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PubMed1985

Identification and characterization of pipecolic acid binding sites in mouse brain.

Pipecolic acid (PA, piperidine-2-carboxylic acid) is the major product of lysine metabolism in the mammalian brain (Giacobini et al., 1980). In this study we have characterized the binding of [3H]PA to P2 fraction membranes and its distribution in the mouse brain. The binding was found to be saturable (70 nM), temperature and Na+ and Cl- dependent. A high affinity binding site with an apparent KD of 33.2 nM and a Bmax of 0.2 pmol/mg protein was demonstrated. The regional distribution of [3H]PA specific binding in mouse brain showed the highest concentration in cerebral cortex, thalamus and olfactory bulb. Unlabeled PA (10(-3)-10(-11) M) displaced specific binding of [3H]PA in a concentration dependent manner. Out of several substances tested, only proline showed a similar pattern of displacement. Pre-incubation of the membrane preparation with GABA (10(-3)-10(-11) M) resulted in either an increase or decrease of [3H]PA binding depending on the concentrations of GABA and PA. These results suggest a modulatory action of GABA on PA binding sites. The postnatal development of [3H]PA specific binding was studied in the whole brain of the mouse. [3H]Pipecolic acid binding increased progressively (8-fold) from one day after birth to 16 days. Following this developmental peak, the binding decreased gradually to 30 days at which age, adult values were attained.

Aging↗
PubMed1983

Determination of pipecolic acid in rat brain areas by high-performance liquid chromatography of dansyl derivatives with fluorimetric detection.

A method for the determination of pipecolic acid in the rat brain is reported. The identification and quantification of pipecolic acid is accomplished with reverse-phase high-performance liquid chromatography including precolumn dansylation procedure by using nipecotic acid, a regio-isomer of pipecolic acid, as an internal standard. The lower limit of quantification for the method is in the picomole range. Higher concentration of pipecolic acid in the rat brain regions were found in cerebellum, medulla oblongata, hypothalamus, and midbrain than the other regions. The method establishes the usefulness of dansyl chloride for the simple and sensitive detection of pipecolic acid, and is easily adapted to routine analysis of pipecolic acid in the rat brain regions.

Animals↗
PubMed1982

Comparative rates of metabolism of pipecolic acid in several animal species.

1. The rate of metabolism of pipecolic acid, measured in liver and kidney, varied 1000 fold among 10 animal species. Degradation of L-pipecolic acid by kidney in rat and mouse was 0.11 and 0.31 pmoles/min/mg protein, respectively; in monkey and human. 3.0 and 6.5; in guinea-pig and rabbit 101 and 106. 2. Activity with D-pipecolic acid was consistently 50-60% higher than the L-isomer except in the rabbit. 3. Degradation of L-lysine presumably through the saccharopine-alpha-aminoadipic acid pathway, was effective in all species, contrasting with the variable performance in the pipecolic acid-alpha-aminoadipic acid pathway.

Animals↗
PubMed1986

Determination of pipecolic acid in urine and plasma by isotope dilution mass fragmentography.

A capillary gas chromatographic method with mass spectrometric detection for the determination of pipecolic acid in urine and plasma (or serum) has been developed. Using a quantification based on stable isotope dilution mass fragmentography the concentration of pipecolic acid was determined in urines of 34 healthy children and 8 patients with Zellweger's syndrome. The urinary pipecolic acid excretion of healthy infants decreases with age. Its concentration in urines of patients with Zellweger's syndrome was not consistently elevated. Normal values for pipecolic acid in plasma were established for 19 healthy children. Pipecolic acid concentrations in 47 urine samples (range 0.02-228.3 mmol/mol of creatinine) and 6 serum samples of Zellweger patients after oral loading with DL-pipecolic acid (range 65-1334 mumol/l) were found to correlate satisfactorily with the results obtained by an amino acid analyzer method. The major advantage of the presented method over the amino acid analyzer method concerns its greater sensitivity and its much shorter analysis time.

Abnormalities, Multiple↗
PubMed1983

Blood-brain barrier transport of L-pipecolic acid in various rat brain regions.

