Significance of the Natural Occurrence of L‐ Versus D‐Pipecolic Acid: A Review

Vranová, Valerie; Lojková, Lea; Rejšek, Klement; Formánek, Pavel

doi:10.1002/chir.22237

Cited by 43 publications

(35 citation statements)

References 119 publications

(317 reference statements)

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“…Because d ‐pipecolate decreased cell viability, the mechanism appears to be independent of pipecolate oxidase activity, which is specific for l ‐pipecolate [Matsumoto et al, ]. Different roles for d ‐ and l ‐pipecolate have also been found in other biological contexts such as l ‐pipecolate acting as an anti‐hypertensive by competitively inhibiting the angiotensin I‐converting enzyme, whereas, the d ‐enantiomer does not have an antihypertensive function [Vranova et al, ]. Future studies will investigate the protective role of pipecolate metabolism and downstream pathways involving mTORC2, Akt and FoxO3 using other cell types to broaden our understanding of how pipecolate impacts the cellular redox environment.…”

Section: Discussionmentioning

confidence: 99%

Evidence for Pipecolate Oxidase in Mediating Protection Against Hydrogen Peroxide Stress

Natarajan

Muthukrishnan

Khalimonchuk

et al. 2016

J of Cellular Biochemistry

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Pipecolate, an intermediate of the lysine catabolic pathway, is oxidized to Δ1-piperideine-6-carboxylate (P6C) by the flavoenzyme L-pipecolate oxidase (PIPOX). P6C spontaneously hydrolyzes to generate α-aminoadipate semialdehyde, which is then converted into α-aminoadipate acid by α-aminoadipatesemialdehyde dehydrogenase. L-pipecolate was previously reported to protect mammalian cells against oxidative stress. Here, we examined whether PIPOX is involved in the mechanism of pipecolate stress protection. Knockdown of PIPOX by small interference RNA abolished pipecolate protection against hydrogen peroxide-induced cell death in HEK293 cells suggesting a critical role for PIPOX. Subcellular fractionation analysis showed that PIPOX is localized in the mitochondria of HEK293 cells consistent with its role in lysine catabolism. Signaling pathways potentially involved in pipecolate protection were explored by treating cells with small molecule inhibitors. Inhibition of both mTORC1 and mTORC2 kinase complexes or inhibition of Akt kinase alone blocked pipecolate protection suggesting the involvement of these signaling pathways. Phosphorylation of the Akt downstream target, forkhead transcription factor O 3 (FoxO3), was also significantly increased in cells treated with pipecolate, further implicating Akt in the protective mechanism and revealing FoxO3 inhibition as a potentially key step. The results presented here demonstrate that pipecolate metabolism can influence cell signaling during oxidative stress to promote cell survival and suggest that the mechanism of pipecolate protection parallels that of proline, which is also metabolized in the mitochondria.

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Section: Discussionmentioning

confidence: 99%

Evidence for Pipecolate Oxidase in Mediating Protection Against Hydrogen Peroxide Stress

Natarajan

Muthukrishnan

Khalimonchuk

et al. 2016

J of Cellular Biochemistry

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“…Pipecolic acid (PA) is a diagnostic marker of pyridoxinedependent epilepsy (Plecko et al, 2005), which is synthesized in brain and accumulated in physiological fluids of humans with peroxisomal disorders (Vranova et al, 2013). The activities of some antioxidant enzymes, such as catalase and glutathione peroxidase, were significantly decreased by PA (Dalazen et al, 2014).…”

Section: Potential Neurotoxicity Of Asmentioning

confidence: 99%

Neuroprotection or neurotoxicity? new insights into the effects of Acanthopanax senticosus harms on nervous system through cerebral metabolomics analysis

Zhang

Wang

et al. 2014

Journal of Ethnopharmacology

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“…Here we showed that F. oxysporum c8D produced trans-4-L-HyPip in the culture medium using the substrate of Pip4Hs, L-Pip. Now then, L-Pip is produced by microorganisms, plants, and animals and is therefore readily available for use by fungi (29). Alternatively, L-Pip might be synthesized by these fungi themselves.…”

