Pyridoxal phosphate de-activation by pyrroline-5-carboxylic acid: increased risk of vitamin B6 deficiency and seizures in hyperprolinemia type II
Pyridoxal phosphate de-activation by pyrroline-5-carboxylic acid: increased risk of vitamin B6 deficiency and seizures in hyperprolinemia type II
We previously identified vitamin B6 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 B6 coenzyme) was de-activated by L-Delta(1)-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 1H 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 B6 de-activation may contribute to seizures in hyperprolinemia type II, which are so far unexplained, but they may be preventable with long term vitamin B6 supplementation.
5-carboxylate dehydrogenase, pyrroline 5-carboxylate, rat-liver, metabolism, identification, spectroscopy, purification, diffusion, plasma
15107-15116
Farrant, R.D.
f6c40b78-5159-4fc6-ac57-fce52e219608
Walker, V.
60118e30-565e-42c4-8d7d-ab1c39c1436c
Mills, G.A.
841f321a-5d31-4381-b87a-418614d03d4a
Mellor, J.M.
748aff30-b9fb-420a-8c4b-8b95beb6ecd0
Langley, G.J.
7ac80d61-b91d-4261-ad17-255f94ea21ea
2001
Farrant, R.D.
f6c40b78-5159-4fc6-ac57-fce52e219608
Walker, V.
60118e30-565e-42c4-8d7d-ab1c39c1436c
Mills, G.A.
841f321a-5d31-4381-b87a-418614d03d4a
Mellor, J.M.
748aff30-b9fb-420a-8c4b-8b95beb6ecd0
Langley, G.J.
7ac80d61-b91d-4261-ad17-255f94ea21ea
Farrant, R.D., Walker, V., Mills, G.A., Mellor, J.M. and Langley, G.J.
(2001)
Pyridoxal phosphate de-activation by pyrroline-5-carboxylic acid: increased risk of vitamin B6 deficiency and seizures in hyperprolinemia type II.
The Journal of Biological Chemistry, 276 (18), .
(doi:10.1074/jbc.M010860200).
Abstract
We previously identified vitamin B6 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 B6 coenzyme) was de-activated by L-Delta(1)-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 1H 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 B6 de-activation may contribute to seizures in hyperprolinemia type II, which are so far unexplained, but they may be preventable with long term vitamin B6 supplementation.
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Published date: 2001
Keywords:
5-carboxylate dehydrogenase, pyrroline 5-carboxylate, rat-liver, metabolism, identification, spectroscopy, purification, diffusion, plasma
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Local EPrints ID: 19474
URI: http://eprints.soton.ac.uk/id/eprint/19474
ISSN: 0021-9258
PURE UUID: 27ef4b5e-685f-4bef-9cd4-8479d6cb4ab9
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Date deposited: 15 Feb 2006
Last modified: 16 Mar 2024 02:41
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Author:
R.D. Farrant
Author:
V. Walker
Author:
G.A. Mills
Author:
J.M. Mellor
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