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Background Mycorrhizal strategies are very effective in enhancing plant acquisition of poorly-mobile nutrients, particularly phosphorus (P) from infertile soil. However, on very old and severely P-impoverished soils, a carboxylate-releasing and P-mobilising cluster-root strategy is more effective at acquiring this growth-limiting resource. Carboxylates are released during a period of only a few days from ephemeral cluster roots. Despite the cluster-root strategy being superior for P acquisition in such environments, these species coexist with a wide range of mycorrhizal species, raising questions about the mechanisms contributing to their coexistence. Scope We surmise that the coexistence of mycorrhizal and non-mycorrhizal strategies is primarily accounted for by a combination of belowground mechanisms, namely (i) facilitation of P acquisition by mycorrhizal plants from neighbouring cluster-rooted plants, and (ii) interactions between roots, pathogens and mycorrhizal fungi, which enhance the plants' defence against pathogens. Facilitation of nutrient acquisition by cluster-rooted plants involves carboxylate exudation, making more P available for both themselves and their mycorrhizal neighbours. Belowground nutrient exchanges between carboxylate-exuding plants and mycorrhizal N2-fixing plants appear likely, but require further experimental testing to determine their nutritional and ecological relevance. Anatomical studies of roots of cluster-rooted Proteaceae species show that they do not form a complete suberised exodermis. Conclusions The absence of an exodermis may well be important to rapidly release carboxylates, but likely lowers root structural defences against pathogens, particularly oomycetes. Conversely, roots of mycorrhizal plants may not be as effective at acquiring P when P availability is very low, but they are better defended against pathogens, and this superior defence likely involves mycorrhizal fungi. Taken together, we are beginning to understand how an exceptionally large number of plant species and P-acquisition strategies coexist on the most severely P-impoverished soils.

Cell metabolism is strongly influenced by mechano-environment. We show here that a fraction of kindlin-2 localizes to mitochondria and interacts with pyrroline-5-carboxylate reductase 1 (PYCR1), a key enzyme for proline synthesis. Extracellular matrix (ECM) stiffening promotes kindlin-2 translocation into mitochondria and its interaction with PYCR1, resulting in elevation of PYCR1 level and consequent increase of proline synthesis and cell proliferation. Depletion of kindlin-2 reduces PYCR1 level, increases reactive oxygen species (ROS) production and apoptosis, and abolishes ECM stiffening-induced increase of proline synthesis and cell proliferation. In vivo, both kindlin-2 and PYCR1 levels are markedly increased in lung adenocarcinoma. Ablation of kindlin-2 in lung adenocarcinoma substantially reduces PYCR1 and proline levels, and diminishes fibrosis in vivo, resulting in marked inhibition of tumor growth and reduction of mortality rate. Our findings reveal a mechanoresponsive kindlin-2-PYCR1 complex that links mechano-environment to proline metabolism and signaling, and suggest a strategy to inhibit tumor growth. The mechano-properties of the Extracellular Matrix (ECM) are important for tumorigenesis. Here, the authors show that the stiffening of the ECM promotes translocation of the focal adhesion protein—Kindlin-2—to the mitochondria, where it interacts with the proline synthesis enzyme PYCR1, stimulating proline synthesis and cell proliferation.

Tumours can require certain amino acids for their proliferation, and the diricore method described here helps to identify such restrictive amino acids; using this method in kidney cancer tissue and breast carcinoma cells, the authors observe an association between proline deficiency and upregulation of PYCR1, an enzyme required for proline synthesis. Amino acid deprivation as an antitumour weapon Tumours can require certain amino acids for their proliferation. To identify such restrictive amino acids, Reuven Agami and colleagues have developed a ribosome profiling-based method — termed diricore — to assess the availability of specific amino acids for protein synthesis. Using this method in kidney cancer tissue, the authors observe an association between proline deficiency and upregulation of PYRC1, an enzyme required for proline synthesis. Application of diricore to breast carcinoma cells also revealed proline deficiency. In growth-limiting conditions, PYRC1 was required to maintain tumorigenic growth. These results illustrate an approach to identifying critical amino acid vulnerabilities that can be used therapeutically to target key metabolic pathways. Tumour growth and metabolic adaptation may restrict the availability of certain amino acids for protein synthesis. It has recently been shown that certain types of cancer cells depend on glycine, glutamine, leucine and serine metabolism to proliferate and survive 1 , 2 , 3 , 4 . In addition, successful therapies using L -asparaginase-induced asparagine deprivation have been developed for acute lymphoblastic leukaemia 5 . However, a tailored detection system for measuring restrictive amino acids in each tumour is currently not available. Here we harness ribosome profiling 6 for sensing restrictive amino acids, and develop diricore, a procedure for differential ribosome measurements of codon reading. We first demonstrate the functionality and constraints of diricore using metabolic inhibitors and nutrient deprivation assays. Notably, treatment with L -asparaginase elicited both specific diricore signals at asparagine codons and high levels of asparagine synthetase (ASNS). We then applied diricore to kidney cancer and discover signals indicating restrictive proline. As for asparagine, this observation was linked to high levels of PYCR1, a key enzyme in proline production 7 , suggesting a compensatory mechanism allowing tumour expansion. Indeed, PYCR1 is induced by shortage of proline precursors, and its suppression attenuated kidney cancer cell proliferation when proline was limiting. High PYCR1 is frequently observed in invasive breast carcinoma. In an in vivo model system of this tumour, we also uncover signals indicating restrictive proline. We further show that CRISPR-mediated knockout of PYCR1 impedes tumorigenic growth in this system. Thus, diricore has the potential to reveal unknown amino acid deficiencies, vulnerabilities that can be used to target key metabolic pathways for cancer treatment.