Blood-brain barrier transport of L-[1-14C]pipecolic acid was studied in the ray by single intracarotid injection using 3H2O as a diffusible internal standard. Brain uptake index (BUI) for L-[14C]pipecolic acid (0.036 mM) was found to be 18.1, 10.5, and 12.6 for the cerebral cortex, brain stem, and cerebellum, respectively which was substantially higher than that reported for its analog L-proline in the whole brain. Influx of L-pipecolic acid into the brain was concentration dependent and differed significantly between the cerebral cortex and the brain stem, and between the cerebral cortex and the cerebellum, but not between the brain stem and the cerebellum. Kinetic study of L-pipecolic acid influx revealed a low- and a high-capacity uptake mechanisms. The low-capacity saturable component has Km values ranging from 38 to 73 microM, and Vmax values ranging from 10 to 13 nmol/g/min for the three brain regions. The nonsaturable component has a Km of 4 mM, a Vmax of 200 nmol/g/min and similar diffusion constant (Kd) (0.03 to 0.06 mlg-1 min-1) for all three brain regions. A possible role of the two-component brain uptake mechanism in the regulation of the neuronal function of L-pipecolic acid was suggested.

Animals↗
PubMed2002

High-performance liquid chromatography determination of pipecolic acid after precolumn ninhydrin derivatization using domestic microwave.

A novel procedure to specifically quantify low amounts of pipecolic acid and structurally related compounds in several types of biological materials has been characterized. From crude extracts of various types of biological material, the first step was to clear all low-molecular-weight compounds containing primary amino groups by a treatment of nitrous acid. Using a microwave-assisted reaction, the remaining substances containing secondary amino groups were then derivatized with ninhydrin and made soluble in glacial acetic acid. The derivatives produced were resolved by reverse-phase HPLC and detected by spectrophotometry at 570nm. This procedure allowed more rapid determination of pipecolic acid since microwave heating shortened the time needed for derivatization compared with heating at 95 degrees C in a water bath. The complete analysis of the chromogens for pipecolic acid and related substances was achieved in 20min. Under such conditions, the detection threshold for pipecolic acid was about 20pmol. The suitability of the technique was assessed in various biological matrices known to contain significant amounts of this amino acid. The data obtained are in accordance with those available in the literature. To our knowledge, this is the first method using the ninhydrin reaction in a precolumn, microwave-assisted derivatization procedure for detection and determination of heterocyclic alpha-amino acids.

Brassica napus↗
PubMed1986

D-pipecolic acid inhibits ethanol tolerance in mice.

The effects of graded doses of D-pipecolic acid (0.005-5 micrograms/animals s.c.) on tolerance to the hypothermic effect of ethanol (4 g/kg i.p.) were investigated in mice. D-Pipecolic acid itself did not change the core temperature or the acute hypothermic response to a single dose of ethanol. Repeated D-pipecolic acid administration, however, blocked the development of tolerance to the hypothermic effect of ethanol. The development of tolerance could be observed in the control group. It is assumed that D-pipecolic acid is capable of counteracting the tolerance effect of ethanol.

Animals↗
PubMed1993

L-pipecolic acid oxidation in rat: subcellular localization and developmental study.

By using a sensitive radioactive assay method, we present here evidence that L-pipecolic acid oxidase is localized in both mitochondria and peroxisomes of rat liver. Brain white matter contained a more than 2-fold higher activity of L-pipecolic acid oxidation than the brain cortex. Suborganellar fractionation studies indicate that while the enzyme is a matrix protein in mitochondria, it is membrane-associated in peroxisomes. Both rotenone and antimycin A completely inhibited the enzyme activity in mitochondria but not in peroxisomes. The enzyme was shown to be inducible in mitochondria and peroxisomes of rat liver and brain tissues by glucagon and di-(2-ethylhexyl)phthalate, respectively. We report here for the first time the developmental aspects of L-pipecolic acid oxidation activity in rat liver and brain tissues. L-Pipecolic acid oxidase activity was detectable in whole rat embryo at 10 days of gestation, suggesting active L-pipecolic acid metabolism early during development. In both liver and brain tissues L-pipecolic acid oxidation activity was highest at 15 days of gestation and decreased with age in prenatal and postnatal conditions.

