Disease relevance of pipecolic acids

• We present here genome wide linkage analysis of an atypical Refsum disease family where L-pipecolic acid level in blood was also increased, suggesting that the patients suffer from a new peroxisomal disorder intermediate between ARD and Infantile Refsum Disease (IRD, a peroxisomal deficiency disease) [1].
• Plasma levels of pipecolic acid in patients with chronic liver disease [2].
• We identified a periplasmic peptidyl-prolyl cis/trans-isomerase (PPIase) of the (FK506-binding protein (FKBP) type in Escherichia coli (FK506 represents a natural peptidomacrolide containing an acylated pipecolic acid residue) [3].
• 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 [4].
• An enzyme activating L-pipecolic acid has been isolated from Streptomyces hygroscopicus var. ascomyceticus, which produces immunomycin [5].

Psychiatry related information on pipecolic acids

• These results suggest that the critical period from pipecolic acid neurotoxic effect is prenatal, probably due to a selective vulnerability of developing neurons to high levels of pipecolic acid [6].

High impact information on pipecolic acids

• The presence of increased concentrations of serum pipecolic acid and the bile acid intermediate, trihydroxycoprostanic acid, in the neonatal ALD patient are associated with a generalized diminution of peroxisomal activities that was not observed in the patient with X-linked ALD [7].
• Although the level of the bile acid intermediate trihydroxycoprostanoic acid was slightly elevated in plasma, phytanic acid and L-pipecolic acid levels were normal, as was plasmalogen synthesis in cultured fibroblasts [8].
• The plasma pipecolic acid concentration in two newborn infants with Zellweger syndrome at ages 4 and 10 days were 7.8 and 7.7 microM [9].
• Surprisingly, L-pipecolic acid was elevated in plasma, and microscopy of the liver showed a reduced number of peroxisomes per cell and a larger average peroxisome size [10].
• Patients with non-pyridoxine-dependent epilepsy had normal pipecolic acid concentrations in plasma and significantly lower concentrations in CSF [11].

Chemical compound and disease context of pipecolic acids

• This osmotically inducible system allows the uptake of glycine betaine, proline, ectoine, and pipecolic acid and presents strong similarities in nucleotide sequence and protein function with the proline/betaine porter of Escherichia coli encoded by proP [12].
• 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 [13].
• Our data suggest that some patients with the infantile form of Refsum disease may show some clinical benefit from dietary management and this is reflected biochemically by decreases in the plasma levels of phytanic acid and pipecolic acid [14].
• 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 [15].
• 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) [13].

Biological context of pipecolic acids

• 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 [2].
• Biosynthesis of pipecolic acid by RapL, a lysine cyclodeaminase encoded in the rapamycin gene cluster [16].
• Experiments are described that measure DNA dissociation kinetics and thermal denaturation temperatures for a series of actinomycin analogs containing, in the 3' amino acid position, pipecolic acid, proline or azetidine-2-carboxylic acid [17].
• Previous work by ourselves and other groups exploring the structure-activity relationships (SAR) of small molecules that mimic only the FKBP binding domain portion of FK506 has focused on esters of proline and pipecolic acid [18].
• From the enzymatic characteristics, substrate specificity, and immunological properties, we propose that we have isolated the enzyme responsible for activating pipecolic acid for immunomycin biosynthesis [5].

Anatomical context of pipecolic acids

• Here, we report on 2 patients with pyridoxine-dependent epilepsy with significant elevation of pipecolic acid concentrations in plasma and cerebrospinal fluid (CSF) and further increase of pipecolic acid in CSF during a 72-hour pyridoxine withdrawal in 1 of them [11].
• In the rabbit, L-pipecolic acid oxidation was greatest in kidney cortex with progressively lesser specific activities in liver, heart, and brain [19].
• The metabolic role and fate of pipecolic acid in the human central nervous system are largely unknown [20].
• Lysine metabolism in the rat brain: blood-brain barrier transport, formation of pipecolic acid and human hyperpipecolatemia [21].
• Evidence is presented which suggests that proline, pipecolic acid, and glycine are accumulated by a common transport system in rat brain cortical synaptosomes and synaptosomal plasma membrane vesicles [22].

Associations of pipecolic acids with other chemical compounds

• Levels of both pipecolic acid and certain metabolites shown to be elevated in patients with PNPO mutations should be measured, and therapeutic trials of pyridoxal phosphate as well as pyridoxine should be considered early in the course of the management of infants and young children with intractable seizures [23].
• The results account for previously unattributed carbons in the two alkaloids and suggest the formation of an eight-carbon intermediate common to both alkaloids by acylation of malonate with pipecolic acid [24].
• The phytopathogen Rhizoctonia leguminicola has previously been shown to incorporate pipecolic acid into the piperidine alkaloids 1-acetoxy-6-aminooctahydroindolizine (slaframine) and 3,4,5-trihydroxyoctahydro-1-pyrindine [24].
• Most of these dipeptides containing a homoproline phosphonate residue (PipP) or a Pro phosphonate residue (ProP) at the P1 site are stable in a pH 7.8 buffer with half-lives of several hours to several days [25].
• L-Pipecolic acid oxidase, a human enzyme essential for the degradation of L-pipecolic acid, is most similar to the monomeric sarcosine oxidases [26].

Gene context of pipecolic acids

• These mutants lacked, respectively, the pipecolate oxidase that converts pipecolic acid into piperideine-6-carboxylic acid and the saccharopine reductase that catalyzes the transformation of piperideine-6-carboxylic acid into saccharopine [27].
• Lysine auxotrophs lys1, lys2 and lys3 of R. glutinis, unlike lysine auxotrophs of Saccharomyces cerevisiae, satisfied their growth requirement with L-pipecolate [28].
• Replacement of pyroglutamic acid by pyro-2-aminoadipic acid, 2-oxoimidazolidine-4-carboxylic acid or gamma-butyrolactone-gamma-carboxylic acid and that of proline by pipecolic acid, thiazolidine-4-carboxylic acid, or homoproline in [Leu2]- and [Nva2]TRH led to tripeptides structurally widely different from TRH [29].
• Synthesis and biological activity of selective pipecolic acid-based TNF-alpha converting enzyme (TACE) inhibitors [30].
• Increase in the rate of L-pipecolic acid production using lat-expressing Escherichia coli by lysP and yeiE amplification [31].

Analytical, diagnostic and therapeutic context of pipecolic acids

• The younger sibling has been treated with a protein-restricted diet, with lowering of the serum pipecolic acid concentration [32].
• High-performance liquid chromatography determination of pipecolic acid after precolumn ninhydrin derivatization using domestic microwave [33].
• Analysis of pipecolic acid in biological fluids using capillary gas chromatography with electron-capture detection and [2H11]pipecolic acid as internal standard [34].
• 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 [35].
• In an effort to develop an animal model of hyperpipecolatemia, the uptake of pipecolic acid (PA) in the brain and changes of PA levels in serum following administration of D,L-PA were studied in the mouse using a new sensitive HPLC-EC method [36].

References