid, 10(-4) M, significantly reduced the synaptosomal and glial uptake of [14C]GABA. GABA, 10(-4) M, affected neither spontaneous nor high K+-induced release of [3H]pipecolic acid from brain slices. It is suggested that pipecolic acid is involved in either synaptic transmission or in its modulation at GABA synapses in the central nervous system.

Animals↗
PubMed2006

Pipecolic acid in microbes: biosynthetic routes and enzymes.

Pipecolic acid is an important precursor of many useful microbial secondary metabolites. Pipecolic acid-derived moieties are often crucial for the biological activities of some microbial natural products with pharmaceutical applications. Understanding the biogenesis of pipecolic acid in microorganisms would be a significant step toward the mutasynthesis of novel analogs of choice. This review focuses on various microbial pathways and enzymes for pipecolic acid synthesis, especially those related to the origination of pipecolic acid moieties in secondary metabolites.

2-Aminoadipic Acid↗
PubMed1989

Peroxisomal L-pipecolic acid oxidation is deficient in liver from Zellweger syndrome patients.

L-Pipecolic acid, a cyclic imino acid produced during the degradation of lysine, accumulates in body fluids of infants with the generalized peroxisomal disorders, including Zellweger syndrome, neonatal adrenoleukodystrophy, and infantile Refsum disease. Peroxisome-enriched fractions from normal human liver oxidized L-[3H]pipecolic acid to alpha-[3H]aminoadipic acid (AAA). When human liver organelles were separated on a Percoll gradient, L-[3H]pipecolic acid oxidation activity (as measured by [3H]AAA formation) most closely segregated with the peroxisomal marker, catalase, and was not associated with the mitochondria. L-Pipecolic acid oxidation was not inhibited by antimycin A and rotenone and produced H2O2, consistent with its involving a peroxisomal oxidase. We measured L-pipecolic acid oxidation in liver specimens from patients with peroxisomal disorders. While liver homogenates from adult (n = 5) and infant (n = 10) controls formed 47.1 +/- 6.6 and 48.3 +/- 10.0 pmol AAA/mg protein/h, respectively, Zellweger syndrome livers (n = 8) formed only 1.7 +/- 0.3 pmol AAA/mg protein/h. L-pipecolic acid oxidation in normal infant livers was low at birth and increased with age, but Zellweger syndrome livers showed little activity at any age. Thus, the high circulating levels of L-pipecolic acid in Zellweger syndrome probably result from defective peroxisomal oxidation of L-pipecolic acid to AAA.

2-Aminoadipic Acid↗
PubMed1981

Brain uptake of pipecolic acid, amino acids, amines following intracarotid injection in the mouse.

The uptake of pipecolic acid by the mouse brain was compared to that of several amino acids and amines, following an injection of a double-labeled mixture into the carotid artery. In general, BUI (brain uptake index) values were lower in the mouse than those previously reported in the rat. The only exception was proline. Lysine, a precursor of pipecolic acid biosynthesis in brain, showed a higher BUI than pipecolic acid. The BUI of D,L-[3H]pipecolic acid was found to be 3.39 (at 0.114 mM). This was saturable between a concentration of 0.114 and 3.44 mM. Kinetic analysis suggests the presence of two kinds of transport systems. Substances structurally related to pipecolic acid, such as nipecotic acid, isonipecotic acid, L-proline, and piperidine show a significant inhibitory effect. Amont the amino acids tested, only GABA showed an inhibitory effect. Data are reported which, when considered with other findings (5), present evidence that pipecolic acid is (1) synthesized both in vitro and in vivo in the mouse brain, (2) actively transported in vivo into the brain, and (3) taken up in vitro by synaptosomal preparations.

Amines↗
PubMed1991

Purification and characterization of peroxisomal L-pipecolic acid oxidase from monkey liver.

L-Pipecolic acid oxidase has been purified to near homogeneity from Rhesus monkey liver. The protein, a yellow monomer, has a molecular weight of 46,000 by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and a pI of 8.9. It contains a covalently bound flavin with absorption maxima at 457 and 383 nm and a shoulder at 480 nm. The purified enzyme is most reactive toward L-pipecolic acid, with lesser reactivities toward L-proline and sarcosine. The enzyme has no significant reactivity toward the D-enantiomer of pipecolic acid or toward any other amino acid tested. Benzoic acid is a competitive inhibitor of the enzyme with a Ki of 750 microM. The Km of the purified enzyme is 3.7 mM for L-pipecolic acid. With less purified preparations, the reaction product is alpha-aminodipic acid. The purified enzyme, however, produces an intermediate which reacts with ortho-aminobenzaldehyde to form an alpha-aminoadipic acid semialdehyde adduct. Thus, the formation of alpha-aminoadipic acid requires at least two enzymes.

