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Molecular Genetics and Metabolism 2020Phosphoglucomutase 1 deficiency is a congenital disorder of glycosylation (CDG) with multiorgan involvement affecting carbohydrate metabolism, N-glycosylation and energy...
Phosphoglucomutase 1 deficiency is a congenital disorder of glycosylation (CDG) with multiorgan involvement affecting carbohydrate metabolism, N-glycosylation and energy production. The metabolic management consists of dietary D-galactose supplementation that ameliorates hypoglycemia, hepatic dysfunction, endocrine anomalies and growth delay. Previous studies suggest that D-galactose administration in juvenile patients leads to more significant and long-lasting effects, stressing the urge of neonatal diagnosis (0-6 months of age). Here, we detail the early clinical presentation of PGM1-CDG in eleven infantile patients, and applied the modified Beutler test for screening of PGM1-CDG in neonatal dried blood spots (DBSs). All eleven infants presented episodic hypoglycemia and elevated transaminases, along with cleft palate and growth delay (10/11), muscle involvement (8/11), neurologic involvement (5/11), cardiac defects (2/11). Standard dietary measures for suspected lactose intolerance in four patients prior to diagnosis led to worsening of hypoglycemia, hepatic failure and recurrent diarrhea, which resolved upon D-galactose supplementation. To investigate possible differences in early vs. late clinical presentation, we performed the first systematic literature review for PGM1-CDG, which highlighted respiratory and gastrointestinal symptoms as significantly more diagnosed in neonatal age. The modified Butler-test successfully identified PGM1-CDG in DBSs from seven patients, including for the first time Guthrie cards from newborn screening, confirming the possibility of future inclusion of PGM1-CDG in neonatal screening programs. In conclusion, severe infantile morbidity of PGM1-CDG due to delayed diagnosis could be prevented by raising awareness on its early presentation and by inclusion in newborn screening programs, enabling early treatments and galactose-based metabolic management.
Topics: Cleft Palate; Congenital Disorders of Glycosylation; Dried Blood Spot Testing; Female; Glycogen Storage Disease; Humans; Hypoglycemia; Infant; Infant, Newborn; Male; Neonatal Screening; Phenotype; Phosphoglucomutase
PubMed: 33342467
DOI: 10.1016/j.ymgme.2020.08.003 -
Biomedicines Jan 2022infection is associated with several gastric diseases, including gastritis, peptic ulcer, gastric adenocarcinoma and mucosa-associated lymphatic tissue (MALT) lymphoma....
infection is associated with several gastric diseases, including gastritis, peptic ulcer, gastric adenocarcinoma and mucosa-associated lymphatic tissue (MALT) lymphoma. Due to the prevalence and severeness of infection, a thorough understanding of this pathogen is necessary. Lipopolysaccharide, one of the major virulence factors of , can exert immunomodulating and immunostimulating functions on the host. In this study, the and genes were under investigation. These two genes potentially encode GDP-D-mannose dehydratase (GMD) and phosphomannomutase (PMM)/phosphoglucomutase (PGM), respectively, and are involved in the biosynthesis of fucose. and knockout mutants were generated; both mutants displayed a truncated LPS, suggesting that the encoded enzymes are not only involved in fucose production but are also important for LPS construction. In addition, these two gene knockout mutants exhibited retarded growth, increased surface hydrophobicity and autoaggregation as well as being more sensitive to the detergent SDS and the antibiotic novobiocin. Furthermore, the LPS-defective mutants also had significantly reduced bacterial infection, adhesion and internalization in the in vitro cell line model. Moreover, disruptions of the and genes in altered protein sorting into outer membrane vesicles. The critical roles of and in LPS biosynthesis, bacterial fitness and pathogenesis make them attractive candidates for drug inventions against infection.
PubMed: 35052824
DOI: 10.3390/biomedicines10010145 -
Frontiers in Veterinary Science 2023Inosine monophosphate (IMP) is naturally present in poultry muscle and plays a key role in improving meat flavour. However, IMP deposition is regulated by numerous genes...
BACKGROUND
Inosine monophosphate (IMP) is naturally present in poultry muscle and plays a key role in improving meat flavour. However, IMP deposition is regulated by numerous genes and complex molecular networks. In order to excavate key candidate genes that may regulate IMP synthesis, we performed proteome and metabolome analyses on the leg muscle, compared to the breast muscle control of 180-day-old Jingyuan chickens (hens), which had different IMP content. The key candidate genes identified by a differential analysis were verified to be associated with regulation of IMP-specific deposition.