Section: Figmentioning

confidence: 99%

Novel Enzyme Family Found in Filamentous Fungi Catalyzing trans -4-Hydroxylation of l -Pipecolic Acid

Hibi

Mori

Miyake

et al. 2016

Appl Environ Microbiol

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Hydroxypipecolic acids are bioactive compounds widely distributed in nature and are valuable building blocks for the organic synthesis of pharmaceuticals. We have found a novel hydroxylating enzyme with activity toward L-pipecolic acid (L-Pip) in a filamentous fungus, Fusarium oxysporum c8D. The enzyme L-Pip trans-4-hydroxylase (Pip4H) of F. oxysporum (FoPip4H) belongs to the Fe(II)/␣-ketoglutarate-dependent dioxygenase superfamily, catalyzes the regio-and stereoselective hydroxylation of L-Pip, and produces optically pure trans-4-hydroxy-L-pipecolic acid (trans-4-L-HyPip). Amino acid sequence analysis revealed several fungal enzymes homologous with FoPip4H, and five of these also had L-Pip trans-4-hydroxylation activity. In particular, the homologous Pip4H enzyme derived from Aspergillus nidulans FGSC A4 (AnPip4H) had a broader substrate specificity spectrum than other homologues and reacted with the L and D forms of various cyclic and aliphatic amino acids. Using FoPip4H as a biocatalyst, a system for the preparative-scale production of chiral trans-4-L-HyPip was successfully developed. Thus, we report a fungal family of L-Pip hydroxylases and the enzymatic preparation of trans-4-L-HyPip, a bioactive compound and a constituent of secondary metabolites with useful physiological activities.H ydroxypipecolic acids (HyPips) are naturally occurring sixmembered heterocyclic hydroxy amino acids that are widely distributed in nature. For instance, 4-hydroxy-, 5-hydroxy-, and 4,5-dihydroxypipecolic acids have been found in various members of the plant family (1-4). Likewise, 5-hydroxypipecolic acid was found to be present in mammalian brain and blood (5). HyPips are also components of some peptide antibiotics, terpenoids, and alkaloids, for example, Thus, the enzymatic hydroxylation of L-Pip was achieved as a side reaction of L-proline hydroxylase. To date, specific L-Piphydroxylating enzymes have not been reported, despite the fact that HyPips are important metabolites found in plants and mammals. In the present study, we identified and characterized L-Pip hydroxylases broadly conserved in some filamentous fungi. We found that the newly discovered L-Pip hydroxylases were particularly suitable biocatalysts for the asymmetric hydroxylation of cyclic amino acids, such as pipecolic acids and prolines. Moreover, the widespread distribution of genes encoding L-Pip hydroxylases indicates some important physiological roles of fungal secondary metabolites related to trans-4-L-HyPip. MATERIALS AND METHODSStrains and culture. Microorganisms isolated from soil and plant samples were cultured in GP medium comprised of 0.15% (wt/vol) KH 2 PO 4 , 0.05% (wt/vol) K 2 HPO 4 , 0.1% (wt/vol) NH 4 Cl, 0.03% (wt/vol) MgSO 4 ·7H 2 O, 0.01% (wt/vol) yeast extract, 0.025% (wt/vol) glucose, and 0.1% (wt/vol) L-Pip (pH 7.0) and grown at 28°C with shaking. Escherichia coli JM109 and Rosetta2(DE3) (Novagen, WI, USA) were used as host strains for the overexpression of the recombinant enzymes and cultured at 28°C in LB medium, comprised of 1% (wt/v...

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Significance of the Natural Occurrence of L‐ Versus D‐Pipecolic Acid: A Review

Cited by 43 publications

References 119 publications

Evidence for Pipecolate Oxidase in Mediating Protection Against Hydrogen Peroxide Stress

Evidence for Pipecolate Oxidase in Mediating Protection Against Hydrogen Peroxide Stress

Neuroprotection or neurotoxicity? new insights into the effects of Acanthopanax senticosus harms on nervous system through cerebral metabolomics analysis

Novel Enzyme Family Found in Filamentous Fungi Catalyzing trans -4-Hydroxylation of l -Pipecolic Acid

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