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Cell May 2024Purine nucleotides are vital for RNA and DNA synthesis, signaling, metabolism, and energy homeostasis. To synthesize purines, cells use two principal routes: the de novo...
Purine nucleotides are vital for RNA and DNA synthesis, signaling, metabolism, and energy homeostasis. To synthesize purines, cells use two principal routes: the de novo and salvage pathways. Traditionally, it is believed that proliferating cells predominantly rely on de novo synthesis, whereas differentiated tissues favor the salvage pathway. Unexpectedly, we find that adenine and inosine are the most effective circulating precursors for supplying purine nucleotides to tissues and tumors, while hypoxanthine is rapidly catabolized and poorly salvaged in vivo. Quantitative metabolic analysis demonstrates comparative contribution from de novo synthesis and salvage pathways in maintaining purine nucleotide pools in tumors. Notably, feeding mice nucleotides accelerates tumor growth, while inhibiting purine salvage slows down tumor progression, revealing a crucial role of the salvage pathway in tumor metabolism. These findings provide fundamental insights into how normal tissues and tumors maintain purine nucleotides and highlight the significance of purine salvage in cancer.
PubMed: 38823389
DOI: 10.1016/j.cell.2024.05.011 -
Cell Feb 2024Methods from artificial intelligence (AI) trained on large datasets of sequences and structures can now "write" proteins with new shapes and molecular functions de novo,... (Review)
Review
Methods from artificial intelligence (AI) trained on large datasets of sequences and structures can now "write" proteins with new shapes and molecular functions de novo, without starting from proteins found in nature. In this Perspective, I will discuss the state of the field of de novo protein design at the juncture of physics-based modeling approaches and AI. New protein folds and higher-order assemblies can be designed with considerable experimental success rates, and difficult problems requiring tunable control over protein conformations and precise shape complementarity for molecular recognition are coming into reach. Emerging approaches incorporate engineering principles-tunability, controllability, and modularity-into the design process from the beginning. Exciting frontiers lie in deconstructing cellular functions with de novo proteins and, conversely, constructing synthetic cellular signaling from the ground up. As methods improve, many more challenges are unsolved.
Topics: Artificial Intelligence; Protein Conformation; Proteins; Protein Engineering; Deep Learning
PubMed: 38306980
DOI: 10.1016/j.cell.2023.12.028 -
Aging Cell Sep 2023Recent advances highlight the pivotal role of nicotinamide adenine dinucleotide (NAD ) in ovarian aging. However, the roles of de novo NAD biosynthesis on ovarian aging...
Recent advances highlight the pivotal role of nicotinamide adenine dinucleotide (NAD ) in ovarian aging. However, the roles of de novo NAD biosynthesis on ovarian aging are still unknown. Here, we found that genetic ablation of Ido1 (indoleamine-2,3-dioxygenase 1) or Qprt (Quinolinate phosphoribosyl transferase), two critical genes in de novo NAD biosynthesis, resulted in decreased ovarian NAD levels in middle-aged mice, leading to subfertility, irregular estrous cycles, reduced ovarian reserve, and accelerated aging. Moreover, we observed impaired oocyte quality, characterized by increased reactive oxygen species and spindle anomalies, which ultimately led to reduced fertilization ability and impaired early embryonic development. A transcriptomic analysis of ovaries in both mutant and wild-type mice revealed alterations in gene expression related to mitochondrial metabolism. Our findings were further supported by the observation of impaired mitochondrial distribution and decreased mitochondrial membrane potential in the oocytes of knockout mice. Supplementation with nicotinamide riboside (NR), an NAD booster, in mutant mice increased ovarian reserve and improved oocyte quality. Our study highlights the importance of the NAD de novo pathway in middle-aged female fertility.
Topics: Female; Mice; Animals; NAD; Ovary; Mice, Knockout
PubMed: 37332134
DOI: 10.1111/acel.13904 -
Nature Chemical Biology Jan 2024O-linked β-N-acetyl glucosamine (O-GlcNAc) is at the crossroads of cellular metabolism, including glucose and glutamine; its dysregulation leads to molecular and...