RESULTS
The results showed that the differentially expressed (DE) proteins and metabolites jointly involve 14 metabolic pathways, among which the purine metabolic pathway closely related to IMP synthesis and metabolism is enriched with four DE proteins downregulated (with higher expression in breast muscles than in leg muscles), including adenylate kinase 1 (), adenosine monophosphate deaminase 1 (), pyruvate kinase muscle isoenzyme 2 () and phosphoglucomutase 1 (), six DE metabolites, Hypoxanthine, Guanosine, L-Glutamine, AICAR, AMP and Adenylsuccinic acid. Analysis of gene showed that the high expression of promoted the proliferation and differentiation of myoblasts and inhibited the apoptosis of myoblasts. ELISA tests have shown that reduced adenosine triphosphate (ATP) and IMP and uric acid (UA), while enhancing the biosynthesis of hypoxanthine (HX). In addition, up-regulation of inhibited the expression of purine metabolism pathway related genes, and promoted the IMP and salvage synthesis pathways.
CONCLUSION
This study preliminarily explored the mechanism of action of in regulating the growth and development of myoblasts and specific IMP deposition in Jingyuan chickens, which provided certain theoretical basis for the development and utilization of excellent traits in Jingyuan chickens.
PubMed: 38164393
DOI: 10.3389/fvets.2023.1276582 -
Brain : a Journal of Neurology Dec 2019It is important to understand how the disease process affects the metabolic pathways in amyotrophic lateral sclerosis and whether these pathways can be manipulated to...
It is important to understand how the disease process affects the metabolic pathways in amyotrophic lateral sclerosis and whether these pathways can be manipulated to ameliorate disease progression. To analyse the basis of the metabolic defect in amyotrophic lateral sclerosis we used a phenotypic metabolic profiling approach. Using fibroblasts and reprogrammed induced astrocytes from C9orf72 and sporadic amyotrophic lateral sclerosis cases we measured the production rate of reduced nicotinamide adenine dinucleotides (NADH) from 91 potential energy substrates simultaneously. Our screening approach identified that C9orf72 and sporadic amyotrophic lateral sclerosis induced astrocytes have distinct metabolic profiles compared to controls and displayed a loss of metabolic flexibility that was not observed in fibroblast models. This loss of metabolic flexibility, involving defects in adenosine, fructose and glycogen metabolism, as well as disruptions in the membrane transport of mitochondrial specific energy substrates, contributed to increased starvation induced toxicity in C9orf72 induced astrocytes. A reduction in glycogen metabolism was attributed to loss of glycogen phosphorylase and phosphoglucomutase at the protein level in both C9orf72 induced astrocytes and induced neurons. In addition, we found alterations in the levels of fructose metabolism enzymes and a reduction in the methylglyoxal removal enzyme GLO1 in both C9orf72 and sporadic models of disease. Our data show that metabolic flexibility is important in the CNS in times of bioenergetic stress.
Topics: Adult; Aged; Amyotrophic Lateral Sclerosis; Astrocytes; C9orf72 Protein; Disease Progression; Energy Metabolism; Female; Glycogen Phosphorylase; Humans; Male; Middle Aged; Mitochondria; Motor Neurons
PubMed: 31647549
DOI: 10.1093/brain/awz302 -
The New Phytologist Aug 2021Rice (Oryza sativa) tiller angle is a key component for achieving ideal plant architecture and higher grain yield. However, the molecular mechanism underlying rice...
Rice (Oryza sativa) tiller angle is a key component for achieving ideal plant architecture and higher grain yield. However, the molecular mechanism underlying rice tiller angle remains elusive. We characterized a novel rice tiller angle mutant lazy2 (la2) and isolated the causative gene LA2 through map-based cloning. Biochemical, molecular and genetic studies were conducted to elucidate the LA2-involved tiller angle regulatory mechanism. The la2 mutant shows large tiller angle with impaired shoot gravitropism and defective asymmetric distribution of auxin. We found that starch granules in amyloplasts are completely lost in the gravity-sensing leaf sheath base cells of la2, whereas the seed development is not affected. LA2 encodes a novel chloroplastic protein that can interact with the starch biosynthetic enzyme Oryza sativa plastidic phosphoglucomutase (OspPGM) to regulate starch biosynthesis in rice shoot gravity-sensing cells. Genetic analysis showed that LA2 regulates shoot gravitropism and tiller angle by acting upstream of LA1 to mediate lateral auxin transport. Our studies revealed that LA2 acts as a novel regulator of rice tiller angle by specifically regulating starch biosynthesis in gravity-sensing cells, and established the framework of the starch-statolith-dependent rice tiller angle regulatory pathway, providing new insights into the rice tiller angle regulatory network.
Topics: Gene Expression Regulation, Plant; Gravitropism; Oryza; Plant Proteins; Starch
PubMed: 34042184
DOI: 10.1111/nph.17426 -
Cancer Cell International 2019Phosphoglucomutase (PGM), a key enzyme in the metabolism of glucose-1-phosphate and glucose-6-phosphate, has been found to be associated with proliferation, invasion,...
