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PubMed1994

Clinical and biochemical characteristics of peroxisomal disorders: an update.

Peroxisomal disorders represent a recently recognized group of inherited diseases in man, now comprising 14 different disorders. If discussion is restricted to those peroxisomal disorders in which there is neurological involvement (thereby excluding hyperoxaluria and acatalasaemia), results over the least few years have shown that analysis of very-long-chain fatty acids (VLCFAs) is a highly reliable initial test to establish whether or not one is dealing with a peroxisomal disorder. Rhizomelic chondrodysplasia punctata, its recently identified variant form and glutaryl-CoA oxidase deficiency will show no abnormalities and must be identified by other means. Recently we have found a few clinically proven cases of adrenoleukodystrophy showing normal VLCFA in plasma but clearly abnormal values in fibroblasts. This suggests that great care is warranted in interpreting plasma VLCFA analyses. Furthermore, plasma bile acids, phytanic acid, pristanic acid and pipecolic acid should be analysed in any patient with clinical symptoms suggestive for a peroxisomal disorder but normal plasma VLCFAs.

Adrenoleukodystrophy↗
PubMed2002

Application of a new chiral derivatizing agent to the enantioseparation of secondary amino acids.

A new chiral derivatizing agent, (S)-N-(4-nitrophenoxycarbonyl)phenylalanine methoxyethyl ester, (S)-NIFE, was applied for the high-performance liquid chromatographic separation of enantiomers of 19 unnatural secondary amino acids: proline, pipecolic acid analogues, piperazine-2-carboxylic acid, morpholine-3-carboxylic acid, thiomorpholine-3-carboxylic acid and analogues containing the 1,2,3,4-tetrahydroisoquinoline, 1,2,3,4-tetrahydronorharmane, 1,2,3,4-tetrahydro-2-carboline and 2-benzazepine skeletons. Excellent resolutions were achieved for most of the investigated compounds by using a reversed-phase mobile phase system. The conditions of separation were optimized by variation of the mobile phase composition.

Amino Acids↗
PubMed1986

Pseudo-Zellweger syndrome: deficiencies in several peroxisomal oxidative activities.

We describe an infant girl with a clinical, chemical, and pathologic syndrome remarkably similar to Zellweger cerebrohepatorenal syndrome but whose liver parenchymal cells contained abundant peroxisomes. Peroxisomal L-alpha hydroxy acid oxidase, catalase, and the plasmalogen synthesizing enzyme dihydroxy acetone phosphate-acyl transferase activities were normal; other peroxisomal enzymatic activities, including fatty acyl-CoA oxidase and D-amino acid oxidase, were reduced by 80% to 85%. Oxidation of bile acids and pipecolic acid was also deficient. Autopsy revealed the presence of neuronal heterotopia, renal cortical cysts, adrenal atrophy, and accumulation of very long chain fatty acids. The clinical and pathologic features of this case of "pseudo-Zellweger syndrome" reflect a deficiency in multiple peroxisomal activities rather than a defect in peroxisomal biogenesis. The deficient enzymatic activities require flavin adenine dinucleotide, and the underlying defect may be in the utilization of this cofactor.

Acyl-CoA Oxidase↗
PubMed2005

Molecular cloning of the mouse IMINO system: an Na+- and Cl--dependent proline transporter.

Neurotransmitter transporters of the SLC6 family play an important role in the removal of neurotransmitters in brain tissue and in amino acid transport in epithelial cells. Here we demonstrate that the mouse homologue of slc6a20 has all properties of the long-sought IMINO system. The mouse has two homologues corresponding to the single human SLC6A20 gene: these have been named XT3 and XT3s1. Expression of mouse XT3s1, but not XT3, in Xenopus laevis oocytes induced an electrogenic Na+-and-Cl--dependent transporter for proline, hydroxyproline, betaine, N-methylaminoisobutyric acid and pipecolic acid. Expression of XT3s1 was found in brain, kidney, small intestine, thymus, spleen and lung, whereas XT3 prevailed in kidney and lung. Accordingly we suggest that the two homologues be termed 'XT3s1 IMINO(B)' and 'XT3 IMINO(K)' to indicate the tissue expression of the two genes.

Amino Acid Transport Systems, Neutral↗
PubMed1995

Synthesis of dipeptide 4-nitroanilides containing non-proteinogenic amino acids.

