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J. Biol. Chem., Vol. 276, Issue 18, 15107-15116, May 4, 2001

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Pyridoxal Phosphate De-activation by Pyrroline-5-carboxylic Acid
INCREASED RISK OF VITAMIN B₆ DEFICIENCY AND SEIZURES IN HYPERPROLINEMIA TYPE II^*

R. Duncan Farrant^§, Valerie Walker^¶, Graham A. Mills, John M. Mellor^**, and G. John Langley^**

From the  Physical Sciences, GlaxoWellcome Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, the ^¶ Department of Chemical Pathology, Southampton General Hospital, Tremona Road, Southampton, Hampshire SO16 6YD, the  School of Pharmacy and Biomedical Sciences, University of Portsmouth, White Swan Road, Portsmouth, Hampshire PO1 2DT, and the ^** Department of Chemistry, University of Southampton, Highfield, Southampton, Hampshire SO17 1BJ, United Kingdom

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-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.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EMBL Data Bank with accession number(s) .

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