TY - JOUR
T1 - Identification of Δ-1-pyrroline-5-carboxylate derived biomarkers for hyperprolinemia type II
AU - Merx, Jona
AU - van Outersterp, Rianne E
AU - Engelke, Udo F H
AU - Hendriks, Veronique
AU - Wevers, Ron A
AU - Huigen, Marleen C D G
AU - Waterval, Huub W A H
AU - Körver-Keularts, Irene M L W
AU - Mecinović, Jasmin
AU - Rutjes, Floris P J T
AU - Oomens, Jos
AU - Coene, Karlien L M
AU - Martens, Jonathan
AU - Boltje, Thomas J
N1 - © 2022. The Author(s).
PY - 2022/9/21
Y1 - 2022/9/21
N2 - 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.
AB - 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.
KW - 1-Pyrroline-5-Carboxylate Dehydrogenase/deficiency
KW - Amino Acid Metabolism, Inborn Errors
KW - Biomarkers
KW - Phosphates
KW - Proline/metabolism
KW - Proline Oxidase/genetics
KW - Pyridoxal
KW - Pyrroles
U2 - 10.1038/s42003-022-03960-2
DO - 10.1038/s42003-022-03960-2
M3 - Article
C2 - 36131087
SN - 2399-3642
VL - 5
JO - Communications Biology
JF - Communications Biology
IS - 1
M1 - 997
ER -