Pyridoxal phosphate de-activation by pyrroline-5-carboxylic acid: increased risk of vitamin B-6 deficiency and seizures in hyperprolinemia type II


Farrant, R. Duncan, Walker, Valerie, Mills, Graham A., Mellor, John M. and Langley, G. John (2001) Pyridoxal phosphate de-activation by pyrroline-5-carboxylic acid: increased risk of vitamin B-6 deficiency and seizures in hyperprolinemia type II. Journal of Biological Chemistry, 276, (18), 15107-15116. (doi:10.1074/jbc.M010860200).

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Original Publication URL: http://dx.doi.org/10.1074/jbc.M010860200

Description/Abstract

We previously identified vitamin B-6 deficiency in a child presenting with seizures whose primary diagnosis was the inherited disorder hyperprolinemia type II. This is an unrecognized association, which was not explained by diet or medication. We hypothesized that pyridoxal phosphate (vitamin B-6 coenzyme) was de-activated by L-Δ1-pyrroline-5-carboxylic acid, the major intermediate that accumulates endogenously in hyperprolinemia type II. The proposed interaction has now been investigated in vitro with high resolution H-1 nuclear magnetic resonance spectroscopy and mass spectrometry at a pH of 7.4 and temperature of 310 K. Three novel adducts were identified. These were the result of a Claisen condensation (or Knoevenagel type of reaction) of the activated C-4 carbon of the pyrroline ring with the aldehyde carbon of pyridoxal phosphate. The structures of the adducts were confirmed by a combination of high performance liquid chromatography, nuclear magnetic resonance, and mass spectrometry. This interaction has not been reported before. From preliminary observations, pyrroline-5-carboxylic acid also condenses with other aromatic and aliphatic aldehydes and ketones, and this may be a previously unsuspected generic addition reaction. Pyrroline-5 carboxylic acid is thus found to be a unique endogenous vitamin antagonist. Vitamin B-6 de-activation may contribute to seizures in hyperprolinemia type II, which are so far unexplained, but they may be preventable with long term vitamin B-6 supplementation.

Item Type: Article
ISSNs: 0021-9258 (print)
Related URLs:
Keywords: 5-carboxylate dehydrogenase, pyrroline 5-carboxylate, rat-liver, metabolism, identification, spectroscopy, purification, diffusion, plasma
Subjects: R Medicine > RC Internal medicine > RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry
Q Science > QD Chemistry
R Medicine > RJ Pediatrics > RJ101 Child Health. Child health services
Divisions: University Structure - Pre August 2011 > School of Chemistry
University Structure - Pre August 2011 > School of Medicine > Human Genetics
ePrint ID: 19474
Date Deposited: 15 Feb 2006
Last Modified: 27 Mar 2014 18:09
URI: http://eprints.soton.ac.uk/id/eprint/19474

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