Animals↗
PubMedDate not supplied

Plasma levels of pipecolic acid in patients with chronic liver disease.

Plasma levels of pipecolic acid, which is a minor metabolite of lysine, were determined by high-performance liquid chromatography in 22 patients with chronic liver disease, composed of 6 patients with chronic active hepatitis, 11 with liver cirrhosis and 5 with hepatocellular carcinoma. The plasma levels of pipecolic acid, when compared to those in normal subjects (1.00 +/- 0.08 nmoles per ml), were found to be significantly elevated (p less than 0.01) in patients with liver cirrhosis (1.93 +/- 0.24 nmoles per ml) and hepatocellular carcinoma (2.22 +/- 0.49 nmoles per ml), but did not show any significant change in patients with chronic active hepatitis. Plasma levels of pipecolic acid correlated positively with serum bile acid and bilirubin, and negatively with indocyanine green disappearance rate, cholinesterase and prothrombin time but not with plasma lysine levels. These results suggest that plasma levels of pipecolic acid increase almost parallel to the severity of liver damage, and that this increase in pipecolic acid may reflect the injury of liver peroxisomes which appear to be related to the degradation of pipecolic acid.

Aged↗
PubMed1991

Species variation in organellar location and activity of L-pipecolic acid oxidation in mammals.

The oxidation of L-pipecolic acid to alpha-aminoadipic acid was studied in eight species of mammals using an assay system more sensitive than those previously employed. After percoll-gradient fractionation, activity was localized to the mitochondrial-enriched fractions in tissues from rabbit, guinea pig, pig, dog, and sheep, with guinea pig kidney cortex showing greatest specific activity. These results contrast with the peroxisomal oxidation of L-pipecolic acid observed in macaques and man (Mihalik and Rhead 1989; Mihalik et al. 1989). Rats and mice had undetectable levels of both peroxisomal and mitochondrial L-pipecolic acid oxidation. In the rat, peroxisomal oxidation activity was not induced by feeding with either clofibrate or clofibrate and L-pipecolic acid. Thus, among mammals, both the ability to oxidize L-pipecolic acid and the organellar location of this oxidation is species dependent.

Animals↗
PubMed1983

Metabolism of cadaverine and pipecolic acid in brain and other organs of the mouse.

Cadaverine and pipecolic acid metabolism was investigated in vitro in several organs of the mouse by measuring 14CO2 formation from labeled precursors. The liver showed the highest formation of 14CO2 from [1,5-14C]-cadaverine, whereas brain demonstrated a much lower formation. Anaerobiosis or inhibition of monoamineoxidase (MAO) activity significantly reduced 14CO2 formation in every organ, but inhibition of diamine oxidase (DAO) activity had no effect in brain and kidney. Piperidine was formed from cadaverine in vitro only in the large intestine and its content. This formation is probably of bacterial origin. Under a variety of experimental conditions we were unable to demonstrate any formation of piperidine in brain from cadaverine. Biosynthesis in vitro of [3H]-piperidine from D,L-[3H]-pipecolic acid was very low in brain and kidney. With the exception of brain and kidney, no other organs showed any formation of [3H]-piperidine. Neither MAO nor DAO inhibition influenced [3H]-piperidine formation in the large intestine with its content. Following 1 hr incubation at 37 degrees C under aerobic conditions, the levels of [14C]-pipecolic acid and [3H]-piperidine recovered from mouse brain homogenate did not indicate any significant degradation of these two substances. Our results suggest that under in vitro conditions, cadaverine is not a precursor of piperidine in brain, liver, heart, and kidney and that only very low levels of piperidine can be formed from pipecolic acid in brain. Outside the brain, formation of piperidine from pipecolic acid is detectable only in kidney and in the content of the large intestine. The latter is probably of bacterial origin. Our results do not support previous findings from other authors on an endogenous origin of piperidine in brain from cadaverine and pipecolic acid, and they suggest that a) cadaverine is not a precursor of piperidine in brain, b) the conversion of pipecolic acid into piperidine in the brain does not constitute a major metabolic pathway, and c) the main source of piperidine in the CNS may be of nonneural origin.

Animals↗
PubMed1999

Plasma levels of pipecolic acid, both L- and D-enantiomers, in patients with chronic liver diseases, especially hepatic encephalopathy.

