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1.
Plant Cell Environ ; 47(9): 3541-3560, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-39132738

RESUMEN

C2 photosynthesis is a photosynthetic pathway in which photorespiratory CO2 release and refixation are enhanced in leaf bundle sheath (BS) tissues. The evolution of C2 photosynthesis has been hypothesized to be a major step in the origin of C4 photosynthesis, highlighting the importance of studying C2 evolution. In this study, physiological, anatomical, ultrastructural, and immunohistochemical properties of leaf photosynthetic tissues were investigated in six non-C4 Tribulus species and four C4 Tribulus species. At 42°C, T. cristatus exhibited a photosynthetic CO2 compensation point in the absence of respiration (C*) of 21 µmol mol-1, below the C3 mean C* of 73 µmol mol-1. Tribulus astrocarpus had a C* value at 42°C of 55 µmol mol-1, intermediate between the C3 species and the C2 T. cristatus. Glycine decarboxylase (GDC) allocation to BS tissues was associated with lower C*. Tribulus cristatus and T. astrocarpus allocated 86% and 30% of their GDC to the BS tissues, respectively, well above the C3 mean of 11%. Tribulus astrocarpus thus exhibits a weaker C2 (termed sub-C2) phenotype. Increased allocation of mitochondria to the BS and decreased length-to-width ratios of BS cells, were present in non-C4 species, indicating a potential role in C2 and C4 evolution.


Asunto(s)
Evolución Biológica , Fotosíntesis , Hojas de la Planta , Fotosíntesis/fisiología , Hojas de la Planta/fisiología , Hojas de la Planta/metabolismo , Dióxido de Carbono/metabolismo , Glicina-Deshidrogenasa (Descarboxilante)/metabolismo
2.
Mol Genet Metab ; 142(3): 108496, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38761651

RESUMEN

Non-Ketotic Hyperglycinemia (NKH) is a rare inborn error of metabolism caused by impaired function of the glycine cleavage system (GCS) and characterised by accumulation of glycine in body fluids and tissues. NKH is an autosomal recessive condition and the majority of affected individuals carry mutations in GLDC (glycine decarboxylase). Current treatments for NKH have limited effect and are not curative. As a monogenic condition with known genetic causation, NKH is potentially amenable to gene therapy. An AAV9-based expression vector was designed to target sites of GCS activity. Using a ubiquitous promoter to drive expression of a GFP reporter, transduction of liver and brain was confirmed following intra-venous and/or intra-cerebroventricular administration to neonatal mice. Using the same capsid and promoter with transgenes to express mouse or human GLDC, vectors were then tested in GLDC-deficient mice that provide a model of NKH. GLDC-deficient mice exhibited elevated plasma glycine concentration and accumulation of glycine in liver and brain tissues as previously observed. Moreover, the folate profile indicated suppression of folate one­carbon metabolism (FOCM) in brain tissue, as found at embryonic stages, and reduced abundance of FOCM metabolites including betaine and choline. Neonatal administration of vector achieved reinstatement of GLDC mRNA and protein expression in GLDC-deficient mice. Treated GLDC-deficient mice showed significant lowering of plasma glycine, confirming functionality of vector expressed protein. AAV9-GLDC treatment also led to lowering of brain tissue glycine, and normalisation of the folate profile indicating restoration of glycine-derived one­carbon supply. These findings support the hypothesis that AAV-mediated gene therapy may offer potential in treatment of NKH.


Asunto(s)
Encéfalo , Dependovirus , Modelos Animales de Enfermedad , Terapia Genética , Vectores Genéticos , Glicina-Deshidrogenasa (Descarboxilante) , Glicina , Hiperglicinemia no Cetósica , Hígado , Animales , Hiperglicinemia no Cetósica/genética , Hiperglicinemia no Cetósica/metabolismo , Hiperglicinemia no Cetósica/terapia , Glicina-Deshidrogenasa (Descarboxilante)/genética , Glicina-Deshidrogenasa (Descarboxilante)/metabolismo , Dependovirus/genética , Ratones , Humanos , Vectores Genéticos/genética , Glicina/metabolismo , Hígado/metabolismo , Encéfalo/metabolismo , Biomarcadores/metabolismo , Ácido Fólico/metabolismo
3.
Am J Med Genet A ; 194(8): e63622, 2024 08.
Artículo en Inglés | MEDLINE | ID: mdl-38572626

RESUMEN

Nonketotic hyperglycinemia (NKH) is a relatively well-characterized inborn error of metabolism that results in a combination of lethargy, hypotonia, seizures, developmental arrest, and, in severe cases, death early in life. Three genes encoding components of the glycine cleavage enzyme system-GLDC, AMT, and GCSH-are independently associated with NKH. We report on a patient with severe NKH in whom the homozygous pathogenic variant in AMT (NM_000481.3):c.602_603del (p.Lys201Thrfs*75) and the homozygous likely pathogenic variant in GLDC(NM_000170.2):c.2852C>A (p.Ser951Tyr) were both identified. Our patient demonstrates a novel combination of two homozygous disease-causing variants impacting the glycine cleavage pathway at two different components, and elicits management- and genetic counseling-related challenges for the family.


