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

Jona Merx, Rianne E van Outersterp, Udo F H Engelke, Veronique Hendriks, Ron A Wevers, Marleen C D G Huigen, Huub W A H Waterval, Irene M L W Körver-Keularts, Jasmin Mecinović, Floris P J T Rutjes, Jos Oomens, Karlien L M Coene, Jonathan Martens*, Thomas J Boltje*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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.

Original languageEnglish
Article number997
Number of pages8
JournalCommunications Biology
Volume5
Issue number1
DOIs
Publication statusPublished - 21 Sept 2022

Keywords

  • 1-Pyrroline-5-Carboxylate Dehydrogenase/deficiency
  • Amino Acid Metabolism, Inborn Errors
  • Biomarkers
  • Phosphates
  • Proline/metabolism
  • Proline Oxidase/genetics
  • Pyridoxal
  • Pyrroles

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