Proline dehydrogenase is essential for proline protection against hydrogen peroxide-induced cell death

Natarajan, Sathish Kumar; Zhu, Weidong; Liang, Xinwen; Zhang, Lu; Demers, Andrew; Zimmerman, Matthew C.; Simpson, Melanie A.; Becker, Donald F.

doi:10.1016/j.freeradbiomed.2012.07.002

Cited by 120 publications

(113 citation statements)

References 56 publications

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“…Proline is a multifaceted amino acid with important roles in carbon and nitrogen metabolism; protein synthesis; and protection against various environmental factors such as drought (44), metal toxicity (45,46), osmotic stress (24,25), ultraviolent irradiation (47), unfolded protein stress (26,48), and oxidative stress (19,23,27,28,49). In this study, we explored the role of proline metabolism in oxidative stress protection by characterizing the oxidative stress response of wild-type and putA mutant E. coli strains.…”

Section: Discussionmentioning

confidence: 99%

“…Proline is a well-known osmoprotectant (24,25), and in E. coli, proline has been described as being a thermoprotectant by diminishing protein aggregation during heat stress (26). Proline has also been found to help combat oxidative stress, a property which has been explored in eukaryotes such as fungi, plants, and animals (19,20,27,28). The mechanism by which proline protects against oxidative stress appears to involve protection of intracellular redox homeostasis and, in the fungal pathogen Colletotrichum trifolii, upregulation of catalase (27).…”

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confidence: 99%

“…The mechanism by which proline protects against oxidative stress appears to involve protection of intracellular redox homeostasis and, in the fungal pathogen Colletotrichum trifolii, upregulation of catalase (27). In mammalian cells, proline protection was shown to require PRODH activity and activation of signaling cascades that promote cell survival (28).…”

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confidence: 99%

“…Here, proline metabolism may also provide a preconditioning effect by generating H 2 O 2 as a by-product and elevating hydroperoxidase I levels, thereby increasing the overall stress tolerance of the cell. Various studies of proline metabolism in eukaryotes have shown that proline oxidation, which in eukaryotes occurs in the mitochondrion, generates ROS (19,23,63,64), which can mediate cell death (63), cell survival against oxidative stress (28), and life span (64). The results from this work further illustrate the fundamental importance of how H 2 O 2 , as a metabolic by-product, can enhance oxidative stress tolerance and appears to be an underlying feature of proline metabolism that is conserved between E. coli and mammals.…”

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Proline Metabolism IncreaseskatGExpression and Oxidative Stress Resistance in Escherichia coli

2014

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The oxidation of L-proline to glutamate in Gram-negative bacteria is catalyzed by the proline utilization A (PutA) flavoenzyme, which contains proline dehydrogenase (PRODH) and ⌬ 1 -pyrroline-5-carboxylate (P5C) dehydrogenase domains in a single polypeptide. Previous studies have suggested that aside from providing energy, proline metabolism influences oxidative stress resistance in different organisms. To explore this potential role and the mechanism, we characterized the oxidative stress resistance of wild-type and putA mutant strains of Escherichia coli. Initial stress assays revealed that the putA mutant strain was significantly more sensitive to oxidative stress than the parental wild-type strain. Expression of PutA in the putA mutant strain restored oxidative stress resistance, confirming that depletion of PutA was responsible for the oxidative stress phenotype. Treatment of wild-type cells with proline significantly increased hydroperoxidase I (encoded by katG) expression and activity. Furthermore, the ⌬katG strain failed to respond to proline, indicating a critical role for hydroperoxidase I in the mechanism of proline protection. The global regulator OxyR activates the expression of katG along with several other genes involved in oxidative stress defense. In addition to katG, proline increased the expression of grxA (glutaredoxin 1) and trxC (thioredoxin 2) of the OxyR regulon, implicating OxyR in proline protection. Proline oxidative metabolism was shown to generate hydrogen peroxide, indicating that proline increases oxidative stress tolerance in E. coli via a preadaptive effect involving endogenous hydrogen peroxide production and enhanced catalase-peroxidase activity.T he conversion of L-proline to glutamate is a four-electron oxidation process that is coordinated in two successive steps by the enzymes proline dehydrogenase (PRODH) and ⌬ 1 -pyrroline-5-carboxylate dehydrogenase (P5CDH) (Fig. 1) (1). In eukaryotes, PRODH and P5CDH are separately encoded enzymes localized in the mitochondrion. In Gram-negative bacteria, PRODH and P5CDH are combined into a bifunctional enzyme known as proline utilization A (PutA) (1, 2). The PRODH domain contains a noncovalently bound flavin adenine dinucleotide (FAD) cofactor and couples the two-electron oxidation of proline to the reduction of ubiquinone in the cytoplasmic membrane (3). The product of the PRODH reaction, ⌬ 1 -pyrroline-5-carboxylate (P5C), is subsequently hydrolyzed to glutamate-␥-semialdehyde (GSA), which is then oxidized to glutamate by the NAD ϩ -dependent P5CDH domain (2). In certain Gram-negative bacteria such as Escherichia coli, PutA also has an N-terminal ribbon-helix-helix (RHH) DNA-binding domain (residues 1 to 47) (4). The RHH domain enables PutA to act as an autogenous transcriptional regulator of the putA and putP (highaffinity Na ϩ -proline transporter) genes (4). PutA represses put gene expression by binding to five operator sites in the put regulatory region (5). Transcription of the put genes is activated by proline, which causes a r...