Asunto(s)
Homocigoto , Hiperglicinemia no Cetósica , Humanos , Hiperglicinemia no Cetósica/genética , Hiperglicinemia no Cetósica/patología , Masculino , Glicina-Deshidrogenasa (Descarboxilante)/genética , Aminometiltransferasa/genética , Femenino , Mutación/genética , Lactante , Glicina/genética , Recién Nacido , Fenotipo , Predisposición Genética a la Enfermedad , Aminoácido Oxidorreductasas , Complejos Multienzimáticos , Transferasas
4.
Int J Mol Sci ; 25(5)2024 Feb 28.
Artículo en Inglés | MEDLINE | ID: mdl-38474060

RESUMEN

The pathophysiology of nonketotic hyperglycinemia (NKH), a rare neuro-metabolic disorder associated with severe brain malformations and life-threatening neurological manifestations, remains incompletely understood. Therefore, a valid human neural model is essential. We aimed to investigate the impact of GLDC gene variants, which cause NKH, on cellular fitness during the differentiation process of human induced pluripotent stem cells (iPSCs) into iPSC-derived astrocytes and to identify sustainable mechanisms capable of overcoming GLDC deficiency. We developed the GLDC27-FiPS4F-1 line and performed metabolomic, mRNA abundance, and protein analyses. This study showed that although GLDC27-FiPS4F-1 maintained the parental genetic profile, it underwent a metabolic switch to an altered serine-glycine-one-carbon metabolism with a coordinated cell growth and cell cycle proliferation response. We then differentiated the iPSCs into neural progenitor cells (NPCs) and astrocyte-lineage cells. Our analysis showed that GLDC-deficient NPCs had shifted towards a more heterogeneous astrocyte lineage with increased expression of the radial glial markers GFAP and GLAST and the neuronal markers MAP2 and NeuN. In addition, we detected changes in other genes related to serine and glycine metabolism and transport, all consistent with the need to maintain glycine at physiological levels. These findings improve our understanding of the pathology of nonketotic hyperglycinemia and offer new perspectives for therapeutic options.


Asunto(s)
Hiperglicinemia no Cetósica , Células Madre Pluripotentes Inducidas , Humanos , Hiperglicinemia no Cetósica/genética , Hiperglicinemia no Cetósica/patología , Glicina-Deshidrogenasa (Descarboxilante)/genética , Astrocitos/patología , Células Madre Pluripotentes Inducidas/patología , Glicina , Serina
5.
PeerJ ; 12: e16716, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38188180

RESUMEN

Objective: The objective is to explore whether the flagellin-TLR5 complex signal can enhance the antigen presentation ability of myeloid DCs through the TRIF-ERK1/2 pathway, and the correlation between this pathway and intestinal mucosal inflammation response. Methods: Mouse bone marrow-derived DC line DC2.4 was divided into four groups: control group (BC) was DC2.4 cells cultured normally; flagellin single signal stimulation group (DC2.4+CBLB502) was DC2.4 cells stimulated with flagellin derivative CBLB502 during culture; TLR5-flagellin complex signal stimulation group (ov-TLR5-DC2.4+CBLB502) was flagellin derivative CBLB502 stimulated ov-TLR5-DC2.4 cells with TLR5 gene overexpression; TRIF signal interference group (ov-TLR5-DC2.4+CBLB502+Pepinh-TRIFTFA) was ov-TLR5-DC2.4 cells with TLR5 gene overexpression stimulated with flagellin derivative CBLB502 and intervened with TRIF-specific inhibitor Pepinh-TRIFTFA. WB was used to detect the expression of TRIF and p-ERK1/2 proteins in each group of cells; CCK8 was used to detect cell proliferation in each group; flow cytometry was used to detect the expression of surface molecules MHCI, MHCII, CD80, 86 in each group of cells; ELISA was used to detect the levels of IL-12 and IL-4 cytokines in each group. Results: Compared with the BC group, DC2.4+CBLB502 group, and ov-TLR5-DC2.4+CBLB502+Pepinh-TRIFTFA group, the expression of TRIF protein and p-ERK1/2 protein in ov-TLR5-DC2.4+CBLB502 group was significantly upregulated (TRIF: p = 0.02,  = 0.007,  = 0.048) (ERK1: p < 0.001, =0.0003,  = 0.0004; ERK2:p = 0.0003,  = 0.0012,  = 0.0022). The cell proliferation activity in ov-TLR5-DC2.4+CBLB502 group was enhanced compared with the other groups (p = 0.0001, p < 0.0001, p = 0.0015); at the same time, the expression of surface molecules MHCI, MHCII, CD80, 86 on DCs was upregulated (p < 0.05); and the secretion of IL-12 and IL-4 cytokines was increased, with significant differences (IL-12: p < 0.0001, p < 0.0001, p = 0.0005; IL-4: p =  < 0.0001, p =  < 0.0001, p = 0.0001). However, the ov-TLR5-DC2.4+CBLB502+Pepinh-TRIFTFA group, which was treated with TRIF signal interference, showed a decrease in intracellular TRIF protein and p-ERK1/2 protein, as well as a decrease in cell proliferation ability and surface stimulation molecules, and a decrease in the secretion of IL-12 and IL-4 cytokines (p < 0.05). Conclusion: After stimulation of flagellin protein-TLR5 complex signal, TRIF protein and p-ERK1/2 protein expression in myeloid dendritic cells were significantly up-regulated, accompanied by increased proliferation activity and maturity of DCs, enhanced antigen presentation function, increased secretion of pro-inflammatory cytokines IL-12 and IL-4. This process can be inhibited by the specific inhibitor of TRIF signal, suggesting that the TLR5-TRIF-ERK1/2 pathway may play an important role in abnormal immune response and mucosal chronic inflammation infiltration mediated by flagellin protein in DCs, which can provide a basis for our subsequent animal experiments.