BACKGROUND
Phosphoglucomutase (PGM), a key enzyme in the metabolism of glucose-1-phosphate and glucose-6-phosphate, has been found to be associated with proliferation, invasion, and metastasis of cancer. However, the expression and function of PGM5 in colorectal cancer (CRC) remains unknown.
METHODS
We tested PGM5 mRNA and protein expression levels in 79 CRC tissue and their matched adjacent tissue samples by qRT-PCR and immunohistochemistry, respectively. Overall survival (OS) was estimated with the Kaplan-Meier method and compared between groups with the log-rank test. We performed multivariable Cox regression analyses to identify factors associated with CRC risk. The cell proliferation, migration and invasion abilities of CRC cells were detected by using CCK-8, Transwell migration and invasion assays, respectively.
RESULTS
The PGM5 protein levels expression in CRC tissues were significantly lower than those in the adjacent tissues (t = 5.035, < 0.001), and Kaplan-Meier analysis indicated that low PGM5 expression were significantly associated with poor overall survival (= 0.0069). Univariate and multivariate analyses demonstrated that PGM5 was an independent risk factor for overall survival (hazard ratio = 0.3951, = 0.014). PGM5 overexpression significantly inhibited the proliferation, invasion and migration abilities of CRC cells. On the contrary, knockdown of PGM5 promotes the invasion and migration of CRC cells.
CONCLUSIONS
PMG5 regulates proliferation, invasion, and migration in the CRC and decreased PGM5 is associated with poor prognosis. Therefore, PGM5 is a promising biomarker in CRC and decreased PGM5 may predict poor overall survival in patients with CRC.
PubMed: 31582909
DOI: 10.1186/s12935-019-0967-y -
Poultry Science Dec 2023Chronic heat stress has detrimental effects on the growth performance of broilers, and the potential mechanism is under exploration. In this study, the protein carbonyl...
Chronic heat stress has detrimental effects on the growth performance of broilers, and the potential mechanism is under exploration. In this study, the protein carbonyl modification was introduced to glycolytic enzymes to evaluate its relationship with the growth performance of heat-stressed (HS) broilers. A total of 144 male 28-day-old broilers were assigned to 3 treatments: the normal control group (NC, raised at 22°C with free access to feed and water), the HS group (raised at 32°C with free access to feed and water), and the pair-fed group (PF, raised at 22°C with an amount of feed equal to that consumed by the HS group on a previous day). Results showed that heat stress decreased the average daily growth, increased the feed-to-gain ratio (F/G), decreased breast muscle rate, and increased abdominal fat rate compared with the NC and PF groups (P < 0.05). Higher cloacal temperature and serum creatine kinase activity were found in the HS group than those of the NC and PF groups (P < 0.05). Heat stress increased the contents of carbonyl, advanced glycation end-products, malonaldehyde, and the activities of catalase, glutathione peroxidase, and total antioxidant capacity compared with the NC and PF groups (P < 0.05). Heat stress increased the contents of glucose and lactate, declined the glycogen content, and lowered the relative protein expressions of pyruvate kinase muscle type, lactate dehydrogenase A type (LDHA), and citrate synthase compared to those of the NC group (P < 0.05). In contrast to the NC and PF groups, heat stress intensified the carbonylation levels of phosphoglucomutase 1, triosephosphate isomerase 1, β-enolase, and LDHA, which were positively correlated with the F/G (P < 0.05). These findings demonstrate that heat stress depresses growth performance on account of oxidative stress and glycolysis disorders. It further increases the carbonylation of glycolytic enzymes, which potentially correlates with the F/G by disturbing the mode of energy supply of broilers.
Topics: Male; Animals; Chickens; Heat-Shock Response; Glycolysis; Pectoralis Muscles; Water; Animal Feed; Dietary Supplements; Hot Temperature; Diet
PubMed: 37837679
DOI: 10.1016/j.psj.2023.103103 -
Genes Nov 2022Sweet potato (Ipomoea batatas), an important root crop, has storage roots rich in starch that are edible and serve as a raw material in bioenergy production. Increasing...
