Communications Biology ( IF 5.2 ) Pub Date : 2022-09-21 , 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 2 , Thomas J Boltje 1
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.
中文翻译:
鉴定 Δ-1-pyrroline-5-carboxylate 衍生的高脯氨酸血症 II 型生物标志物
高脯氨酸血症 II 型 (HPII) 是由于ALDH4A1基因变异导致的先天性代谢错误,导致 Δ-1-pyrroline-5-carboxylate (P5C) 脱氢酶缺乏。这导致 P5C(脯氨酸分解代谢的中间体)毒性水平的积累。积累的 P5C 自发地与 5'-磷酸吡哆醛反应并使其失活,吡哆醛 5'-磷酸是许多酶促过程的关键辅助因子,这被认为是 HPII 的病理生理机制。在这里,我们描述了使用 LC-QTOF 非靶向代谢组学、NMR 光谱和红外离子光谱 (IRIS) 的组合来识别和表征 HPII 的生物标志物,这些标志物是 P5C 与丙二酸和乙酰乙酸的自发反应的结果。我们表明,这些生物标志物可以区分由脯氨酸氧化酶活性不足引起的 HPI 和 HPII。