Asunto(s)
Flagelina , Sistema de Señalización de MAP Quinasas , Animales , Ratones , Proteínas Adaptadoras del Transporte Vesicular/genética , Presentación de Antígeno , Antígeno B7-1 , Proliferación Celular , Citocinas , Flagelina/farmacología , Glicina-Deshidrogenasa (Descarboxilante) , Interleucina-12 , Interleucina-4 , Mucosa Intestinal , Transducción de Señal , Receptor Toll-Like 5/genética
6.
Plant Biol (Stuttg) ; 26(2): 270-281, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38168881

RESUMEN

C3 -C4 intermediate photosynthesis has evolved at least five times convergently in the Brassicaceae, despite this family lacking bona fide C4 species. The establishment of this carbon concentrating mechanism is known to require a complex suite of ultrastructural modifications, as well as changes in spatial expression patterns, which are both thought to be underpinned by a reconfiguration of existing gene-regulatory networks. However, to date, the mechanisms which underpin the reconfiguration of these gene networks are largely unknown. In this study, we used a pan-genomic association approach to identify genomic features that could confer differential gene expression towards the C3 -C4 intermediate state by analysing eight C3 species and seven C3 -C4 species from five independent origins in the Brassicaceae. We found a strong correlation between transposable element (TE) insertions in cis-regulatory regions and C3 -C4 intermediacy. Specifically, our study revealed 113 gene models in which the presence of a TE within a gene correlates with C3 -C4 intermediate photosynthesis. In this set, genes involved in the photorespiratory glycine shuttle are enriched, including the glycine decarboxylase P-protein whose expression domain undergoes a spatial shift during the transition to C3 -C4 photosynthesis. When further interrogating this gene, we discovered independent TE insertions in its upstream region which we conclude to be responsible for causing the spatial shift in GLDP1 gene expression. Our findings hint at a pivotal role of TEs in the evolution of C3 -C4 intermediacy, especially in mediating differential spatial gene expression.


Asunto(s)
Brassicaceae , Brassicaceae/genética , Brassicaceae/metabolismo , Elementos Transponibles de ADN/genética , Glicina/genética , Glicina/metabolismo , Fotosíntesis/genética , Glicina-Deshidrogenasa (Descarboxilante)/genética , Glicina-Deshidrogenasa (Descarboxilante)/metabolismo , Hojas de la Planta/metabolismo
7.
Int J Biol Sci ; 19(15): 4726-4743, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37781511

RESUMEN

Glycine decarboxylase (GLDC) is one of the core enzymes for glycine metabolism, and its biological roles in prostate cancer (PCa) are unclear. First, we found that GLDC plays a central role in glycolysis in 540 TCGA PCa patients. Subsequently, a metabolomic microarray showed that GLDC enhanced aerobic glycolysis in PCa cells, and GLDC and its enzyme activity enhanced glucose uptake, lactate production and lactate dehydrogenase (LDH) activity in PCa cells. Next, we found that GLDC was highly expressed in PCa, was directly regulated by hypoxia-inducible factor (HIF1-α) and regulated downstream LDHA expression. In addition, GLDC and its enzyme activity showed a strong ability to promote the migration and invasion of PCa both in vivo and in vitro. Furthermore, we found that the GLDC-high group had a higher TP53 mutation frequency, lower CD8+ T-cell infiltration, higher immune checkpoint expression, and higher immune exclusion scores than the GLDC-low group. Finally, the GLDC-based prognostic risk model by applying LASSO Cox regression also showed good predictive power for the clinical characteristics and survival in PCa patients. This evidence indicates that GLDC plays crucial roles in glycolytic metabolism, invasion and metastasis, and immune escape in PCa, and it is a potential therapeutic target for prostate cancer.


