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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 -
Nature Reviews. Chemistry Jan 2022Natural metalloproteins perform many functions - ranging from sensing to electron transfer and catalysis - in which the position and property of each ligand and metal,...
Natural metalloproteins perform many functions - ranging from sensing to electron transfer and catalysis - in which the position and property of each ligand and metal, is dictated by protein structure. De novo protein design aims to define an amino acid sequence that encodes a specific structure and function, providing a critical test of the hypothetical inner workings of (metallo)proteins. To date, de novo metalloproteins have used simple, symmetric tertiary structures - uncomplicated by the large size and evolutionary marks of natural proteins - to interrogate structure-function hypotheses. In this Review, we discuss de novo design applications, such as proteins that induce complex, increasingly asymmetric ligand geometries to achieve function, as well as the use of more canonical ligand geometries to achieve stability. De novo design has been used to explore how proteins fine-tune redox potentials and catalyse both oxidative and hydrolytic reactions. With an increased understanding of structure-function relationships, functional proteins including O-dependent oxidases, fast hydrolases, and multi-proton/multi-electron reductases, have been created. In addition, proteins can now be designed using xeno-biological metals or cofactors and principles from inorganic chemistry to derive new-to-nature functions. These results and the advances in computational protein design suggest a bright future for the de novo design of diverse, functional metalloproteins.
PubMed: 35811759
DOI: 10.1038/s41570-021-00339-5 -
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 -
Orvosi Hetilap Feb 2018Endogenous glucocorticoids exert a diverse array of physiological processes and play an important role in immune modulatory and anti-inflammatory responses. The... (Review)
Review
Endogenous glucocorticoids exert a diverse array of physiological processes and play an important role in immune modulatory and anti-inflammatory responses. The secretion of cortisol by the adrenal gland is regulated through two mechanisms. Systemic regulation is substantiating by the hypothalamo-pituitary-adrenal axis. Furthermore, a tissue-specific local regulatory system, containing the 11β-hydroxysteroid dehydrogenase enzyme responsible for local glucocorticoid synthesis and the glucocorticoid receptor, has also been demonstrated. Based on the recent evidences, an extra-adrenal corticosteroid synthesis exists in various tissues. Steroidogenic enzymes necessary for this de novo corticosteroid synthesis have been observed in the skin, intestine, thymus and possibly in the brain, heart and lung. These locally synthesized steroids most likely act in an autocrine and paracrine manner and their regulation is mediated by local regulatory loops. The importance of this de novo corticosteroid synthesis seems to be important in the regulation of local homeostasis, immune processes and tissue-specific inflammatory reactions. Orv Hetil. 2018; 159(7): 260-268.
Topics: Adrenal Glands; Glucocorticoids; Homeostasis; Humans; Metabolic Networks and Pathways
PubMed: 29429352
DOI: 10.1556/650.2018.31019 -
Drug Discovery Today Nov 2021Molecular design strategies are integral to therapeutic progress in drug discovery. Computational approaches for de novo molecular design have been developed over the... (Review)
Review
Molecular design strategies are integral to therapeutic progress in drug discovery. Computational approaches for de novo molecular design have been developed over the past three decades and, recently, thanks in part to advances in machine learning (ML) and artificial intelligence (AI), the drug discovery field has gained practical experience. Here, we review these learnings and present de novo approaches according to the coarseness of their molecular representation: that is, whether molecular design is modeled on an atom-based, fragment-based, or reaction-based paradigm. Furthermore, we emphasize the value of strong benchmarks, describe the main challenges to using these methods in practice, and provide a viewpoint on further opportunities for exploration and challenges to be tackled in the upcoming years.
Topics: Artificial Intelligence; Computer Simulation; Drug Design; Drug Discovery; Drug Evaluation, Preclinical; Humans; Machine Learning; Workflow
PubMed: 34082136
DOI: 10.1016/j.drudis.2021.05.019 -
Proteins Oct 2022Membrane transport proteins, which include transporters and channels, are delicate protein machineries that mediate the exchange of a variety of substances across... (Review)
Review
Membrane transport proteins, which include transporters and channels, are delicate protein machineries that mediate the exchange of a variety of substances across biomembranes. Accumulated structural and functional knowledge allows for the de novo design of transport proteins with new structures that do not exist in nature. Analysis based on these novel proteins provides new insights into the principles that govern protein assembly, conformational change, and substrate recognition. Here, we review the advances in the de novo design of transporters and channels over recent years and highlight the challenges and opportunities in this field.
