Reprogramming the genetic code.
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ABSTRACT:
SUBMITTER: Chin JW
PROVIDER: S-EPMC3116288 | biostudies-literature | 2011 May
REPOSITORIES: biostudies-literature
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Project description:The reprogramming of the genetic code through the introduction of noncanonical amino acids (ncAAs) has enabled exciting advances in synthetic biology and peptide drug discovery. Ribosomes that function with high efficiency and fidelity are necessary for all of these efforts, but for challenging ncAAs, the competing processes of near-cognate readthrough and peptidyl-tRNA dropoff can be issues. Here we uncover the surprising extent of these competing pathways in the PURE translation system using mRNAs encoding peptides with affinity tags at the N- and C-termini. We also show that hyperaccurate or error restrictive ribosomes with mutations in ribosomal protein S12 lead to significant improvements in yield and fidelity in the context of both canonical AAs and a challenging α,α-disubstituted ncAA. Hyperaccurate ribosomes also improve yields for quadruplet codon readthrough for a tRNA containing an expanded anticodon stem-loop, although they are not able to eliminate triplet codon reading by this tRNA. The impressive improvements in fidelity and the simplicity of introducing this mutation alongside other efforts to engineer the translation apparatus make hyperaccurate ribosomes an important advance for synthetic biology.
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Project description:The genetic code-the language used by cells to translate their genomes into proteins that perform many cellular functions-is highly conserved throughout natural life. Rewriting the genetic code could lead to new biological functions such as expanding protein chemistries with noncanonical amino acids (ncAAs) and genetically isolating synthetic organisms from natural organisms and viruses. It has long been possible to transiently produce proteins bearing ncAAs, but stabilizing an expanded genetic code for sustained function in vivo requires an integrated approach: creating recoded genomes and introducing new translation machinery that function together without compromising viability or clashing with endogenous pathways. In this review, we discuss design considerations and technologies for expanding the genetic code. The knowledge obtained by rewriting the genetic code will deepen our understanding of how genomes are designed and how the canonical genetic code evolved.
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Project description:Lactate is an end product of glycolysis. As a critical energy source for mitochondrial respiration, lactate also acts as a precursor of gluconeogenesis and a signaling molecule. We briefly summarize emerging concepts regarding lactate metabolism, such as the lactate shuttle, lactate homeostasis, and lactate-microenvironment interaction. Accumulating evidence indicates that lactate-mediated reprogramming of immune cells and enhancement of cellular plasticity contribute to establishing disease-specific immunity status. However, the mechanisms by which changes in lactate states influence the establishment of diverse functional adaptive states are largely uncharacterized. Posttranslational histone modifications create a code that functions as a key sensor of metabolism and are responsible for transducing metabolic changes into stable gene expression patterns. In this review, we describe the recent advances in a novel lactate-induced histone modification, histone lysine lactylation. These observations support the idea that epigenetic reprogramming-linked lactate input is related to disease state outputs, such as cancer progression and drug resistance.
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Project description:When using a compacted version of the "I Ching" genetic code, the number of symbols is reduced to only 8 symbolic binary constants, integrated by only three symbols, being each: either the continuous or the broken horizontal line, plus the respective one word abbreviations of their resulting amino acids, namely, between four to eight accompanying the triad of lines, giving a total set of 46 possible combinations. This study is an alternate way of file compression for the genetic code, focused in the nucleotides, while another one I explored elsewhere, was focused in the groupings of amino acids, both individually and by their codon equivalents. As an Appendix 1 & 2 analogy, I add an example of "mutations" in literature, based on two early versions of "The Fair" (in its first edition of 1963, and in its first red edition of 1971), comparing its vignettes, and written in Spanish by my professor Juan José Arreola, now at his 101 year of birth.
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Project description:Expanding the genetic code to enable the incorporation of unnatural amino acids into proteins in biological systems provides a powerful tool for studying protein structure and function. While this technology has been mostly developed and applied in bacterial and mammalian cells, it recently expanded into animals, including worms, fruit flies, zebrafish, and mice. In this review, we highlight recent advances toward the methodology development of genetic code expansion in animal model organisms. We further illustrate the applications, including proteomic labeling in fruit flies and mice and optical control of protein function in mice and zebrafish. We summarize the challenges of unnatural amino acid mutagenesis in animals and the promising directions toward broad application of this emerging technology.
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Project description:#1. Bottom-up data of ALDOA-K147 purified protein ALDOA-K147-purified-protein #2. Bottom-up data of IP-MS analysis of Klac and KlacOEt 20231016-DIA-IP-N1-con 20231016-DIA-IP-N2-con 20231016-DIA-IP-N3-con 20231016-DIA-IP-N1-Klac 20231016-DIA-IP-N2-Klac 20231016-DIA-IP-N3-Klac 20231016-DIA-IP-N1-KlacOEt 20231016-DIA-IP-N2-KlacOEt 20231016-DIA-IP-N3-KlacOEt 20231016-DDA-IP-con 20231016-DDA-IP-Klac 20231016-DDA-IP-KlacOEt 20231016-input-con 20231016-input-Klac 20231016-input-KlacOEt #3. TRAP analysis of ALDOA-WT and ALDOA-K147 20240307-TRAP-A1 20240307-TRAP-A2 20240307-TRAP-A3 20240307-TRAP-A4 20240307-TRAP-K1 20240307-TRAP-K2 20240307-TRAP-K3 20240307-TRAP-K4
2024-12-15 | PXD052776 | Pride
Project description:A dynamical theory for the evolution of the genetic code is presented, which accounts for its universality and optimality. The central concept is that a variety of collective, but non-Darwinian, mechanisms likely to be present in early communal life generically lead to refinement and selection of innovation-sharing protocols, such as the genetic code. Our proposal is illustrated by using a simplified computer model and placed within the context of a sequence of transitions that early life may have made, before the emergence of vertical descent.
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Project description:Genetic code expansion (GCE) is a versatile tool to site-specifically incorporate a noncanonical amino acid (ncAA) into a protein, for example, to perform fluorescent labeling inside living cells. To this end, an orthogonal aminoacyl-tRNA-synthetase/tRNA (RS/tRNA) pair is used to insert the ncAA in response to an amber stop codon in the protein of interest. One of the drawbacks of this system is that, in order to achieve maximum efficiency, high levels of the orthogonal tRNA are required, and this could interfere with host cell functionality. To minimize the adverse effects on the host, we have developed an inducible GCE system that enables us to switch on tRNA or RS expression when needed. In particular, we tested different promotors in the context of the T-REx or Tet-On systems to control expression of the desired orthogonal tRNA and/or RS. We discuss our result with respect to the control of GCE components as well as efficiency. We found that only the T-REx system enables simultaneous control of tRNA and RS expression.
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