Asunto(s)
Glucólisis , Neoplasias de la Próstata , Masculino , Humanos , Glicina-Deshidrogenasa (Descarboxilante)/genética , Glicina-Deshidrogenasa (Descarboxilante)/metabolismo , Glucólisis/genética , Neoplasias de la Próstata/genética
8.
Med Oncol ; 40(10): 293, 2023 Sep 05.
Artículo en Inglés | MEDLINE | ID: mdl-37668829

RESUMEN

Cancer metastasis remains a major cause of death in cancer patients, and epithelial-mesenchymal transition (EMT) plays a decisive role in cancer metastasis. Recently, abnormal expression of Glycine Decarboxylase (GLDC) has been demonstrated in tumor progression, and GLDC is up-regulated in cancers, such as lung, prostate, bladder, and cervical cancers. However, the exact role of GLDC in colorectal cancer (CRC) progression remains to be elucidated. The aim of our study was to explore the role of GLDC in CRC metastasis. The GSE75117 database was used to investigate GLDC expression in tumor center and invasive front tissues and we found that GLDC expression levels were higher in the invasive front tissue. GLDC expression levels were negatively correlated with the prognosis of CRC patients. In vitro studies have showed that GLDC can promote invasion and migration of CRC cells by inhibiting the Hippo signaling pathway and regulating the EMT process. Blocking the Hippo signaling pathway with Verteporfin reduced the effect of GLDC on CRC metastasis. In vivo metastasis assays further confirmed that tail vein injection of GLDC+/+ cells induced more lung metastasis, compared to normal CRC cells. The results of this study suggest that GLDC promotes EMT through the Hippo signaling pathway, providing a new therapeutic target for CRC metastasis.


Asunto(s)
Neoplasias Colorrectales , Glicina-Deshidrogenasa (Descarboxilante) , Vía de Señalización Hippo , Femenino , Humanos , Masculino , Transición Epitelial-Mesenquimal
9.
Cell Metab ; 34(5): 775-782.e9, 2022 05 03.
Artículo en Inglés | MEDLINE | ID: mdl-35508111

RESUMEN

The folic acid cycle mediates the transfer of one-carbon (1C) units to support nucleotide biosynthesis. While the importance of serine as a mitochondrial and cytosolic donor of folate-mediated 1C units in cancer cells has been thoroughly investigated, a potential role of glycine oxidation remains unclear. We developed an approach for quantifying mitochondrial glycine cleavage system (GCS) flux by combining stable and radioactive isotope tracing with computational flux decomposition. We find high GCS flux in hepatocellular carcinoma (HCC), supporting nucleotide biosynthesis. Surprisingly, other than supplying 1C units, we found that GCS is important for maintaining protein lipoylation and mitochondrial activity. Genetic silencing of glycine decarboxylase inhibits the lipoylation and activity of pyruvate dehydrogenase and impairs tumor growth, suggesting a novel drug target for HCC. Considering the physiological role of liver glycine cleavage, our results support the notion that tissue of origin plays an important role in tumor-specific metabolic rewiring.


Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Ácido Fólico/metabolismo , Glicina/metabolismo , Glicina-Deshidrogenasa (Descarboxilante)/metabolismo , Humanos , Lipoilación/genética , Proteínas Mitocondriales/metabolismo , Nucleótidos/metabolismo
10.
Am J Clin Nutr ; 116(2): 500-510, 2022 08 04.
Artículo en Inglés | MEDLINE | ID: mdl-35460232