A series of tert-butyloxycarbonyl amino acid 4-nitroanilides, including N-alkylated amino acids and (R)-thiazolidine-4-carboxylic acid, (S)-oxazolidine-4-carboxylic acid. (4S,5S)-5-methyloxazolidine-4-carboxylic acid, (4S,5R)-5-methyloxazolidine-4-carboxylic acid, (S)-azetidine-2-carboxylic acid, (S)-pipecolic acid and (S)-3,4-dehydroproline, were prepared conveniently by the isocyanate method or the mixed anhydride procedure. The resulting amino acid 4-nitroanilides were extended to corresponding dipeptide 4-nitroanilides with tert-butyloxycarbonyl-(S)-alanine. In the case of sterically hindered amino acid 4-nitroanilides the mixed anhydride procedure with diphenylphosphinyl chloride was successful.

Amino Acids↗
PubMed2001

Cyclic hydroxamic-acid-containing peptide 31, a potent synthetic histone deacetylase inhibitor with antitumor activity.

Cyclic hydroxamic-acid-containing peptide 1 (CHAP1), designed as a hybrid of trichostatin A and trapoxin, is a lead compound for the development of potent inhibitors of histone deacetylase (HDAC). In this study, we synthesized a series of CHAP derivatives and evaluated their biological activities by monitoring the potency of their inhibition of HDAC activity, their ability to augment the expression of MHC class-I molecules in B16/BL6 cells, and their effect on cell proliferation. A structure-activity relationship study using these three assay systems revealed several requirements of their structure for the strong inhibition of HDAC not only in the cell-free situation, but also in cells. When the structures of CHAP derivatives are represented as cyclo(-Asu(NHOH)-AA(2)-AA(3)-Pro or Pip-)(n), where Asu(NHOH) and Pip are zeta-hydroxamide-alpha-aminosuberic acid and pipecolic acid, respectively, (a) the tetrapeptide structure (n = 1) was better than the octapeptide one (n = 2); (b) AA(2) and AA(3) should be hydrophobic; and (c) the combination of amino acid chirality should be LDLD for the strongest inhibition of HDAC in cells (LDLD > LLLD, LDLL > LLDL). cyclo(-L-Asu(NHOH)-D-Tyr(Me)-L-Ile-D-Pro-) or CHAP31 was selected as one of the strongest CHAPs, and its biological activity was characterized further. CHAP31 was much more stable in the presence of cultured cells (t(1/2) > 3000 h) than trichostatin A (t(1/2) = 14.7 h) or trapoxin A (t(1/2) = 2.10 h). CHAP31 exhibited antitumor activity in C57BL x DBA/2 F(1) (BD2F(1)) mice bearing B16/BL6 tumor cells. Furthermore, CHAP31 inhibited the growth in four of five human tumor lines implanted into nude mice. These results suggest CHAP31 to be promising as a novel therapeutic agent for cancer treatment.

Animals↗
PubMed1975

Effects of crude oil on the feeding behaviour of the zoanthid Palythoa variabilis.

Palythoa variabilis (Duerden 1898) has a well-coordinated, sterotyped feeding response similar to that described for other zoanthids. The feeding reaction can be elicited by the heterocyclic amino acid proline and by some of its analogs. The addition of an OH group (hydroxyproline) or of a glycyl group (prolylglycine) annuls the activity of the proline molecule. Substitutions (thiazolidine-4-carboxylic acid) or additions (glycylproline) to the amino group do not alter the effectivity of the activator. The size of the ring can be altered within certain limits (azetidine-2-carbocylic acid and pipecolic acid) without affecting the activity of the molecule. Feeding reactions culminating with ingestion can be elicited by Marine Diesel and Bunker-C oils. Exposure to oil affects the ability of polyps to discriminate between inert and chemically active particles for 3 to 5 days; responses to proline are not altered for at least 3 days following the exposure, but become slower and are present in fewer polyps after that period. Oil is retained in the coelenteron for several days following exposure and is periodically released in the form of timy droplets.

Amino Acids↗
PubMed1988

A new peroxisomal disorder with enlarged peroxisomes and a specific deficiency of acyl-CoA oxidase (pseudo-neonatal adrenoleukodystrophy).