Sweet potato (Ipomoea batatas), an important root crop, has storage roots rich in starch that are edible and serve as a raw material in bioenergy production. Increasing the storage-root starch contents is a key sweet potato breeding goal. Phosphoglucomutase (PGM) is the catalytic enzyme for the interconversion of glucose-6-phosphate and glucose-1-phosphate, precursors in the plant starch synthetic pathway. Plant PGMs have plastidial and cytosolic isoforms, based on their subcellular localization. Here, , containing 22 exons and 21 introns, was cloned from the sweet potato line Xu 781. This gene was highly expressed in the storage roots and leaves, and its expression was induced by exogenous sucrose treatments. The mature IbpPGM protein was successfully expressed in when a 73-aa chloroplastic transit peptide detected in the N-terminus was excised. The subcellular localization confirmed that IbpPGM was localized to the chloroplasts. The low-starch sweet potato cultivar Lizixiang -overexpression lines showed significantly increased starch, glucose, and fructose levels but a decreased sucrose level. Additionally, the expression levels of the starch synthetic pathway genes in the storage roots were up-regulated to different extents. Thus, significantly increased the starch content of the sweet potato storage roots, which makes it a candidate gene for the genetic engineering of the sweet potato.
Topics: Starch; Ipomoea batatas; Phosphoglucomutase; Plant Roots; Plant Breeding; Sucrose
PubMed: 36553501
DOI: 10.3390/genes13122234 -
ELife Oct 2022The most common cause of human congenital disorders of glycosylation (CDG) are mutations in the phosphomannomutase gene which affect protein -linked glycosylation. The...
The most common cause of human congenital disorders of glycosylation (CDG) are mutations in the phosphomannomutase gene which affect protein -linked glycosylation. The yeast gene encodes a homolog of human . We evolved 384 populations of yeast harboring one of two human-disease-associated alleles, V238M and -F126L, or wild-type . We find that after 1000 generations, most populations compensate for the slow-growth phenotype associated with the human-disease-associated alleles. Through whole-genome sequencing we identify compensatory mutations, including known genetic interactors. We observe an enrichment of compensatory mutations in other genes whose human homologs are associated with Type 1 CDG, including , which encodes the minor isoform of phosphoglucomutase in yeast. By genetic reconstruction, we show that evolved mutations are dominant and allele-specific genetic interactors that restore both protein glycosylation and growth of yeast harboring the -V238M allele. Finally, we characterize the enzymatic activity of purified Pgm1 mutant proteins. We find that reduction, but not elimination, of Pgm1 activity best compensates for the deleterious phenotypes associated with the -V238M allele. Broadly, our results demonstrate the power of experimental evolution as a tool for identifying genes and pathways that compensate for human-disease-associated alleles.
Topics: Humans; Saccharomyces cerevisiae; Congenital Disorders of Glycosylation; Phosphoglucomutase; Mutant Proteins; Saccharomyces cerevisiae Proteins
PubMed: 36214454
DOI: 10.7554/eLife.79346 -
MBio Aug 2022The reactions of α-d-phosphohexomutases (αPHM) are ubiquitous, key to primary metabolism, and essential for several processes in all domains of life. The functionality...
The reactions of α-d-phosphohexomutases (αPHM) are ubiquitous, key to primary metabolism, and essential for several processes in all domains of life. The functionality of these enzymes relies on an initial phosphorylation step which requires the presence of α-d-glucose-1,6-bisphosphate (Glc-1,6-BP). While well investigated in vertebrates, the origin of this activator compound in bacteria is unknown. Here we show that the Slr1334 protein from the unicellular cyanobacterium sp. PCC 6803 is a Glc-1,6-BP-synthase. Biochemical analysis revealed that Slr1334 efficiently converts fructose-1,6-bisphosphate (Frc-1,6-BP) and α-d-glucose-1-phosphate/α-d-glucose-6-phosphate into Glc-1,6-BP and also catalyzes the reverse reaction. As inferred from phylogenetic analysis, the product belongs to a primordial subfamily of αPHMs that is present especially in deeply branching bacteria and also includes human commensals and pathogens. Remarkably, the homologue of Slr1334 in the human gut bacterium Bacteroides salyersiae catalyzes the same reaction, suggesting a conserved and essential role for the members of this αPHM subfamily. Glc-1,6-BP is known as an essential activator of phosphoglucomutase (PGM) and other members of the αPHM superfamily, making it a central regulator in glycogen metabolism, glycolysis, amino sugar formation as well as bacterial cell wall and capsule formation. Despite this essential role in carbon metabolism, its origin in prokaryotes has so far remained elusive. In this study we identify a member of a specific αPHM subfamily as the first bacterial Glc-1,6-BP synthase, forming free Glc-1,6-BP by using Frc-1,6-BP as phosphoryl-donor. PGMs of this subfamily are widely distributed among prokaryotes including human commensals and pathogens. By showing that a distinct subfamily member can also form Glc-1,6-BP, we provide evidence that Glc-1,6-BP synthase activity is a general feature of this group.
Topics: Animals; Glucose; Glucose-6-Phosphate; Humans; Phosphoglucomutase; Phylogeny
PubMed: 35856562
DOI: 10.1128/mbio.01469-22