RESUMEN

BACKGROUND: Glycine is a proteogenic amino acid that is required for numerous metabolic pathways, including purine, creatine, heme, and glutathione biosynthesis. Glycine formation from serine, catalyzed by serine hydroxy methyltransferase, is the major source of this amino acid in humans. Our previous studies in a mouse model have shown a crucial role for the 10-formyltetrahydrofolate dehydrogenase enzyme in serine-to-glycine conversion. OBJECTIVES: We sought to determine the genomic influence on the serine-glycine ratio in 803 Hispanic children from 319 families of the Viva La Familia cohort. METHODS: We performed a genome-wide association analysis for plasma serine, glycine, and the serine-glycine ratio in Sequential Oligogenic Linkage Analysis Routines while accounting for relationships among family members. RESULTS: All 3 parameters were significantly heritable (h2 = 0.22-0.78; P < 0.004). The strongest associations for the serine-glycine ratio were with single nucleotide polymorphisms (SNPs) in aldehyde dehydrogenase 1 family member L1 (ALDH1L1) and glycine decarboxylase (GLDC) and for glycine with GLDC (P < 3.5 × 10-8; effect sizes, 0.03-0.07). No significant associations were found for serine. We also conducted a targeted genetic analysis with ALDH1L1 exonic SNPs and found significant associations between the serine-glycine ratio and rs2886059 (ß = 0.68; SE, 0.25; P = 0.006) and rs3796191 (ß = 0.25; SE, 0.08; P = 0.003) and between glycine and rs3796191 (ß = -0.08; SE, 0.02; P = 0.0004). These exonic SNPs were further associated with metabolic disease risk factors, mainly adiposity measures (P < 0.006). Significant genetic and phenotypic correlations were found for glycine and the serine-glycine ratio with metabolic disease risk factors, including adiposity, insulin sensitivity, and inflammation-related phenotypes [estimate of genetic correlation = -0.37 to 0.35 (P < 0.03); estimate of phenotypic correlation = -0.19 to 0.13 (P < 0.006)]. The significant genetic correlations indicate shared genetic effects among glycine, the serine-glycine ratio, and adiposity and insulin sensitivity phenotypes. CONCLUSIONS: Our study suggests that ALDH1L1 and GLDC SNPs influence the serine-to-glycine ratio and metabolic disease risk.


Asunto(s)
Glicina-Deshidrogenasa (Descarboxilante) , Resistencia a la Insulina , Oxidorreductasas actuantes sobre Donantes de Grupo CH-NH , Serina , Niño , Estudio de Asociación del Genoma Completo , Glicina/genética , Glicina-Deshidrogenasa (Descarboxilante)/genética , Glicina-Deshidrogenasa (Descarboxilante)/metabolismo , Hispánicos o Latinos/genética , Humanos , Oxidorreductasas actuantes sobre Donantes de Grupo CH-NH/genética , Serina/genética
11.
Annu Rev Plant Biol ; 73: 43-65, 2022 05 20.
Artículo en Inglés | MEDLINE | ID: mdl-35231181

RESUMEN

The discovery of C3-C4 intermediate species nearly 50 years ago opened up a new avenue for studying the evolution of photosynthetic pathways. Intermediate species exhibit anatomical, biochemical, and physiological traits that range from C3 to C4. A key feature of C3-C4 intermediates that utilize C2 photosynthesis is the improvement in photosynthetic efficiency compared with C3 species. Although the recruitment of some core enzymes is shared across lineages, there is significant variability in gene expression patterns, consistent with models that suggest numerous evolutionary paths from C3 to C4 photosynthesis. Despite the many evolutionary trajectories, the recruitment of glycine decarboxylase for C2 photosynthesis is likely required. As technologies enable high-throughput genotyping and phenotyping, the discovery of new C3-C4 intermediates species will enrich comparisons between evolutionary lineages. The investigation of C3-C4 intermediate species will enhance our understanding of photosynthetic mechanisms and evolutionary processes and will potentially aid in crop improvement.


Asunto(s)
Evolución Biológica , Fotosíntesis , Glicina-Deshidrogenasa (Descarboxilante)/genética , Glicina-Deshidrogenasa (Descarboxilante)/metabolismo , Fotosíntesis/genética , Hojas de la Planta/metabolismo
13.
J Exp Bot ; 73(5): 1581-1601, 2022 03 02.
Artículo en Inglés | MEDLINE | ID: mdl-34910813

RESUMEN

C4 photosynthesis concentrates CO2 around Rubisco in the bundle sheath, favouring carboxylation over oxygenation and decreasing photorespiration. This complex trait evolved independently in >60 angiosperm lineages. Its evolution can be investigated in genera such as Flaveria (Asteraceae) that contain species representing intermediate stages between C3 and C4 photosynthesis. Previous studies have indicated that the first major change in metabolism probably involved relocation of glycine decarboxylase and photorespiratory CO2 release to the bundle sheath and establishment of intercellular shuttles to maintain nitrogen stoichiometry. This was followed by selection for a CO2-concentrating cycle between phosphoenolpyruvate carboxylase in the mesophyll and decarboxylases in the bundle sheath, and relocation of Rubisco to the latter. We have profiled 52 metabolites in nine Flaveria species and analysed 13CO2 labelling patterns for four species. Our results point to operation of multiple shuttles, including movement of aspartate in C3-C4 intermediates and a switch towards a malate/pyruvate shuttle in C4-like species. The malate/pyruvate shuttle increases from C4-like to complete C4 species, accompanied by a rise in ancillary organic acid pools. Our findings support current models and uncover further modifications of metabolism along the evolutionary path to C4 photosynthesis in the genus Flaveria.


