Human Pyrroline-5-carboxylate Reductase (PYCR1) Acts on Δ(1)-piperideine-6-carboxylate Generating L-pipecolic Acid

Overview

Journal J Inherit Metab Dis

Publisher Wiley

Date 2014 Jan 17

PMID 24431009

Citations 14

Authors

Eduard A Struys

Erwin E W Jansen

Gajja S Salomons

Affiliations

Soon will be listed here.

Abstract

We have conducted biochemical studies with commercial available pyrroline-5-carboxylate (P5C) reductase (PYCR1) to investigate whether this enzyme plays a role in L-lysine degradation. Our recent studies with antiquitin/ALDH7A1 deficient fibroblasts revealed an alternative genesis of L-pipecolic acid, and we then hypothesized that PYCR1 was responsible for the conversion of Δ(1)-piperideine-6-carboxylate (P6C) into pipecolic acid. We here present evidence that PYCR1 is indeed able to produce L-pipecolic acid from P6C preparations, and the observed K m for this conversion is of the same magnitude as the K m described for the conversion of P5C to L-proline by PYCR1. Urine samples from antiquitin deficient individuals, who accumulate P6C, were also incubated with PYCR1 which resulted in a marked decrease of P6C and a huge increase of L-pipecolic acid as measured by LC-MS/MS, confirming that indeed PYCR1 generates L-pipecolic acid from P6C.

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References

Struys E, Bok L, Emal D, Houterman S, Willemsen M, Jakobs C . The measurement of urinary Δ¹-piperideine-6-carboxylate, the alter ego of α-aminoadipic semialdehyde, in Antiquitin deficiency. J Inherit Metab Dis. 2012; 35(5):909-16. PMC: 3432202. DOI: 10.1007/s10545-011-9443-0. View

Struys E, Jakobs C . Metabolism of lysine in alpha-aminoadipic semialdehyde dehydrogenase-deficient fibroblasts: evidence for an alternative pathway of pipecolic acid formation. FEBS Lett. 2009; 584(1):181-6. DOI: 10.1016/j.febslet.2009.11.055. View

Struys E, Jakobs C . Alpha-aminoadipic semialdehyde is the biomarker for pyridoxine dependent epilepsy caused by alpha-aminoadipic semialdehyde dehydrogenase deficiency. Mol Genet Metab. 2007; 91(4):405. DOI: 10.1016/j.ymgme.2007.04.016. View

Linster C, Van Schaftingen E, Hanson A . Metabolite damage and its repair or pre-emption. Nat Chem Biol. 2013; 9(2):72-80. DOI: 10.1038/nchembio.1141. View

Struys E, Jakobs C . Enantiomeric analysis of D- and L-pipecolic acid in plasma using a chiral capillary gas chromatography column and mass fragmentography. J Inherit Metab Dis. 1999; 22(5):677-8. DOI: 10.1023/a:1005558903769. View

Mills P, Struys E, Jakobs C, Plecko B, Baxter P, Baumgartner M . Mutations in antiquitin in individuals with pyridoxine-dependent seizures. Nat Med. 2006; 12(3):307-9. DOI: 10.1038/nm1366. View

Navarova H, Bernsdorff F, Doring A, Zeier J . Pipecolic acid, an endogenous mediator of defense amplification and priming, is a critical regulator of inducible plant immunity. Plant Cell. 2012; 24(12):5123-41. PMC: 3556979. DOI: 10.1105/tpc.112.103564. View

Valle D, DOWNING S, Phang J . Proline inhibition of pyrroline-5-carboxylate reductase: differences in enzymes obtained from animal and tissue culture sources. Biochem Biophys Res Commun. 1973; 54(4):1418-24. DOI: 10.1016/0006-291x(73)91144-3. View

Martinelli D, Haberle J, Rubio V, Giunta C, Hausser I, Carrozzo R . Understanding pyrroline-5-carboxylate synthetase deficiency: clinical, molecular, functional, and expression studies, structure-based analysis, and novel therapy with arginine. J Inherit Metab Dis. 2011; 35(5):761-76. DOI: 10.1007/s10545-011-9411-8. View

10.

Fujii T, Mukaihara M, Agematu H, Tsunekawa H . Biotransformation of L-lysine to L-pipecolic acid catalyzed by L-lysine 6-aminotransferase and pyrroline-5-carboxylate reductase. Biosci Biotechnol Biochem. 2002; 66(3):622-7. DOI: 10.1271/bbb.66.622. View

11.

Guernsey D, Jiang H, Evans S, Ferguson M, Matsuoka M, Nightingale M . Mutation in pyrroline-5-carboxylate reductase 1 gene in families with cutis laxa type 2. Am J Hum Genet. 2009; 85(1):120-9. PMC: 2706970. DOI: 10.1016/j.ajhg.2009.06.008. View

12.

Wanders R, Romeyn G, Schutgens R, Tager J . L-pipecolate oxidase: a distinct peroxisomal enzyme in man. Biochem Biophys Res Commun. 1989; 164(1):550-5. DOI: 10.1016/0006-291x(89)91754-3. View