In the present paper two siblings are presented with clinical manifestations very similar to those of patients affected by neonatal adrenoleukodystrophy. In contrast to neonatal adrenoleukodystrophy patients, hepatic peroxisomes in these siblings were enlarged in size and not decreased in number. Accumulation of very-long-chain fatty acids (VLCFA) was associated with an isolated deficiency of the fatty acyl-CoA oxidase, the enzyme that catalyzes the first step of the peroxisomal beta-oxidation. Plasma levels of di- and trihydroxy-coprostanoic acid, phytanic acid, and pipecolic acid were normal; furthermore, acyl-CoA:dihydroxyacetone phosphate acyltransferase activity in cultured fibroblasts was also found to be normal. The clinical, biochemical, and cytochemical features found in these two siblings are compared with those seen in two other disorders characterized by the absence of a decreased number of hepatic peroxisomes and the presence of VLCFA: (1) pseudo-Zellweger syndrome (deficiency of peroxisomal thiolase activity) and (2) X-linked childhood adrenoleukodystrophy (deficiency of activation of lignoceric acid). Review of the different biochemical defects possible in very-long-chain fatty-acid oxidation reveals different clinical pictures of varying severity, depending on the level at which the biochemical defect occurs.

Acetyl-CoA C-Acetyltransferase↗
PubMed1995

Zellweger syndrome: first reported case in Thailand and literature review.

We describe an infant boy with facial dysmorphism, profound hypotonia, psychomotor retardation, seizure and hepatomegaly. Biochemical study revealed elevation of very long chain fatty acids and pipecolic acid, consistent with peroxisomal disorder. He died at the age of 4 months. Electron microscopic study demonstrated decreased amounts of peroxisomes in liver and kidneys. The clinical characteristic, accompanied the biochemical and microscopic findings led to the diagnosis of Zellweger syndrome. The recognition of this syndrome is important since it is a fatal disease. The pattern of inheritance is autosomal recessive, hence genetic counseling is necessary. We emphasize that peroxisomal disorder should be included in the differential diagnosis in patients with infantile hypotonia. This patient is the first reported case of Zellweger syndrome in Thailand.

Fatal Outcome↗
PubMed2002

Synthesis and biological activity of selective pipecolic acid-based TNF-alpha converting enzyme (TACE) inhibitors.

A series of novel, selective TNF-alpha converting enzyme inhibitors based on 4-hydroxy and 5-hydroxy pipecolate hydroxamic acid scaffolds is described. The potency and selectivity of TACE inhibition is dramatically influenced by the nature of the sulfonamide group which interacts with the S1' site of the enzyme. Substituted 4-benzyloxybenzenesulfonamides exhibit excellent TACE potency with >100x selectivity over inhibition of matrix metalloprotease-1 (MMP-1). Alkyl substituents on the ortho position of the benzyl ether moiety give the most potent inhibition of TNF-alpha release in LPS-treated human whole blood.

ADAM Proteins↗
PubMed1994

Acute toxicity of bupivacaine metabolites in mice.

1. This study was designed to document the acute toxicity of two metabolites of bupivacaine, desbutylbupivacaine (2,6, desbutylbupivacaine; PPX) and pipecolic acid in mice. All the compounds were administered by the intraperitoneal (i.p.) route. 2. The mean convulsant activity was 100% for controls, 30, 100, 100, 100 and 90% for 400, 200, 150, 125 and 112.5 mg/kg i.p. of PPX, respectively, and 0% for the animals receiving pipecolic acid. 3. The acute induced mortality was 60% for bupivacaine control group (50 mg/kg/i.p.), 60, 30 and 0% for 800, 400 and 200 mg/kg of pipecolic acid, respectively, and 100, 90, 60, 80 and 10% for 400, 200, 150, 125 and 112.5 mg/kg i.p. of PPX, respectively. 4. The time to convulse was 158 +/- 16 s for bupivacaine, 230 +/- 30, 270 +/- 24, 255 +/- 21, 442 +/- 84 and 418 +/- 32 s for 200, 150, 125, 112.5 and 100 mg/kg i.p. of PPX, respectively; any pipecolic acid treated animal have convulsed. 5. In conclusion, the present study demonstrated that PPX is more toxic than expected since we found that its induced mortality was approximately three times that found for bupivacaine and its CNS toxicity was about two times that of bupivacaine.

Animals↗
PubMed1982

Cerebro-hepato-renal syndrome of Zellweger: clinical symptoms and relevant laboratory findings in 16 patients.

The clinical features of 16 patients suffering from cerebro-hepato-renal syndrome are presented. Five of these children lived beyond 2 years. Four of them are still alive. The increase of pipecolic acid in serum and cerebrospinal fluid (CSF), the abnormality of the bile acids and the increased excretion of p-OH-phenyl lactate were a consistent finding. The concentration of pipecolic acid in urine was not always distinctly elevated. A loading test with DL-pipecolic acid was always abnormal.