Asunto(s)
Flaveria , Flaveria/genética , Flaveria/metabolismo , Glicina-Deshidrogenasa (Descarboxilante)/genética , Glicina-Deshidrogenasa (Descarboxilante)/metabolismo , Metaboloma , Fotosíntesis , Ribulosa-Bifosfato Carboxilasa/genética , Ribulosa-Bifosfato Carboxilasa/metabolismo
14.
J Plant Res ; 135(1): 15-27, 2022 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-34519912

RESUMEN

Proto-Kranz plants represent an initial phase in the evolution from C3 to C3-C4 intermediate to C4 plants. The ecological and adaptive aspects of C3-C4 plants would provide an important clue to understand the evolution of C3-C4 plants. We investigated whether growth temperature and nitrogen (N) nutrition influence the expression of C3-C4 traits in Chenopodium album (proto-Kranz) in comparison with Chenopodium quinoa (C3). Plants were grown during 5 weeks at 20 or 30 °C under standard or low N supply levels (referred to as 20SN, 20LN, 30SN, and 30LN). Net photosynthetic rate and leaf N content were higher in 20SN and 30SN plants than in 20LN and 30LN plants of C. album but did not differ among growth conditions in C. quinoa. The CO2 compensation point (Γ) of C. album was lowest in 30LN plants (36 µmol mol-1), highest in 20SN plants (51 µmol mol-1), and intermediate in 20LN and 30SN plants, whereas Γ of C. quinoa did not differ among the growth conditions (51-52 µmol mol-1). The anatomical structure of leaves was not considerably affected by growth conditions in either species. However, ultrastructural observations in C. album showed that the number of mitochondria per mesophyll or bundle sheath (BS) cell was lower in 20LN and 30LN plants than in 20SN and 30SN plants. Immunohistochemical observations revealed that lower accumulation level of P-protein of glycine decarboxylase (GDC-P) in mesophyll mitochondria than in BS mitochondria is the major factor causing the decrease in Γ values in C. album plants grown under low N supply and high temperature. These results suggest that high growth temperature and low N supply lead to the expression of C3-C4 traits (the reduction of Γ) in the proto-Kranz plants of C. album through the regulation of GDC-P expression.


Asunto(s)
Chenopodium album , Chenopodium album/metabolismo , Glicina-Deshidrogenasa (Descarboxilante)/metabolismo , Nitrógeno , Fotosíntesis , Hojas de la Planta/metabolismo , Temperatura
15.
Cell Mol Life Sci ; 78(23): 7451-7468, 2021 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-34718827

RESUMEN

In human metabolism, pyruvate dehydrogenase complex (PDC) is one of the most intricate and large multimeric protein systems representing a central hub for cellular homeostasis. The worldwide used antiepileptic drug valproic acid (VPA) may potentially induce teratogenicity or a mild to severe hepatic toxicity, where the underlying mechanisms are not completely understood. This work aims to clarify the mechanisms that intersect VPA-related iatrogenic effects to PDC-associated dihydrolipoamide dehydrogenase (DLD; E3) activity. DLD is also a key enzyme of α-ketoglutarate dehydrogenase, branched-chain α-keto acid dehydrogenase, α-ketoadipate dehydrogenase, and the glycine decarboxylase complexes. The molecular effects of VPA will be reviewed underlining the data that sustain a potential interaction with DLD. The drug-associated effects on lipoic acid-related complexes activity may induce alterations on the flux of metabolites through tricarboxylic acid cycle, branched-chain amino acid oxidation, glycine metabolism and other cellular acetyl-CoA-connected reactions. The biotransformation of VPA involves its complete ß-oxidation in mitochondria causing an imbalance on energy homeostasis. The drug consequences as histone deacetylase inhibitor and thus gene expression modulator have also been recognized. The mitochondrial localization of PDC is unequivocal, but its presence and function in the nucleus were also demonstrated, generating acetyl-CoA, crucial for histone acetylation. Bridging metabolism and epigenetics, this review gathers the evidence of VPA-induced interference with DLD or PDC functions, mainly in animal and cellular models, and highlights the uncharted in human. The consequences of this interaction may have significant impact either in mitochondrial or in nuclear acetyl-CoA-dependent processes.


Asunto(s)
Dihidrolipoamida Deshidrogenasa/metabolismo , Inhibidores de Histona Desacetilasas/efectos adversos , Enfermedad Iatrogénica , Complejo Piruvato Deshidrogenasa/metabolismo , Ácido Valproico/efectos adversos , 3-Metil-2-Oxobutanoato Deshidrogenasa (Lipoamida)/metabolismo , Acetilcoenzima A/biosíntesis , Acetilación , Animales , Glicina-Deshidrogenasa (Descarboxilante)/metabolismo , Humanos , Complejo Cetoglutarato Deshidrogenasa/metabolismo , Cetona Oxidorreductasas/metabolismo , Hígado/patología , Mitocondrias/metabolismo , Oxidación-Reducción/efectos de los fármacos , Teratógenos/metabolismo
16.
Physiol Rep ; 9(15): e14991, 2021 08.
Artículo en Inglés | MEDLINE | ID: mdl-34342168