Pyrroline-5-Carboxylate Reductase 1 (PYCR1), a member of the PYCR family, is a key enzyme in the proline biosynthesis pathway. Notably, PYCR1 was originally identified via genetic disease research, linking its mutations to the occurrence of cutis laxa. PYCR1 contributes to the pathogenesis of malignancies and fibrotic diseases via mechanisms involving metabolic reprogramming, Extracellular Matrix (ECM) remodelling, and redox homeostasis maintenance. PYCR1 upregulation has been reported in multiple malignancies including Hepatocellular Carcinoma (HCC), Lung Cancer (LC), Breast Cancer (BC), Bladder Cancer (BlC), and Gastric Cancer (GC), where it has been shown to promote cancer proliferation, migration, and therapy resistance, correlating significantly with advanced cancer stages and poor prognosis. On the other hand, in fibrotic disorders, PYCR1-mediated proline metabolism has been linked to the progression of pulmonary, myocardial, and cutaneous fibroses. Notably, although PYCR1-targeted small-molecule inhibitors have demonstrated therapeutic potential in preclinical studies, their clinical translation is yet to be validated.

Aims Zinc (Zn) and phosphorus (P) often interact negatively with each other in soil-plant systems. We investigated the effects of P-Zn interaction on Zn and P accumulation and partitioning in alfalfa. Methods Plants were grown in a calcareous soil supplied with different rates of Zn (0, 200, and 800 mg kg −1 ) and P (0, 20, and 80 mg kg −1 ). Plant dry mass, Zn and P concentrations in shoots and roots, bulk soil and rhizosheath pH, rhizosheath carboxylates, and DTPA-extractable Zn concentration in the bulk soil were determined. Results Phosphorus-Zn interaction significantly affected DTPA-extractable Zn concentration, plant dry mass, accumulation of Zn and P, and partitioning of Zn in alfalfa, but did not affect rhizosheath pH or the amounts of rhizosheath carboxylates. Increasing P rate promoted plant growth at all soil Zn rates and might enhance the plants’ capacity to cope with excessive Zn; it resulted in a lower rhizosheath pH, which likely contributed to greater Zn and P uptake. Zinc deficiency enhanced exudation of citrate, malonate and malate, while the release of tartrate was related with P deficiency. Conclusions There are strong P-Zn interactions in calcareous soil-plant system, such interactions significantly affect Zn bioavailability, plant growth, accumulation of Zn and P, and partitioning of Zn in alfalfa. Rational P fertilization should be considered for efficient Zn biofortification on Zn-deficient soils and phytoremediation of Zn-contaminated soils.

Characterization of tumor metabolism with spatial information contributes to our understanding of complex cancer metabolic reprogramming, facilitating the discovery of potential metabolic vulnerabilities that might be targeted for tumor therapy. However, given the metabolic variability and flexibility of tumors, it is still challenging to characterize global metabolic alterations in heterogeneous cancer. Here, we propose a spatially resolved metabolomics approach to discover tumor-associated metabolites and metabolic enzymes directly in their native state. A variety of metabolites localized in different metabolic pathways were mapped by airflow-assisted desorption electrospray ionization mass spectrometry imaging (AFADESI-MSI) in tissues from 256 esophageal cancer patients. In combination with in situ metabolomics analysis, this method provided clues into tumor-associated metabolic pathways, including proline biosynthesis, glutamine metabolism, uridine metabolism, histidine metabolism, fatty acid biosynthesis, and polyamine biosynthesis. Six abnormally expressed metabolic enzymes that are closely associated with the altered metabolic pathways were further discovered in esophageal squamous cell carcinoma (ESCC). Notably, pyrroline-5-carboxylate reductase 2 (PYCR2) and uridine phosphorylase 1 (UPase1) were found to be altered in ESCC. The spatially resolved metabolomics reveal what occurs in cancer at the molecular level, from metabolites to enzymes, and thus provide insights into the understanding of cancer metabolic reprogramming.

