PYCR3

Last update 08 May 2025

Basic Info

Synonyms

FLJ13852, P5C reductase 3, P5CR 3

+ [4]

Introduction

Oxidoreductase that catalyzes the last step in proline biosynthesis, which corresponds to the reduction of pyrroline-5-carboxylate (P5C) to L-proline using NAD(P)H (PubMed:23024808, PubMed:36414121). Proline is synthesized from either glutamate or ornithine; both are converted to P5C, and then to proline via pyrroline-5-carboxylate reductases (PYCRs) (PubMed:23024808). PYCR3 is exclusively linked to the biosynthesis of proline from ornithine (PubMed:23024808).

100 Clinical Results associated with PYCR3

100 Translational Medicine associated with PYCR3

0 Patents (Medical) associated with PYCR3

Literatures (Medical) associated with PYCR3

01 Jun 2024·The International Journal of Biochemistry & Cell Biology

PYCR3 modulates mtDNA copy number to drive proliferation and doxorubicin resistance in triple-negative breast cancer

Article

Author: Liu, Lei ; Zhuang, Feifei ; Huang, Shaoyan

Triple-negative breast cancer (TNBC) poses significant challenges in treatment due to its aggressive nature and limited therapeutic targets. Understanding the underlying molecular mechanisms driving TNBC progression and chemotherapy resistance is imperative for developing effective therapeutic strategies. Thus, in this study, we aimed to elucidate the role of pyrroline-5-carboxylate reductase 3 (PYCR3) in TNBC pathogenesis and therapeutic response. We observed that PYCR3 is significantly upregulated in TNBC specimens compared to normal breast tissues, correlating with a poorer prognosis in TNBC patients. Knockdown of PYCR3 not only suppresses TNBC cell proliferation but also reverses acquired resistance of TNBC cells to doxorubicin, a commonly used chemotherapeutic agent. Mechanistically, we identified the mitochondrial localization of PYCR3 in TNBC cells and demonstrated its impact on TNBC cell proliferation and sensitivity to doxorubicin through the regulation of mtDNA copy number and mitochondrial respiration. Importantly, Selective reduction of mtDNA copy number using the mtDNA replication inhibitor 2', 3'-dideoxycytidine effectively recapitulates the phenotypic effects observed in PYCR3 knockout, resulting in decreased TNBC cell proliferation and the reversal of doxorubicin resistance through apoptosis induction. Thus, our study underscores the clinical relevance of PYCR3 and highlight its potential as a therapeutic target in TNBC management. By elucidating the functional significance of PYCR3 in TNBC, our findings contribute to a deeper understanding of TNBC biology and provide a foundation for developing novel therapeutic strategies aimed at improving patient outcomes.

01 Mar 2024·Molecular Metabolism

Loss of mitochondrial pyruvate carrier 1 supports proline-dependent proliferation and collagen biosynthesis in ovarian cancer

Article

Author: Horlock, Anthony D ; Croxford, Zack ; Jones, Nicholas ; Farook, M Rufaik ; Cronin, James G ; Holt, Amy K ; Tse, Carmen ; Davies, D Mark ; Vincent, Emma E ; Stanton, Emma ; Morgan, Steffan ; Rees, April ; Thornton, Catherine A ; Sheldon, I Martin ; Jenkins, Benjamin J

The pyruvate transporter MPC1 (mitochondrial pyruvate carrier 1) acts as a tumour-suppressor, loss of which correlates with a pro-tumorigenic phenotype and poor survival in several tumour types. In high-grade serous ovarian cancers (HGSOC), patients display copy number loss of MPC1 in around 78% of cases and reduced MPC1 mRNA expression. To explore the metabolic effect of reduced expression, we demonstrate that depleting MPC1 in HGSOC cell lines drives expression of key proline biosynthetic genes; PYCR1, PYCR2 and PYCR3, and biosynthesis of proline. We show that altered proline metabolism underpins cancer cell proliferation, reactive oxygen species (ROS) production, and type I and type VI collagen formation in ovarian cancer cells. Furthermore, exploring The Cancer Genome Atlas, we discovered the PYCR3 isozyme to be highly expressed in a third of HGSOC patients, which was associated with more aggressive disease and diagnosis at a younger age. Taken together, our study highlights that targeting proline metabolism is a potential therapeutic avenue for the treatment of HGSOC.

01 Jan 2023·Archives of Biochemistry and Biophysics

Expression and kinetic characterization of PYCR3

Article

Author: Tanner, John J ; Meeks, Kaylen R

PYCRs are proline biosynthetic enzymes that catalyze the NAD(P)H-dependent reduction of Δ¹-pyrroline-5-carboxylate (P5C) to proline in humans. PYCRs - especially PYCR1 - are upregulated in many types of cancers and have been implicated in the altered metabolism of cancer cells. Of the three isoforms of PYCR, PYCR3 remains the least studied due in part to the lack of a robust recombinant expression. Herein, we describe a procedure for the expression of soluble SUMO-PYCR3 in Escherichia coli, purification of the fusion protein, and removal of the SUMO tag. PYCR3 is active with either NADPH or NADH as the coenzyme. Bi-substrate kinetic measurements obtained by varying the concentrations of both L-P5C and NADH, along with product inhibition data for l-proline, suggest a random ordered bi bi mechanism. A panel of 19 proline analogs was screened for inhibition, and the kinetics of competitive inhibition (with L-P5C) were measured for five of the compounds screened, including N-formyl-l-proline, a validated inhibitor of PYCR1. N-formyl-l-proline was found to be ten times more selective for PYCR1 over PYCR3. The SUMO-PYCR3 expression system should be useful for testing the isoform specificity of PYCR1 inhibitors.

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