{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nPhosphoserine phosphatase (PSPH) is the terminal, rate‐limiting enzyme in the L‑serine biosynthesis pathway, essential for producing serine and its derivatives such as glycine and d‑serine. Detailed structural studies—including high‐resolution crystal structures of PSPH in complexes with its substrate, product, inhibitors, and noncleavable analogues—have elucidated its catalytic mechanism. These analyses reveal that PSPH operates via an open‑to‑closed conformational change governed by a divalent metal–dependent active site normally coordinated by Mg²⁺, with Ca²⁺ able to inhibit activity by altering the coordination geometry. Such insights have advanced our understanding of how substrate binding and product release are modulated at the molecular level."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its canonical metabolic role, PSPH has emerged as a pivotal mediator in cancer progression. Upregulation of PSPH is linked to oncogenic metabolic reprogramming—such as cMyc‑driven activation of serine biosynthesis—and is observed in several malignancies including hepatocellular carcinoma, non‑small cell lung cancer, melanoma, and colorectal cancer. In these contexts, PSPH promotes tumor growth by facilitating cell cycle progression, enhancing invasion and metastasis, modulating signaling pathways (for example, via MAPK activation), and even exerting non‑canonical effects such as dephosphorylating target proteins (e.g. IRS‑1). Moreover, PSPH influences epigenetic modifications by indirectly regulating metabolites like 2‑hydroxyglutarate, thereby impacting oncogenic gene expression programs."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "10"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its roles in tumor metabolism, genetic alterations in PSPH have been implicated in severe serine‑deficiency disorders. Specifically, loss‑of‑function mutations—such as homozygous frameshift changes—highlight the enzyme’s critical function in normal developmental and neurological homeostasis, as exemplified by its involvement in the clinical spectrum of Neu‑Laxova syndrome."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Yves Peeraer, Anja Rabijns, Christel Verboven, et al. 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