-
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 -
Annals of Indian Academy of Neurology 2023
PubMed: 38022433
DOI: 10.4103/aian.aian_824_23 -
Frontiers in Chemistry 2023Drug Design (dnDD) aims to create new molecules that satisfy multiple conflicting objectives. Since several desired properties can be considered in the optimization... (Review)
Review
Drug Design (dnDD) aims to create new molecules that satisfy multiple conflicting objectives. Since several desired properties can be considered in the optimization process, dnDD is naturally categorized as a many-objective optimization problem (ManyOOP), where more than three objectives must be simultaneously optimized. However, a large number of objectives typically pose several challenges that affect the choice and the design of optimization methodologies. Herein, we cover the application of multi- and many-objective optimization methods, particularly those based on Evolutionary Computation and Machine Learning techniques, to enlighten their potential application in dnDD. Additionally, we comprehensively analyze how molecular properties used in the optimization process are applied as either objectives or constraints to the problem. Finally, we discuss future research in many-objective optimization for dnDD, highlighting two important possible impacts: i) its integration with the development of multi-target approaches to accelerate the discovery of innovative and more efficacious drug therapies and ii) its role as a catalyst for new developments in more fundamental and general methodological frameworks in the field.
PubMed: 38192501
DOI: 10.3389/fchem.2023.1288626 -
Blood Advances Nov 2023Hemogenic endothelial cells (HECs) are specialized cells that undergo endothelial-to-hematopoietic transition (EHT) to give rise to the earliest precursors of...
Hemogenic endothelial cells (HECs) are specialized cells that undergo endothelial-to-hematopoietic transition (EHT) to give rise to the earliest precursors of hematopoietic progenitors that will eventually sustain hematopoiesis throughout the lifetime of an organism. Although HECs are thought to be primarily limited to the aorta-gonad-mesonephros (AGM) during early development, EHT has been described in various other hematopoietic organs and embryonic vessels. Though not defined as a hematopoietic organ, the lung houses many resident hematopoietic cells, aids in platelet biogenesis, and is a reservoir for hematopoietic stem and progenitor cells (HSPCs). However, lung HECs have never been described. Here, we demonstrate that the fetal lung is a potential source of HECs that have the functional capacity to undergo EHT to produce de novo HSPCs and their resultant progeny. Explant cultures of murine and human fetal lungs display adherent endothelial cells transitioning into floating hematopoietic cells, accompanied by the gradual loss of an endothelial signature. Flow cytometric and functional assessment of fetal-lung explants showed the production of multipotent HSPCs that expressed the EHT and pre-HSPC markers EPCR, CD41, CD43, and CD44. scRNA-seq and small molecule modulation demonstrated that fetal lung HECs rely on canonical signaling pathways to undergo EHT, including TGFβ/BMP, Notch, and YAP. Collectively, these data support the possibility that post-AGM development, functional HECs are present in the fetal lung, establishing this location as a potential extramedullary site of de novo hematopoiesis.
Topics: Animals; Mice; Humans; Hematopoiesis; Hematopoietic Stem Cells; Cell Differentiation; Endothelium; Hemangioblasts
PubMed: 37729429
DOI: 10.1182/bloodadvances.2022008347 -
Kidney International Reports Sep 2023Belimumab was recently approved for treating lupus nephritis (LN), yet LN cases during belimumab treatment given for nonrenal causes have been reported. Identification...
INTRODUCTION
Belimumab was recently approved for treating lupus nephritis (LN), yet LN cases during belimumab treatment given for nonrenal causes have been reported. Identification of reliable signals of impending flare is imperative.
METHODS
We evaluated belimumab efficacy in preventing renal flares and factors associated with renal flare occurrence in nephritis-naïve patients with systemic lupus erythematosus (SLE) who are receiving add-on belimumab or placebo in 5 phase 3 clinical trials using Cox regression analysis.
RESULTS
Of 1844 eligible patients, 136 (7.4%) developed a renal flare during a 52-week long follow-up. Asian origin (Adjusted Hazard Ratio [HR]: 1.97; 95% confidence interval [CI]: 1.32-2.94; = 0.001), positive baseline anti-double stranded DNA (anti-dsDNA) levels (HR: 1.32; 95% CI: 1.07-1.63; = 0.008), and increasing mean prednisone dose during follow-up (HR: 1.03; 95% CI: 1.02-1.04; < 0.001) were associated with renal flares. Low-dose intravenous (IV) belimumab (1 mg/kg monthly) yielded a nearly 3-fold lower hazard of renal flare (HR: 0.38; 95% CI: 0.20-0.73; = 0.004). Subcutaneous (SC) belimumab (200 mg weekly) also yielded a lower hazard (HR: 0.69; 95% CI: 0.54-0.88; = 0.003). The labeled IV dose (10 mg/kg monthly) conferred no clear protection (HR: 0.74; 95% CI: 0.50-1.09; = 0.127).
CONCLUSION
We corroborated the substantial vulnerability of the Asian SLE population to renal affliction. Add-on low-dose IV belimumab (1 mg/kg) and SC belimumab appeared protective against renal flares in nephritis-naïve patients with SLE. The approved IV dose (10 mg/kg) yielded no clear protection.
PubMed: 37705915
DOI: 10.1016/j.ekir.2023.06.021