Pipecolic acid is regarded as a gamma-aminobutyric acid receptor agonist. Stereochemical studies of pipecolic acid were performed in patients with chronic liver diseases. Plasma D- and L-pipecolic acid were significantly elevated in 15 liver cirrhotic patients with no history of hepatic encephalopathy (1.05+/-0.24 micromol/l, 1.58+/-0.13 micromol/l, p < 0.01) and in 27 patients with chronic hepatic encephalopathy (1.58+/-0.50 micromol/l, 2.38+/-0.58 micromol/l, p<0.001) compared to 15 normal subjects. In seven patients with chronic hepatic encephalopathy orally treated with kanamycin, plasma pipecolic acid significantly decreased (D-acid: before 1.62+/-0.23 micromol/l, after 0.61+/-0.15 micromol/l; p<0.01, L-acid: before 2.43-0.52 micromol/l, after 2.23+/-0.11 micromol/l; p< 0.05). These results suggest that plasma pipecolic acid, particularly D-acid, is produced from D-lysine by intestinal bacteria in liver cirrhotic patients and that pipecolic acid could be involved in the pathogenesis of hepatic encephalopathy.

Adult↗
PubMed2005

Pipecolic acid concentrations in brain tissue of nutritionally pyridoxine-deficient rats.

Elevated concentrations of pipecolic acid have been reported in plasma and CSF of patients with pyridoxine-dependent epilepsy, but its molecular background is unclear. To investigate any further association of pyridoxine and pipecolic acid metabolism, we have performed an animal trial and have measured the concentration of pipecolic acid in brain tissue of rats with nutritional pyridoxine deficiency and in control littermates. Concentrations of pyridoxal phosphate were significantly reduced in brain tissue of pyridoxine-deficient rats (p < 0.001), while concentrations of pipecolic acid were not significantly different from the normally nourished control group (p = 0.3). These data indicate that a direct association of pyridoxine and pipecolic acid metabolism is unlikely. We therefore assume that the characteristic elevation of pipecolic acid in pyridoxine-dependent epilepsy could rather be a secondary phenomenon with the primary defect of pyridoxine-dependent epilepsy being located outside the pipecolic acid pathway.

Animal Nutritional Physiological Phenomena↗
PubMed1993

Stereochemistry of pipecolic acid found in the urine and plasma of subjects with peroxisomal deficiencies.

Recently it was found that normal adults excrete pipecolic acid primarily as the D-enantiomer even though it is present in the blood stream mainly as the L-enantiomer (i.e. > 98% L). This study of pipecolic acid stereochemistry was extended to subjects with peroxisomal deficiencies since they are known to have high levels of pipecolic acid in their physiological fluids. Also, pipecolic acid stereochemistry was examined in young normal subjects since this group was not considered previously. It was found that the stereochemical composition of pipecolic acid in plasma was very similar for all subjects tested (i.e. > 98% of the L-enantiomer). However, the stereochemical composition of excreted pipecolic varied considerably. Urine samples from subjects with the most severe peroxisomal deficiency, i.e. cerebralhepatorenyl (Zellweger) syndrome (CHRS) contained little D-pipecolic acid. In fact the enantiomeric ratios for pipecolic acid in the urine and plasma of these subjects were very similar. This was not the case for normal subjects. Levels of D-pipecolic acid in the urine of subjects with 'less severe' peroxisomal deficiencies tended to be somewhat higher but they did not approach the levels found in normal adults. Several possible reasons for these results are discussed.

Adult↗
PubMed1989

L-pipecolic acid oxidation in the rabbit and cynomolgus monkey. Evidence for differing organellar locations and cofactor requirements in each species.

L-Pipecolic acid oxidation was studied in the rabbit and cynomolgus monkey. Tissue homogenates from both species incubated with L-[2,3,4,5,6-3H]pipecolic acid produced a single radioactive product identified as alpha-aminoadipic acid. In the rabbit, L-pipecolic acid oxidation was greatest in kidney cortex with progressively lesser specific activities in liver, heart, and brain. When rabbit kidney cortex was fractionated by differential centrifugation or on Percoll gradients, activity paralleled that of the mitochondrial marker, glutamate dehydrogenase. In sonicated mitochondria, 92% of the activity was in the soluble fraction. Activity was inhibited by both rotenone and antimycin A and was maximal when FAD, phenazine ethosulfate, and glycerol were included in the assay; Km,app was 0.74 +/- 0.16 mM. Nipecotic acid, piperidine, and cis-2,4-piperidine dicarboxylic acid did not inhibit L-pipecolic acid oxidation, while L-proline had a Ki greater than or equal to 10 mM. D-Alanine and kojic acid, substrate and inhibitor of D-amino acid oxidase, respectively, were also not inhibitory. When monkey kidney cortex was fractionated on Percoll gradients, L-pipecolic acid oxidation activity paralleled that of the peroxisomal marker, catalase. After organellar subfractionation, the activity was membrane-associated and maximal at pH 8.5; Km,app was 4.22 +/- 0.30 mM. L-Pipecolic acid oxidation produced hydrogen peroxide, suggesting involvement of an oxidase in alpha-aminoadipic acid formation. Antimycin A did not inhibit the reaction. No specific cofactor requirements were identified and phenazine ethosulfate inhibited the reaction. D-Pipecolic acid, L-proline, and the other compounds cited above did not significantly inhibit the activity.