Cross-coupling between two similar or identical functional groups to form a new C–C bond is a powerful tool to rapidly assemble complex molecules from readily available building units, as seen with olefin cross-metathesis or various types of cross-electrophile coupling 1 , 2 . The Kolbe electrolysis involves the oxidative electrochemical decarboxylation of alkyl carboxylic acids to their corresponding radical species followed by recombination to generate a new C–C bond 3 – 12 . As one of the oldest known C sp 3 –C sp 3 bond-forming reactions, it holds incredible promise for organic synthesis, yet its use has been almost non-existent. From the perspective of synthesis design, this transformation could allow one to agnostically execute syntheses without regard to polarity or neighbouring functionality just by coupling ubiquitous carboxylates 13 . In practice, this promise is undermined by the strongly oxidative electrolytic protocol used traditionally since the nineteenth century 5 , thereby severely limiting its scope. Here, we show how a mildly reductive Ni-electrocatalytic system can couple two different carboxylates by means of in situ generated redox-active esters, termed doubly decarboxylative cross-coupling. This operationally simple method can be used to heterocouple primary, secondary and even certain tertiary redox-active esters, thereby opening up a powerful new approach for synthesis. The reaction, which cannot be mimicked using stoichiometric metal reductants or photochemical conditions, tolerates a range of functional groups, is scalable and is used for the synthesis of 32 known compounds, reducing overall step counts by 73%. An Ni-electrocatalytic system can couple two different carboxylates using doubly decarboxylative cross-coupling, tolerating a range of functional groups, being scalable, used for the synthesis of 32 known compounds and reducing overall step counts by 73%.

The saccharopine pathway (SACPATH) involves the conversion of lysine into α-aminoadipate by three enzymatic reactions catalyzed by the bifunctional enzyme lysine-ketoglutarate reductase/saccharopine dehydrogenase (LKR/SDH) and the enzyme α-aminoadipate semialdehyde dehydrogenase (AASADH). The LKR domain condenses lysine and α-ketoglutarate into saccharopine, and the SDH domain hydrolyzes saccharopine to form glutamate and α-aminoadipate semialdehyde, the latter of which is oxidized to α-aminoadipate by AASADH. Glutamate can give rise to proline by the action of the enzymes Δ1-pyrroline-5-carboxylate synthetase (P5CS) and Δ1-pyrroline-5-carboxylate reductase (P5CR), while Δ1-piperideine-6-carboxylate the cyclic form of α-aminoadipate semialdehyde can be used by P5CR to produce pipecolate. The production of proline and pipecolate by the SACPATH can help plants face the damage caused by osmotic, drought, and salt stress. AASADH is a versatile enzyme that converts an array of aldehydes into carboxylates, and thus, its induction within the SACPATH would help alleviate the toxic effects of these compounds produced under stressful conditions. Pipecolate is the priming agent of N-hydroxypipecolate (NHP), the effector of systemic acquired resistance (SAR). In this review, lysine catabolism through the SACPATH is discussed in the context of abiotic stress and its potential role in the induction of the biotic stress response.

First-row transition metal-based catalysts have been developed for the oxygen evolution reaction (OER) during the past years, however, such catalysts typically operate at overpotentials ( η ) significantly above thermodynamic requirements. Here, we report an iron/nickel terephthalate coordination polymer on nickel form ( NiFeCP/NF ) as catalyst for OER, in which both coordinated and uncoordinated carboxylates were maintained after electrolysis. NiFeCP/NF exhibits outstanding electro-catalytic OER activity with a low overpotential of 188 mV at 10 mA cm −2 in 1.0 KOH, with a small Tafel slope and excellent stability. The pH-independent OER activity of NiFeCP/NF on the reversible hydrogen electrode scale suggests that a concerted proton-coupled electron transfer (c-PET) process is the rate-determining step (RDS) during water oxidation. Deuterium kinetic isotope effects, proton inventory studies and atom-proton-transfer measurements indicate that the uncoordinated carboxylates are serving as the proton transfer relays, with a similar function as amino acid residues in photosystem II (PSII), accelerating the proton-transfer rate. Proton-coupled electron transfer (PCET) process is very important for water oxidation catalysis. Here, the authors introduced uncoordinated carboxylate in the second-coordination-sphere of Ni-Fe coordination polymer catalyst as an internal base to promote the water oxidation kinetics by such PCET process.

Background:Altered cellular metabolism is a hallmark of cancer and some are reliant on glutamine for sustained proliferation and survival. We hypothesise that the glutamine-proline regulatory axis has a key role in breast cancer (BC) in the highly proliferative classes.Methods:Glutaminase (GLS), pyrroline-5-carboxylate synthetase (ALDH18A1), and pyrroline-5-carboxylate reductase 1 (PYCR1) were assessed at DNA/mRNA/protein levels in large, well-characterised cohorts.Results:Gain of PYCR1 copy number and high PYCR1 mRNA was associated with Luminal B tumours. High ALDH18A1 and high GLS protein expression was observed in the oestrogen receptor (ER)+/human epidermal growth factor receptor (HER2)- high proliferation class (Luminal B) compared with ER+/HER2- low proliferation class (Luminal A) (P=0.030 and P=0.022 respectively), however this was not observed with mRNA. Cluster analysis of the glutamine-proline regulatory axis genes revealed significant associations with molecular subtypes of BC and patient outcome independent of standard clinicopathological parameters (P=0.012). High protein expression of the glutamine-proline enzymes were all associated with high MYC protein in Luminal B tumours only (P<0.001).Conclusions:We provide comprehensive clinical data indicating that the glutamine-proline regulatory axis plays an important role in the aggressive subclass of luminal BC and is therefore a potential therapeutic target.