O-linked β-N-acetyl glucosamine (O-GlcNAc) is at the crossroads of cellular metabolism, including glucose and glutamine; its dysregulation leads to molecular and pathological alterations that cause diseases. Here we report that O-GlcNAc directly regulates de novo nucleotide synthesis and nicotinamide adenine dinucleotide (NAD) production upon abnormal metabolic states. Phosphoribosyl pyrophosphate synthetase 1 (PRPS1), the key enzyme of the de novo nucleotide synthesis pathway, is O-GlcNAcylated by O-GlcNAc transferase (OGT), which triggers PRPS1 hexamer formation and relieves nucleotide product-mediated feedback inhibition, thereby boosting PRPS1 activity. PRPS1 O-GlcNAcylation blocked AMPK binding and inhibited AMPK-mediated PRPS1 phosphorylation. OGT still regulates PRPS1 activity in AMPK-deficient cells. Elevated PRPS1 O-GlcNAcylation promotes tumorigenesis and confers resistance to chemoradiotherapy in lung cancer. Furthermore, Arts-syndrome-associated PRPS1 R196W mutant exhibits decreased PRPS1 O-GlcNAcylation and activity. Together, our findings establish a direct connection among O-GlcNAc signals, de novo nucleotide synthesis and human diseases, including cancer and Arts syndrome.
Topics: Humans; AMP-Activated Protein Kinases; Phosphorylation; Protein Processing, Post-Translational; Glucose; Nucleotides; N-Acetylglucosaminyltransferases
PubMed: 37308732
DOI: 10.1038/s41589-023-01354-x -
Genes & Diseases Nov 2023nucleotide biosynthetic pathway is a highly conserved and essential biochemical pathway in almost all organisms. Both purine nucleotides and pyrimidine nucleotides are... (Review)
Review
nucleotide biosynthetic pathway is a highly conserved and essential biochemical pathway in almost all organisms. Both purine nucleotides and pyrimidine nucleotides are necessary for cell metabolism and proliferation. Thus, the dysregulation of the nucleotide biosynthetic pathway contributes to the development of many human diseases, such as cancer. It has been shown that many enzymes in this pathway are overactivated in different cancers. In this review, we summarize and update the current knowledge on the nucleotide biosynthetic pathway, regulatory mechanisms, its role in tumorigenesis, and potential targeting opportunities.
PubMed: 37554216
DOI: 10.1016/j.gendis.2022.04.018 -
Molecular Cell Nov 2023PIWI-interacting RNAs (piRNAs) guide transposable element repression in animal germ lines. In Drosophila, piRNAs are produced from heterochromatic loci, called piRNA...
PIWI-interacting RNAs (piRNAs) guide transposable element repression in animal germ lines. In Drosophila, piRNAs are produced from heterochromatic loci, called piRNA clusters, which act as information repositories about genome invaders. piRNA generation by dual-strand clusters depends on the chromatin-bound Rhino-Deadlock-Cutoff (RDC) complex, which is deposited on clusters guided by piRNAs, forming a positive feedback loop in which piRNAs promote their own biogenesis. However, how piRNA clusters are formed before cognate piRNAs are present remains unknown. Here, we report spontaneous de novo piRNA cluster formation from repetitive transgenic sequences. Cluster formation occurs over several generations and requires continuous trans-generational maternal transmission of small RNAs. We discovered that maternally supplied small interfering RNAs (siRNAs) trigger de novo cluster activation in progeny. In contrast, siRNAs are dispensable for cluster function after its establishment. These results reveal an unexpected interplay between the siRNA and piRNA pathways and suggest a mechanism for de novo piRNA cluster formation triggered by siRNAs.
Topics: Animals; RNA, Small Interfering; Piwi-Interacting RNA; Maternal Inheritance; Drosophila; Chromatin; Drosophila Proteins; DNA Transposable Elements; Drosophila melanogaster
PubMed: 37875112
DOI: 10.1016/j.molcel.2023.09.033 -
Annals of Indian Academy of Neurology 2023
PubMed: 38022433
DOI: 10.4103/aian.aian_824_23 -
Current Opinion in Hematology May 2024Lipids play vital roles in platelet structure, signaling, and metabolism. In addition to capturing exogenous lipids, platelets possess the capacity for de novo...
PURPOSE OF REVIEW
Lipids play vital roles in platelet structure, signaling, and metabolism. In addition to capturing exogenous lipids, platelets possess the capacity for de novo lipogenesis, regulated by acetyl-coA carboxylase 1 (ACC1). This review aims to cover the critical roles of platelet de novo lipogenesis and lipidome in platelet production, function, and diseases.
