Isozymes of P5C reductase (PYCR) in human diseases: focus on cancer

Hu, Chien‐An Andy

doi:10.1007/s00726-021-03048-x

Cited by 7 publications

(5 citation statements)

References 43 publications

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“…Furthermore, PYCR3 is cytosolic and prefers NADPH whereas PYCR1/2 prefer NADH and are located in mitochondria matrix. The central role of the PYCRs is emphasized by recent reviews (Li et al 2021 ; Hu 2021 ; Bogner et al 2021 ).…”

Section: Proline Metabolism and Cancermentioning

confidence: 99%

Perspectives, past, present and future: the proline cycle/proline-collagen regulatory axis

Phang

2021

Amino Acids

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In the 35 years since the introduction of the “proline cycle”, its relevance to human tumors has been widely established. These connections are based on a variety of mechanisms discovered by many laboratories and have stimulated the search for small molecule inhibitors to treat cancer or metastases. In addition, the multi-layered connections of the proline cycle and the role of proline and hydroxyproline in collagen provide an important regulatory link between the extracellular matrix and metabolism.

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Section: Proline Metabolism and Cancermentioning

confidence: 99%

Perspectives, past, present and future: the proline cycle/proline-collagen regulatory axis

Phang

2021

Amino Acids

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“…Three PYCR isoforms have been identified in the human body, which are products of three homologous genes: PYCR1 (17q25.3), PYCR2 (1q42.13), and PYCRL (8q24.3.7) [ 30 ]. PYCR1 and PYCR2 show 84% structural homology and are located in the mitochondrial intermembrane space and mitochondrial matrix, respectively [ 57 ]. They are mainly involved in the conversion of P5C to proline, in the glutamine-P5C-proline pathway.…”

Section: Enzymes Of the P5c Metabolismmentioning

confidence: 99%

P5C as an Interface of Proline Interconvertible Amino Acids and Its Role in Regulation of Cell Survival and Apoptosis

Chalecka

Kazberuk

Pałka

et al. 2021

IJMS

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Studies of cancer metabolism have focused on the production of energy and the interconversion of carbons between cell cycles. More recently, amino acid metabolism, especially non-essential amino acids (NEAAs), has been investigated, underlining their regulatory role. One of the important mediators in energy production and interconversion of carbons in the cell is Δ1-pyrroline-5-carboxylate (P5C)—the physiological intracellular intermediate of the interconversion of proline, ornithine, and glutamate. As a central component of these conversions, it links the tricarboxylic acid cycle (TCA), urea cycle (UC), and proline cycle (PC). P5C has a cyclic structure containing a tertiary nitrogen atom (N) and is in tautomeric equilibrium with the open-chain form of L-glutamate-γ-semialdehyde (GSAL). P5C is produced by P5C synthase (P5CS) from glutamate, and ornithine via ornithine δ-amino acid transferase (δOAT). It can also be converted to glutamate by P5C dehydrogenase (P5CDH). P5C is both a direct precursor of proline and a product of its degradation. The conversion of P5C to proline is catalyzed by P5C reductase (PYCR), while proline to P5C by proline dehydrogenase/oxidase (PRODH/POX). P5C-proline-P5C interconversion forms a functional redox couple. Their transformations are accompanied by the transfer of a reducing-oxidizing potential, that affect the NADP+/NADPH ratio and a wide variety of processes, e.g., the synthesis of phosphoribosyl pyrophosphate (PRPP), and purine ribonucleotides, which are crucial for DNA synthesis. This review focuses on the metabolism of P5C in the cell as an interconversion mediator of proline, glutamate, and ornithine and its role in the regulation of survival and death with particular emphasis on the metabolic context.

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“…Evidence for the involvement of PYCR1 in cancer mechanisms is growing rapidly. Several studies have implicated PYCR1 in cancer across various cancer types, including colorectal cancer, − multiple myeloma, kidney cancer, , liver cancer, prostate cancer, − lung cancer, − breast cancer, − and others. ,− Many studies have shown that high PYCR1 expression is associated with tumor aggressiveness and poor patient outcomes. ,− ,,,− Furthermore, the knockdown of the PYCR1 gene or the inhibition of PYCR1 enzyme has been shown to inhibit tumorigenesis in multiple cancer cell lines and in vivo animal models. ,,,− ,,,,,,− Mechanistically, PYCR1 supports cell survival and maintenance in the hypoxic environment of tumor cells when oxygen is not a readily available electron acceptor for NADH. PYCR1 generates NAD + for the TCA cycle in the absence of the electron transport chain, generating proline as a byproduct .…”

Section: Introductionmentioning

confidence: 99%

Novel Fragment Inhibitors of PYCR1 from Docking-Guided X-ray Crystallography

Meeks,

Ji,

Protopopov

et al. 2024

J. Chem. Inf. Model.

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The proline biosynthetic enzyme Δ 1 -pyrroline-5-carboxylate (P5C) reductase 1 (PYCR1) is one of the most consistently upregulated enzymes across multiple cancer types and central to the metabolic rewiring of cancer cells. Herein, we describe a fragment-based, structure-first approach to the discovery of PYCR1 inhibitors. Thirty-seven fragment-like carboxylic acids in the molecular weight range of 143−289 Da were selected from docking and then screened using X-ray crystallography as the primary assay. Strong electron density was observed for eight compounds, corresponding to a crystallographic hit rate of 22%. The fragments are novel compared to existing proline analog inhibitors in that they block both the P5C substrate pocket and the NAD(P)H binding site. Four hits showed inhibition of PYCR1 in kinetic assays, and one has lower apparent IC 50 than the current best proline analog inhibitor. These results show proof-of-concept for our inhibitor discovery approach and provide a basis for fragment-to-lead optimization.

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Isozymes of P5C reductase (PYCR) in human diseases: focus on cancer

Cited by 7 publications

References 43 publications

Perspectives, past, present and future: the proline cycle/proline-collagen regulatory axis

Perspectives, past, present and future: the proline cycle/proline-collagen regulatory axis

P5C as an Interface of Proline Interconvertible Amino Acids and Its Role in Regulation of Cell Survival and Apoptosis

Novel Fragment Inhibitors of PYCR1 from Docking-Guided X-ray Crystallography

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