RESUMEN

In both humans and rodent models, circulating glycine levels are significantly reduced in obesity, glucose intolerance, type II diabetes, and non-alcoholic fatty liver disease. The glycine cleavage system and its rate-limiting enzyme, glycine decarboxylase (GLDC), is a major determinant of plasma glycine levels. The goals of this study were to determine if the increased expression of GLDC contributes to the reduced plasma glycine levels seen in disease states, to characterize the hormonal regulation of GLDC gene expression, and to determine if altered GLDC expression has physiological effects that might affect the development of diabetes. The findings presented here show that hepatic GLDC gene expression is elevated in mouse models of obesity and diabetes, as well as by fasting. We demonstrated that GLDC gene expression is strongly regulated by the metabolic hormones glucagon and insulin, and we identified the signaling pathways involved in this regulation. Finally, we found that GLDC expression is linked to glutathione levels, with increased expression associated with elevated levels of glutathione and reduced expression associated with a suppression of glutathione and increased cellular ROS levels. These findings suggest that the hormonal regulation of GLDC contributes not only to the changes in circulating glycine levels seen in metabolic disease, but also affects glutathione production, possibly as a defense against metabolic disease-associated oxidative stress.


Asunto(s)
Diabetes Mellitus Experimental/patología , Diabetes Mellitus Tipo 2/patología , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Glucagón/farmacología , Glicina-Deshidrogenasa (Descarboxilante)/metabolismo , Glicina/metabolismo , Estrés Oxidativo , Animales , Diabetes Mellitus Experimental/etiología , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/etiología , Diabetes Mellitus Tipo 2/metabolismo , Fármacos Gastrointestinales/farmacología , Glutatión/metabolismo , Glicina-Deshidrogenasa (Descarboxilante)/genética , Células HEK293 , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratas , Ratas Sprague-Dawley
17.
Nat Commun ; 12(1): 4227, 2021 07 09.
Artículo en Inglés | MEDLINE | ID: mdl-34244482

RESUMEN

Glycine decarboxylase (GLDC) is a key enzyme of glycine cleavage system that converts glycine into one-carbon units. GLDC is commonly up-regulated and plays important roles in many human cancers. Whether and how GLDC is regulated by post-translational modifications is unknown. Here we report that mechanistic target of rapamycin complex 1 (mTORC1) signal inhibits GLDC acetylation at lysine (K) 514 by inducing transcription of the deacetylase sirtuin 3 (SIRT3). Upon inhibition of mTORC1, the acetyltransferase acetyl-CoA acetyltransferase 1 (ACAT1) catalyzes GLDC K514 acetylation. This acetylation of GLDC impairs its enzymatic activity. In addition, this acetylation of GLDC primes for its K33-linked polyubiquitination at K544 by the ubiquitin ligase NF-X1, leading to its degradation by the proteasomal pathway. Finally, we find that GLDC K514 acetylation inhibits glycine catabolism, pyrimidines synthesis and glioma tumorigenesis. Our finding reveals critical roles of post-translational modifications of GLDC in regulation of its enzymatic activity, glycine metabolism and tumorigenesis, and provides potential targets for therapeutics of cancers such as glioma.


Asunto(s)
Carcinogénesis/genética , Glioma/genética , Glicina-Deshidrogenasa (Descarboxilante)/metabolismo , Glicina/metabolismo , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Acetil-CoA C-Acetiltransferasa/metabolismo , Acetilación , Animales , Carcinogénesis/metabolismo , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Glioma/metabolismo , Glioma/patología , Células HEK293 , Humanos , Masculino , Ratones , Complejo de la Endopetidasa Proteasomal/metabolismo , Procesamiento Proteico-Postraduccional , Proteolisis , Pirimidinas/biosíntesis , Proteínas Represoras/metabolismo , Sirtuina 3/genética , Sirtuina 3/metabolismo , Activación Transcripcional , Ubiquitinación/genética , Ensayos Antitumor por Modelo de Xenoinjerto
18.
PLoS Genet ; 17(2): e1009307, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33524012

RESUMEN

Hundreds of mutations in a single gene result in rare diseases, but why mutations induce severe or attenuated states remains poorly understood. Defect in glycine decarboxylase (GLDC) causes Non-ketotic Hyperglycinemia (NKH), a neurological disease associated with elevation of plasma glycine. We unified a human multiparametric NKH mutation scale that separates severe from attenuated neurological disease with new in silico tools for murine and human genome level-analyses, gathered in vivo evidence from mice engineered with top-ranking attenuated and a highly pathogenic mutation, and integrated the data in a model of pre- and post-natal disease outcomes, relevant for over a hundred major and minor neurogenic mutations. Our findings suggest that highly severe neurogenic mutations predict fatal, prenatal disease that can be remedied by metabolic supplementation of dams, without amelioration of persistent plasma glycine. The work also provides a systems approach to identify functional consequences of mutations across hundreds of genetic diseases. Our studies provide a new framework for a large scale understanding of mutation functions and the prediction that severity of a neurogenic mutation is a direct measure of pre-natal disease in neurometabolic NKH mouse models. This framework can be extended to analyses of hundreds of monogenetic rare disorders where the underlying genes are known but understanding of the vast majority of mutations and why and how they cause disease, has yet to be realized.