Animals↗
PubMed1990

Pipecolic acid biosynthesis in Rhizoctonia leguminicola. I. The lysine saccharopine, delta 1-piperideine-6-carboxylic acid pathway.

The biosynthesis of pipecolic acid from L-lysine in the fungal parasite, Rhizoctonia leguminicola has been reinvestigated. Pipecolate is then utilized to form the toxic octahydroindolizine alkaloids, slaframine and swainsonine. Incorporation studies of L-versus D-[U-14C]lysine into R. leguminicola metabolites confirmed earlier findings that L-lysine is the predominant substrate for pipecolate formation and D-lysine for alpha-N-acetyllysine (concerned in lysine catabolism). However [alpha-15N]lysine, not [epsilon-15N]lysine as previously reported, labeled pipecolate. Such findings implied that delta 1-piperideine-6-carboxylate, not delta 1-piperideine-2-carboxylate, was formed from lysine and was the immediate precursor of pipecolate. Evidence from cell-free enzyme systems established the following biosynthetic events: L-lysine A----saccharopine B----delta 1-piperideine-6-carboxylate C----pipecolate. Products of reactions A and C were identified from biological and chemical considerations. Reaction B was carried out by a previously undescribed flavin enzyme termed saccharopine oxidase. The product of reaction B, which reacted with p-dimethylaminobenzaldehyde, was reduced with Na-CNB2H3. Its NMR spectrum was identical with that of deuteriated pipecolate prepared from authentic delta 1-piperideine-6-carboxylate, but not from authentic delta 1-piperideine-2-carboxylate. Reaction B represents a branching of primary lysine metabolism from saccharopine to a secondary pathway leading to pipecolate and to octahydroindolizine alkaloids in R. leguminicola.

Lysine↗
PubMed1981

The metabolism of D- and L-pipecolic acid in the rabbit and rat.

The metabolism of D- and L-pipecolic acid has been investigated in rabbits and rats. A rapid evolution of 14CO2 followed the injection of either D- or L-pipe[6-14C]colic acid into rabbits. Rabbit kidney slices degraded to CO2 both isomers of lysine and of pipecolic acid. Rabbit liver was effective with only the L-isomers. In the rat, very little of injected L-pipecolic acid was catabolized to CO2, and large amounts were excreted unchanged into the urine, L-Lysine was efficiently metabolized to CO2 by rat liver and kidney slices but not D-lysine or either isomer of pipecolic acid. Rat kidney converted D-lysine to L-pipecolic acid. The L-isomer was identified by co-precipitation of the radioactive product with authentic compounds.

Amino Acids↗
PubMed1986

Dose pipecolic acid interact with the central GABA-ergic system?

Several previous studies have suggested a strong GABA-mimetic action of the endogenous brain imino acid, L-pipecolic acid (L-PA). In the present study, these observations were evaluated using electrophysiological and neurochemical methods. In contrast to published data our electrophysiological studies on rat cortical neurones in situ showed only a weak, but bicuculline-sensitive depressant action of L-PA on cortical neurones. Furthermore, L-PA proved to have no affinity for any of the three components of the GABA-benzodiazepine-chloride channel receptor complex. However, using a modification of published methods a weak affinity for the GABA-B receptor site was demonstrated (IC50 = 1.8 X 10(-3) M). L-PA showed no anticonvulsive activity in several tests; in particular, it did not protect mice from seizures induced by inhibition of L-glutamate-1-decarboxylase (EC 4.1.1.15: GAD). L-PA had a very weak action on brain GABA levels of mice, and did not modify the rate of GABA synthesis. In conclusion, these results are not compatible with a strong in vivo interaction between L-PA and GABA-mediated inhibitory transmission.

Animals↗
PubMed2005

Recent advances in asymmetric synthesis of pipecolic acid and derivatives.

This review covers the literature relating to asymmetric syntheses of pipecolic acid derivatives from 1997 to present. This review is organized according to the position and the degree of substitution of the piperidinic cycle. In a first section, syntheses of pipecolic acid itself are described. Then, successively, syntheses of C-3, C-4, C-5, C-6 substituted pipecolic acid derivatives are reported. Finally, syntheses of unsaturated pipecolic acid derivatives are presented before the last part devoted to the polysubstituted pipecolic acid derivatives.

Amino Alcohols↗