Identification of Δ-1-pyrroline-5-carboxylate derived biomarkers for hyperprolinemia type II

  • Commun Biol. 2022 Sep 21;5(1):997. doi: 10.1038/s42003-022-03960-2.
Jona Merx  #  1 ,  Rianne E van Outersterp  #  2 ,  Udo F H Engelke  #  3 ,  Veronique Hendriks  1 ,  Ron A Wevers  3  4 ,  Marleen C D G Huigen  3  4 ,  Huub W A H Waterval  5 ,  Irene M L W Körver-Keularts  4  5 ,  Jasmin Mecinović  6 ,  Floris P J T Rutjes  1 ,  Jos Oomens  2 ,  Karlien L M Coene  3  4  7 ,  Jonathan Martens  8 ,  Thomas J Boltje  9
Affiliations
  • 1. Radboud University, Institute for Molecules and Materials, Synthetic Organic Chemistry, Heyendaalseweg 135, 6525 AJ, Nijmegen, The Netherlands.
  • 2. Radboud University, Institute for Molecules and Materials, FELIX Laboratory, Toernooiveld 7, 6525 ED, Nijmegen, the Netherlands.
  • 3. Department of Laboratory Medicine, Translational Metabolic Laboratory, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525 GA, Nijmegen, the Netherlands.
  • 4. United for Metabolic Disease, UMD, Amsterdam, The Netherlands.
  • 5. Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands.
  • 6. Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Campusvej 55, 5230, Odense, Denmark.
  • 7. Department of Clinical Chemistry and Hematology, Elisabeth-TweeSteden Hospital, Tilburg, The Netherlands.
  • 8. Radboud University, Institute for Molecules and Materials, FELIX Laboratory, Toernooiveld 7, 6525 ED, Nijmegen, the Netherlands. [email protected].
  • 9. Radboud University, Institute for Molecules and Materials, Synthetic Organic Chemistry, Heyendaalseweg 135, 6525 AJ, Nijmegen, The Netherlands. [email protected].
  • # Contributed equally.
PMID: 36131087 DOI: 10.1038/s42003-022-03960-2
Abstract

Hyperprolinemia type II (HPII) is an inborn error of metabolism due to genetic variants in ALDH4A1, leading to a deficiency in Δ-1-pyrroline-5-carboxylate (P5C) dehydrogenase. This leads to an accumulation of toxic levels of P5C, an intermediate in proline catabolism. The accumulating P5C spontaneously reacts with, and inactivates, pyridoxal 5'-phosphate, a crucial cofactor for many enzymatic processes, which is thought to be the pathophysiological mechanism for HPII. Here, we describe the use of a combination of LC-QTOF untargeted metabolomics, NMR spectroscopy and infrared ion spectroscopy (IRIS) to identify and characterize biomarkers for HPII that result of the spontaneous reaction of P5C with malonic acid and acetoacetic acid. We show that these biomarkers can differentiate between HPI, caused by a deficiency of proline oxidase activity, and HPII. The elucidation of their molecular structures yields insights into the disease pathophysiology of HPII.

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