Aging↗
PubMed2005

Pipecolic acid as a diagnostic marker of pyridoxine-dependent epilepsy.

Pyridoxine-dependent epilepsy, although described some decades ago, may still be an underdiagnosed disorder. We have recently described isolated pipecolic acid elevations in the plasma and/or CSF of three patients with pyridoxine-dependent epilepsy with an intriguing inverse correlation to the oral intake of pyridoxine. We have now confirmed these findings in a further 6 unrelated patients with pyridoxine-dependent epilepsy. Pipecolic acid in plasma was 4.3- to 15.3 fold elevated compared to the upper normal range before pyridoxine and remained in the mildly elevated range while on pyridoxine. Pipecolic acid was even more markedly elevated in CSF. The extent of pipecolic acid elevation in CSF exceeded that of plasma by a factor of 2.2 to 4.8. This clearly discriminates pyridoxine-dependent epilepsy from other possible defects with elevated pipecolic acid. Determination of pipecolic acid in plasma and/or CSF should be included in the diagnostic work-up of patients with therapy-resistant seizures. It will in addition prevent patients with pyridoxine-dependent epilepsy from experiencing potentially dangerous pyridoxine-withdrawal, which until now has been necessary to prove the diagnosis.

Anticonvulsants↗
PubMed1980

Electrophoretic study of pipecolic acid, a biogenic imino acid, in the mammalian brain.

Pipecolic acid (PA), one of the imino acids, is a normal constituent in the mammalian brain. It is said that PA is a major intermediate of lysine metabolism in the rat brain. Biochemical studies have suggested that PA may be involved in the regulation of synaptic mechanism in the CNS. Moreover, the pathophysiological significance of PA has been also suggested by some investigators. However, there has so far been no good evidence based on the comprehensive electrophysiological experiments. Using unit recording and microelectrophoretic technique, the action of PA on single neuron activities in the rat brain was examined. PA depressed the firing of 88 out of 115 cortical neurons tested. Only 2 were excited and 25 remained unaffected. All the identified hippocampal pyramidal neurons examined were uniformly inhibited. It has been reported that PA inhibits the uptake of GABA into the brain slices and enhances the release of GABA from the slices. Thus, it is likely that the inhibitory response due to PA may have some connections with GABAergic transmission. On the other hand, it remains to be clarified whether the specific PA sensitive receptors exist in the brain. Our findings provide a clue to the elucidation of the presumed synaptic involvement of PA in the CNS.

Animals↗
PubMed1986

Pipecolic acid is oxidized by renal and hepatic peroxisomes. Implications for Zellweger's cerebro-hepato-renal syndrome (CHRS).

Increased levels of pipecolic acid have been reported in patients with cerebro-hepato-renal syndrome (CHRS) of Zellweger and the general deficiency of peroxisomal function has been implicated in its pathogenesis. We have therefore investigated the capacity of normal peroxisomes to metabolize pipecolic acid. Highly purified peroxisomes were obtained from rat liver and rat and beef kidney cortex by a recently developed method using metrizamide gradients and a vertical rotor. These preparations oxidized D,L-pipecolic acid as evidenced by the measurement of H2O2 production. Incubation with either the D- or L-isomer revealed that almost exclusively D-pipecolate is oxidized. The specific activities proved to be 20-50 times higher in renal than in hepatic peroxisomes. A commercially available crystalline suspension of D-amino acid oxidase from porcine kidney also oxidized the pipecolic acid with the following rates 54:36:1 respectively for D-:,D,L-:L-isomers. Incubation of vibratome sections of rat kidney and liver in a medium containing D-pipecolic acid and cerous ions, revealed electron-dense deposits over the matrix of peroxisomes confirming the localization also by fine structural cytochemistry. These observations demonstrate the capability of mammalian peroxisomes to oxidize pipecolic acid and suggest that the absence or deficiency of peroxisomal D-amino acid oxidase may be implicated in the pathogenesis of hyperpipecolatemia in Zellweger's CHRS.

Abnormalities, Multiple↗
PubMed1987

Localization of pipecolic acid metabolism in rat liver peroxisomes: probable explanation for hyperpipecolataemia in Zellweger syndrome.