Asunto(s)
Modelos Animales de Enfermedad , Glicina-Deshidrogenasa (Descarboxilante)/química , Glicina-Deshidrogenasa (Descarboxilante)/genética , Glicina/metabolismo , Hiperglicinemia no Cetósica/genética , Animales , Femenino , Genómica , Genotipo , Glicina/genética , Humanos , Hiperglicinemia no Cetósica/metabolismo , Hiperglicinemia no Cetósica/patología , Masculino , Espectrometría de Masas , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Mutación , Mutación Missense , Fenotipo
19.
FASEB J ; 35(3): e21344, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33566385

RESUMEN

Cancer cells often depend on microenvironment signals from molecules such as cytokines for proliferation and metabolic adaptations. PRL-3, a cytokine-induced oncogenic phosphatase, is highly expressed in multiple myeloma cells and associated with poor outcome in this cancer. We studied whether PRL-3 influences metabolism. Cells transduced to express PRL-3 had higher aerobic glycolytic rate, oxidative phosphorylation, and ATP production than the control cells. PRL-3 promoted glucose uptake and lactate excretion, enhanced the levels of proteins regulating glycolysis and enzymes in the serine/glycine synthesis pathway, a side branch of glycolysis. Moreover, mRNAs for these proteins correlated with PRL-3 expression in primary patient myeloma cells. Glycine decarboxylase (GLDC) was the most significantly induced metabolism gene. Forced GLDC downregulation partly counteracted PRL-3-induced aerobic glycolysis, indicating GLDC involvement in a PRL-3-driven Warburg effect. AMPK, HIF-1α, and c-Myc, important metabolic regulators in cancer cells, were not mediators of PRL-3's metabolic effects. A phosphatase-dead PRL-3 mutant, C104S, promoted many of the metabolic changes induced by wild-type PRL-3, arguing that important metabolic effects of PRL-3 are independent of its phosphatase activity. Through this study, PRL-3 emerges as one of the key mediators of metabolic adaptations in multiple myeloma.


Asunto(s)
Mieloma Múltiple/metabolismo , Proteínas de Neoplasias/fisiología , Proteínas Tirosina Fosfatasas/fisiología , Adenosina Trifosfato/biosíntesis , Línea Celular Tumoral , Proliferación Celular , Glicina/metabolismo , Glicina-Deshidrogenasa (Descarboxilante)/fisiología , Glucólisis , Humanos , Serina/metabolismo
20.
Plant J ; 106(2): 394-408, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33506579

RESUMEN

Lysin motif (LysM) is a carbohydrate-binding module often found in secreted or transmembrane proteins in living organisms from prokaryotes to eukaryotes. Thus far, all characterized LysM-containing proteins in plants are plasma membrane-resident receptors or co-receptors playing roles in plant-microbe interactions. Here, we interrogate the Arabidopsis LysM/F-box-containing protein InLYP1 and reveal its function in glycine metabolism. InLYP1 was mainly expressed by vigorously growing tissues, encoding a nuclear-cytoplasmic protein. We validated InLYP1 as part of the SKP1-CULLIN1-F-box E3 complex for mediating protein degradation. The glycine decarboxylase P-protein 1 (GLDP1) was identified as an InLYP1-interacting protein by both immunoprecipitation/mass spectrometry and yeast two-hybrid library screening. InLYP1 could also interact with GLDP2, a paralog of GLDP1 with weaker catalytic activity, and could mediate the degradation of GLDP2 but not GLDP1. Interestingly, both GLDPs could be O-glycosylated and form homodimers or heterodimers. Overexpression of InLYP1L9A encoding a dominant-negative variant could cause seedling germination retardation on the medium containing glycine. Collectively, these results shed light on the function of plant intracellular LysM-containing proteins, and suggest that InLYP1 may deplete GLDP2 to facilitate glycine decarboxylation in Arabidopsis.


Asunto(s)
Proteínas de Arabidopsis/metabolismo , Arabidopsis/metabolismo , Glicina-Deshidrogenasa (Descarboxilante)/metabolismo , Glicina/metabolismo , Núcleo Celular/metabolismo , Citoplasma/metabolismo
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