RECENT FINDINGS
Upon platelet activation, approximately 20% of the platelet lipidome undergoes significant modifications, primarily affecting arachidonic acid-containing species. Multiple studies emphasize the impact of de novo lipogenesis, with ACC1 as key player, on platelet functions. Mouse models suggest the importance of the AMPK-ACC1 axis in regulating platelet membrane arachidonic acid content, associated with TXA2 secretion, and thrombus formation. In human platelets, ACC1 inhibition leads to reduced platelet reactivity. Remodeling of the platelet lipidome, alongside with de novo lipogenesis, is also crucial for platelet biogenesis. Disruptions in the platelet lipidome are observed in various pathological conditions, including cardiovascular and inflammatory diseases, with associations between these alterations and shifts in platelet reactivity highlighted.
SUMMARY
The platelet lipidome, partially regulated by ACC-driven de novo lipogenesis, is indispensable for platelet production and function. It is implicated in various pathological conditions involving platelets.
PubMed: 38727017
DOI: 10.1097/MOH.0000000000000820 -
Gene Nov 2023The TBL1XR1 gene encodes the protein transducin-beta-like 1 receptor1, widely distributed in the pituitary, hypothalamus, white and brown adipose tissue, muscle, and... (Review)
Review
BACKGROUND
The TBL1XR1 gene encodes the protein transducin-beta-like 1 receptor1, widely distributed in the pituitary, hypothalamus, white and brown adipose tissue, muscle, and liver. Current evidence suggests that heterozygous TBL1XR1 pathogenic variants can lead to a wide spectrum of phenotypes. This study aims to reveal the clinical phenotype and genetic profiles of de novo TBL1XR1 variations and summarize the relevant clinical and genetic features.
METHODS
We analyzed four new cases harboring de novo TBL1XR1 variants and reviewed all reported cases.
RESULTS
All probands suffered from global developmental delay. Moreover, patient 1 exhibited susceptibility to startle, patient 2 had hypovitaminosis D, short stature and hyponatremia, and patients 3 and 4 both presented with ASD (Autism spectrum disorder) and short stature. They all had a de novo TBL1XR1 variant (NM_024665.7), c.1184A > G (p.Tyr395Cys), c.1108G > A (p.Asp370Asn), c.1047 + 1G > C, and c.1097C > T (p.Ser366Phe) respectively. In addition, pooled analysis of 51 cases showed that they had speech impairment (38/39), intellectual developmental disorder (28/28), global developmental delay (42/42), and hypotonia (24/27), and some of them had epilepsy (10/22), ASD (13/25), and developmental regression (4/13).
CONCLUSIONS
We report four new patients with de novo TBL1XR1 variants and provide a comprehensive overview of 47 previously reported individuals with TBL1XR1 variants, enriching the genotypic and phenotypic spectrum of TBL1XR1-related disease. This report further validates the pathogenicity de novo TBL1XR1 variants.
Topics: Humans; Autism Spectrum Disorder; Genotype; Phenotype; Heterozygote; Adipose Tissue, Brown; Repressor Proteins; Receptors, Cytoplasmic and Nuclear
PubMed: 37683765
DOI: 10.1016/j.gene.2023.147777 -
Transplantation Nov 2023Thrombotic microangiopathy (TMA) is a rare and devastating complication of kidney transplantation, which often leads to graft failure. Posttransplant TMA (PT-TMA) may...
Thrombotic microangiopathy (TMA) is a rare and devastating complication of kidney transplantation, which often leads to graft failure. Posttransplant TMA (PT-TMA) may occur either de novo or as a recurrence of the disease. De novo TMA can be triggered by immunosuppressant drugs, antibody-mediated rejection, viral infections, and ischemia/reperfusion injury in patients with no evidence of the disease before transplantation. Recurrent TMA may occur in the kidney grafts of patients with a history of atypical hemolytic uremic syndrome (aHUS) in the native kidneys. Studies have shown that some patients with aHUS carry genetic abnormalities that affect genes that code for complement regulators (CFH, MCP, CFI) and components (C3 and CFB), whereas in 10% of patients (mostly children), anti-FH autoantibodies have been reported. The incidence of aHUS recurrence is determined by the underlying genetic or acquired complement abnormality. Although treatment of the causative agents is usually the first line of treatment for de novo PT-TMA, this approach might be insufficient. Plasma exchange typically resolves hematologic abnormalities but does not improve kidney function. Targeted complement inhibition is an effective treatment for recurrent TMA and may be effective in de novo PT-TMA as well, but it is necessary to establish which patients can benefit from different therapeutic options and when and how these can be applied.
PubMed: 36944606
DOI: 10.1097/TP.0000000000004585