Topics: Biological Transport; Carrier Proteins; Membrane Transport Proteins
PubMed: 35305033
DOI: 10.1002/prot.26336 -
Epigenomes Aug 2022Every cell of an organism shares the same genome; even so, each cellular lineage owns a different transcriptome and proteome. The Polycomb group proteins (PcG) are... (Review)
Review
Every cell of an organism shares the same genome; even so, each cellular lineage owns a different transcriptome and proteome. The Polycomb group proteins (PcG) are essential regulators of gene repression patterning during development and homeostasis. However, it is unknown how the repressive complexes, PRC1 and PRC2, identify their targets and elicit new Polycomb domains during cell differentiation. Classical recruitment models consider the pre-existence of repressive histone marks; still, target binding overcomes the absence of both H3K27me3 and H2AK119ub. The CpG islands (CGIs), non-core proteins, and RNA molecules are involved in Polycomb recruitment. Nonetheless, it is unclear how targets are identified depending on the physiological context and developmental stage and which are the leading players stabilizing Polycomb complexes at domain nucleation sites. Here, we examine the features of sites and the accessory elements bridging its recruitment and discuss the first steps of Polycomb domain formation and transcriptional regulation, comprehended by the experimental reconstruction of the repressive domains through time-resolved genomic analyses in mammals.
PubMed: 35997371
DOI: 10.3390/epigenomes6030025 -
The New Phytologist Jun 2018Contents Summary 1334 I. Introduction 1334 II. Regeneration-initial cell: the origin of regeneration 1335 III. Acquiring regeneration competency: the essential... (Review)
Review
Contents Summary 1334 I. Introduction 1334 II. Regeneration-initial cell: the origin of regeneration 1335 III. Acquiring regeneration competency: the essential intermediate step for hormone-induced regeneration 1335 IV. Hormonal induction of stem cell regulators: the program for de novo establishment of apical meristems 1337 V. Conclusions and perspectives 1337 Acknowledgements 1338 Author contributions 1338 References 1338 SUMMARY: High cellular plasticity confers remarkable regeneration capacity to plants. Based on the activity of stem cells and their regulators, higher plants are capable of regenerating new individuals. De novo organogenesis exemplifies the regeneration of the whole plant body and is exploited widely in agriculture and biotechnology. In this Tansley insight article, we summarize recent advances that facilitate our understanding of the molecular mechanisms underlying de novo organogenesis. According to our current knowledge, this process can be divided into three steps, including activation of regeneration-initial cells, acquisition of competency and de novo establishment of apical meristems. The functions of stem cells and their regulators are critical to de novo organogenesis, whereas auxin and cytokinin act as triggers and linkers between different steps.
Topics: Meristem; Organogenesis; Plant Cells; Plant Growth Regulators; Regeneration; Stem Cells
PubMed: 29574802
DOI: 10.1111/nph.15106 -
Plant & Cell Physiology Nov 2022Most cereal crops were domesticated within the last 12,000 years and subsequently spread around the world. These crops have been nourishing the world by supplying a... (Review)
Review
Most cereal crops were domesticated within the last 12,000 years and subsequently spread around the world. These crops have been nourishing the world by supplying a primary energy and nutrient source, thereby playing a critical role in determining the status of human health and sustaining the global population. Here, we review the major challenges of future agriculture and emphasize the utilization of wild germplasm. De novo domestication is one of the most straightforward strategies to manipulate domestication-related and/or other genes with known function, and thereby introduce desired traits into wild plants. We also summarize known causal variations and their corresponding pathways in order to better understand the genetic basis of crop evolution, and how this knowledge could facilitate de novo domestication. Indeed knowledge-driven de novo domestication has great potential for the development of new sustainable crops that have climate-resilient high yield with low resource input and meet individual nutrient needs. Finally, we discuss current opportunities for and barriers to knowledge-driven de novo domestication.
Topics: Humans; Domestication; Crops, Agricultural; Agriculture; Edible Grain; Phenotype
PubMed: 35762778
DOI: 10.1093/pcp/pcac077 -
Frontiers in Genetics 2022Mosaicism-the existence of genetically distinct populations of cells in a particular organism-is an important cause of genetic disease. Mosaicism can appear as DNA... (Review)
Review
Mosaicism-the existence of genetically distinct populations of cells in a particular organism-is an important cause of genetic disease. Mosaicism can appear as DNA mutations, epigenetic alterations of DNA, and chromosomal abnormalities. Neurodevelopmental or neuropsychiatric diseases, including autism-often arise by mutations that usually not present in either of the parents. mutations might occur as early as in the parental germline, during embryonic, fetal development, and/or post-natally, through ageing and life. Mutation timing could lead to mutation burden of less than heterozygosity to approaching homozygosity. Developmental timing of somatic mutation attainment will affect the mutation load and distribution throughout the body. In this review, we discuss the timing of mutations, spanning from mutations in the germ lineage (all ages), to post-zygotic, embryonic, fetal, and post-natal events, through aging to death. These factors can determine the tissue specific distribution and load of mutations, which can affect disease. The disease threshold burden of somatic mutations of a particular gene in any tissue will be important to define.
PubMed: 36226191
DOI: 10.3389/fgene.2022.983668