The metabolism of [14C]pipecolic acid was studied in peroxisomal fractions of rat liver obtained by density gradient centrifugation in Percoll. The production rate of [14CO2] was used to measure the metabolic activity of the fractions towards [14C]carboxypipecolic acid as a substrate. It was shown that this activity was located in the peroxisomal fractions by comparison with the peroxisomal marker enzyme urate oxidase (EC 1.7.3.3). The process was markedly elevated by the addition of FAD. The apparent Km for DL-pipecolic acid was found to be 1.2 mmol L-1. Addition of ATP (1 mmol L-1) did not influence the decarboxylation rate of pipecolic acid. These results might explain the defective metabolism of pipecolic acid in patients with Zellweger syndrome who are lacking peroxisomes.

Animals↗
PubMed1986

Pipecolic acid antagonizes barbiturate-enhanced GABA binding to bovine brain membranes.

L-Pipecolic acid, a brain L-lysine metabolite, is found to inhibit GABA binding to bovine synaptic membranes strongly in the presence of hexobarbital (IC50 = 2 X 10(-10)M) or pentobarbital (IC50 = 2 X 10(-9)M), but only slightly (less than 10%) by itself. Longer dialysis increases this binding inhibition. Hill plots indicate heterogeneity of L-pipecolic acid displaceable GABA binding sites. L-Pipecolic acid may be an endogenous ligand acting as a neuromodulator on the GABA receptor ionophore complex, or it may act on its own membrane binding sites exerting an allosteric effect on the GABA receptor complex. This discovery may be useful for further defining pharmacological and biochemical differences between the GABA receptors in the brain.

Animals↗
PubMed1987

Stable isotope dilution analysis of pipecolic acid in cerebrospinal fluid, plasma, urine and amniotic fluid using electron capture negative ion mass fragmentography.

A sensitive and accurate stable isotope dilution assay was developed for the measurement of pipecolic acid in body fluids using electron capture negative ion mass fragmentography. The method utilizes [2H11]pipecolic acid as the internal standard. Sample preparation consisted of derivatization in aqueous solution (pH 11.5) of the amine moiety with methyl chloroformate to the N-methylcarbamate, followed by acidic ethyl acetate extraction (pH 2) and further derivatization of the carboxyl moiety to the pentafluorobenzyl ester. Normal values have been determined in cerebrospinal fluid (mean means = 0.041 mumol/l, range 0.010-0.120 mumol/l), in plasma of at term infants (age less than 1 wk, means = 5.73 mumol/l, range 3.75-10.8 mumol/l; age greater than 1 wk, means = 1.46 mumol/l, range 0.70-2.46 mumol/l), in urine of at term infants (age less than 6 mth, means = 32.5 mumol/g. creat., range 9.81-84.5 mumol/g. creat; age greater than 6 mth, means = 6.35 mumol/g. creat., range 0.15-13.6 mumol/g. creat.) and in amniotic fluid (means = 4.65 mumol/l, range 2.24-8.40 mumol/l). The utility of the method was demonstrated for the pipecolic acid quantification in these biofluids of patients with peroxisomal disorders. As affected fetuses with infantile Refsum's disease and Zellweger syndrome showed no significant elevation of pipecolic acid in their surrounding amniotic fluids, the measurement of pipecolic acid in amniotic fluid seemed not to be useful for prenatal diagnosis in these disorders.

Adult↗
PubMed2006

Enzymatic synthesis of L-pipecolic acid by Delta1-piperideine-2-carboxylate reductase from Pseudomonas putida.

L-Pipecolic acid is a chiral pharmaceutical intermediate. An enzymatic system for the synthesis of L-pipecolic acid from L-lysine by commercial L-lysine alpha-oxidase from Trichoderma viride and an extract of recombinant Escherichia coli cells coexpressing Delta1-piperideine-2-carboxylate reductase from Pseudomonas putida and glucose dehydrogenase from Bacillus subtilis is described. A laboratory-scale process provided 27 g/l of L-pipecolic acid in 99.7% e.e.

Bacillus subtilis↗