Bile Acids and Salts↗
PubMed1984

Hyperpipecolic acidemia in neonatal adrenoleukodystrophy.

Serum pipecolic acid was measured in patients with neonatal adrenoleukodystrophy (NALD), sex-linked ALD, and the cerebrohepatorenal syndrome of Zellweger. Pipecolic acid was elevated, often markedly, in most of the patients with NALD but in none of those with X-linked ALD or adrenomyeloneuropathy, or in normal adults and children, or children with cirrhosis or other neurodegenerative disorders. The demonstration of elevated serum pipecolic acid in NALD adds to the previously recognized elevation of very-long-chain fatty acids (another Zellweger syndrome sign) and suggests that generalized peroxisomal dysfunction may be a characteristic of NALD as it appears to be of Zellweger syndrome, which diseases share some clinical characteristics. The nosologic significance of these findings is discussed.

Abnormalities, Multiple↗
PubMed1986

Fungitoxic effects of nonprotein imino acids on growth of saprophytic fungi isolated from the leaf surface of Calliandra haematocephala.

Four saprophytic and pathogenic fungi were isolated from the leaf surface of Calliandra haematocephala, a tropical legume known to contain large amounts of rare nonprotein imino acids in its leaves and seeds. The fungi Aspergillus niger, Aspergillus sp., Curvularia sp., and Penicillium sp. were cultured in the laboratory and tested for susceptibility to leaf extracts of the host plant and to proline, pipecolic acid, cis-5-hydroxypipecolic acid, and 2,4-trans-4,5-cis-4,5-dihydroxypipecolic acid. Fungal spore germination and germ tube growth were measured. Aspergillus sp. was inhibited by plant extracts and by pipecolic acid and cis-5-hydroxypipecolic acid. Curvularia sp. growth was stimulated by plant extracts and by pipecolic acid. The other two fungi were unaffected by any of the treatments. The data indicate that imino acids may play a role in the specific resistance of Calliandra spp. to Aspergillus sp.

Aspergillus↗
PubMed1996

Major hyperpipecolataemia in a normal adult.

We describe the fortuitous discovery of a 44-year-old man with a very high hyperpipecolataemia (250 mumol/L; normal < 2.5). This patient has none of the clinical features seen in peroxisomal diseases, he is a strictly normal intelligent adult. A stereochemical study of this pipecolic acid was performed using D-amino acid oxidase, and identified it as L-pipecolic acid. We suggest that isolated L-hyperpipecolataemia may be a benign trait.

Adult↗
PubMed1995

Uptake and metabolism of delta 1-piperidine-2-carboxylic acid by synaptosomes from rat cerebral cortex.

delta 1-Piperidine-2-carboxylic acid (P2C), an intermediate of the L-lysine metabolic pathway in the brain, was studied for its uptake and metabolism in the synaptosome of the rat cerebral cortex. The results of this study showed that the uptake of P2C into the synaptosome was NA+- and temperature-dependent with a two-tier transport kinetic (Km = 2.6 and 0.7 microM; Vmax = 1.6 and 0.73 pmol/min/mg). P2C uptake was only moderately inhibited (approximately 20%) by L-lysine and its metabolites, L-pipecolic acid and L-alpha-aminoadipic acid at up to 100 microM, and the putative amino acid neurotransmitters, gamma-aminobutyric acid, L-glutamic acid and L-aspartic acid (25-31%) at 5-500 microM. The synaptosomal preparation only has a very low activity for metabolizing P2C to its product L-pipecolic acid. The metabolic activity for P2C was mainly contained in the 27,000 x g supernatant S2 fraction. Since P2C is the precursor of the putative neuromodulator L-pipecolic acid, the understanding of its uptake and metabolic characteristics in the brain should be of significance.

Animals↗
PubMed1982

Hyperpipecolic acidemia. Occurrence in an infant with clinical findings of the cerebrohepatorenal (Zellweger) syndrome.

An infant with clinical presentation of the cerebrohepatorenal syndrome (CHRS) of Zellweger was found to have increased plasma and urinary concentrations of pipecolic acid. When given a loading dose of DL-pipecolic acid hydrochloride, she showed a reduced clearance rate for that acid. Piperidine, delta 6-piperidine-2-carboxylic acid, and alpha-aminoadipic acid were not detected in plasma or urine. Her response to a lysine load was comparable to that of controls. These data provide further evidence of the connection between hyperpipecolic acidemia and CHRS.

2-Aminoadipic Acid↗