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Section: Discussionmentioning

confidence: 99%

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Proline Metabolism IncreaseskatGExpression and Oxidative Stress Resistance in Escherichia coli

2014

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“…Now, numerous laboratories have shown that the imino acid proline impacts a wide range of cellular processes, including bioenergetics, differentiation, growth, lifespan, and apoptosis (30, 70,74,75,84,95,97,99,153). It is well established that proline metabolism leads to increased mitochondrial reactive oxygen species (ROS) production via the electron transport chain (ETC) and that proline metabolism impacts cell survival and cell death in different species (14,30,84,97).…”

Section: Introductionmentioning

confidence: 99%

Proline Mechanisms of Stress Survival

Liang

Zhang

Natarajan

et al. 2013

Antioxidants & Redox Signaling

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Significance: The imino acid proline is utilized by different organisms to offset cellular imbalances caused by environmental stress. The wide use in nature of proline as a stress adaptor molecule indicates that proline has a fundamental biological role in stress response. Understanding the mechanisms by which proline enhances abiotic/biotic stress response will facilitate agricultural crop research and improve human health. Recent Advances: It is now recognized that proline metabolism propels cellular signaling processes that promote cellular apoptosis or survival. Studies have shown that proline metabolism influences signaling pathways by increasing reactive oxygen species (ROS) formation in the mitochondria via the electron transport chain. Enhanced ROS production due to proline metabolism has been implicated in the hypersensitive response in plants, lifespan extension in worms, and apoptosis, tumor suppression, and cell survival in animals. Critical Issues: The ability of proline to influence disparate cellular outcomes may be governed by ROS levels generated in the mitochondria. Defining the threshold at which proline metabolic enzyme expression switches from inducing survival pathways to cellular apoptosis would provide molecular insights into cellular redox regulation by proline. Are ROS the only mediators of proline metabolic signaling or are other factors involved? Future Directions: New evidence suggests that proline biosynthesis enzymes interact with redox proteins such as thioredoxin. An important future pursuit will be to identify other interacting partners of proline metabolic enzymes to uncover novel regulatory and signaling networks of cellular stress response. Antioxid. Redox Signal. 19, 998-1011.

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How signaling pathways link extracellular mechano‐environment to proline biosynthesis: A hypothesis

Chen

Guo

2021

BioEssays

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We propose a signaling pathway in which cell-extracellular matrix (ECM) adhesion components PINCH-1 and kindlin-2 sense mechanical signals from ECM and link them to proline biosynthesis, a vital metabolic pathway for macromolecule synthesis, redox balance, and ECM remodeling. ECM stiffening promotes PINCH-1 expression via integrin signaling, which suppresses dynamin-related protein 1 (DRP1) expression and mitochondrial fission, resulting in increased kindlin-2 translocation into mitochondria and interaction with Δ 1 -pyrroline-5-carboxylate (P5C) reductase 1 (PYCR1). Kindlin-2 interaction with PYCR1 protects the latter from proteolytic degradation, leading to elevated PYCR1 level. Additionally, PINCH-1 promotes P5C synthase (P5CS) expression and P5C synthesis, which, together with increased PYCR1 level, support augmented proline biosynthesis. This signaling pathway is frequently activated in fibrosis and cancer, resulting in increased proline biosynthesis and excessive collagen matrix production, which in turn further promotes ECM stiffening. Targeting this signaling pathway, therefore, may provide an effective strategy for alleviating fibrosis and cancer progression. K E Y W O R D Scancer, collagen, extracellular mechano-environment, fibrosis, focal adhesion proteins, mitochondrial dynamics, proline biosynthesis OMM, outer mitochondrial membrane; P5C, Δ 1 -pyrroline-5-carboxylate; P5CS, Δ 1 -pyrroline-5-carboxylate synthase; PH, pleckstrin homology; PYCR, Δ 1 -pyrroline-5-carboxylate reductase; ROS, reactive oxygen species; TCA, tricarboxylic acid; TGF, transforming growth factor as an electron donor. Proline biosynthesis are influenced by both the availability of the substrate (i.e. P5C) and the expression levels and activities of the enzyme (i.e. PYCR). Three isoforms of PYCR, namely PYCR1, 2, and L, have been identified in mammals. [1,4] PYCR1 and 2 share a high level (approximately 84%) of similarity in amino acid sequence, whereas the similarity in amino acid sequence between PYCRL and PYCR1/2 is considerably lower (approximately 45%).All three PYCRs are encoded by genes (i.e. PYCR1, 2, and L) in the nuclei. However, after PYCR1 and 2 proteins are synthesized, they are transported from the cytosol into mitochondria where they catalyze the final step in proline biosynthesis (i.e. conversion of P5C to proline).

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Proline dehydrogenase is essential for proline protection against hydrogen peroxide-induced cell death

Cited by 120 publications

References 56 publications

Proline Metabolism IncreaseskatGExpression and Oxidative Stress Resistance in Escherichia coli

Proline Metabolism IncreaseskatGExpression and Oxidative Stress Resistance in Escherichia coli

Proline Mechanisms of Stress Survival

How signaling pathways link extracellular mechano‐environment to proline biosynthesis: A hypothesis

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