RNA Second Messengers and Riboswitches: Relics from the RNA World?

Ronald R. Breaker

doi:10.1128/microbe.5.13.1

A revised mechanism for (p)ppGpp synthesis by Rel proteins: The critical role of the 2′-OH of GTP

Journal of Biological Chemistry ◽

10.1074/jbc.ra120.013636 ◽

2020 ◽

Vol 295 (37) ◽

pp. 12851-12867

Author(s):

Pratik Rajendra Patil ◽

Neha Vithani ◽

Virender Singh ◽

Ashok Kumar ◽

Balaji Prakash

Keyword(s):

Active Site ◽

Catalytic Mechanism ◽

Rna World ◽

Second Messengers ◽

Critical Role ◽

Catalytic Role ◽

World Hypothesis ◽

First Time ◽

Selection Of

Bacterial Rel proteins synthesize hyperphosphorylated guanosine nucleotides, denoted as (p)ppGpp, which by inhibiting energy requiring molecular pathways help bacteria to overcome the depletion of nutrients in its surroundings. (p)ppGpp synthesis by Rel involves transferring a pyrophosphate from ATP to the oxygen of 3′-OH of GTP/GDP. Initially, a conserved glutamate at the active site was believed to generate the nucleophile necessary to accomplish the reaction. Later this role was alluded to a Mg2+ ion. However, no study has unequivocally established a catalytic mechanism for (p)ppGpp synthesis. Here we present a revised mechanism, wherein for the first time we explore a role for 2′-OH of GTP and show how it is important in generating the nucleophile. Through a careful comparison of substrate-bound structures of Rel, we illustrate that the active site does not discriminate GTP from dGTP, for a substrate. Using biochemical studies, we demonstrate that both GTP and dGTP bind to Rel, but only GTP (but not dGTP) can form the product. Reactions performed using GTP analogs substituted with different chemical moieties at the 2′ position suggest a clear role for 2′-OH in catalysis by providing an indispensable hydrogen bond; preliminary computational analysis further supports this view. This study elucidating a catalytic role for 2′-OH of GTP in (p)ppGpp synthesis allows us to propose different mechanistic possibilities by which it generates the nucleophile for the synthesis reaction. This study underscores the selection of ribose nucleotides as second messengers and finds its roots in the old RNA world hypothesis.

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Building blocks for 'RNA world' made from simple ingredients

Nature ◽

10.1038/nature.2016.19901 ◽

2016 ◽

Cited By ~ 1

Author(s):

Davide Castelvecchi

Keyword(s):

Rna World ◽

Building Blocks

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A new tool for investigating the function of the two second messengers of the phosphoinositide system: RHC 80267

Acta Endocrinologica ◽

10.1530/acta.0.117s044-a ◽

1988 ◽

Vol 117 (4_Suppl) ◽

pp. S44-S45

Author(s):

A. PFEIFFER ◽

B. NOELKE ◽

H. ROCHLITZ

Keyword(s):

Second Messengers

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Randomness and Complexity

10.1093/oso/9780198814825.003.0007 ◽

2018 ◽

Author(s):

Steven E. Vigdor

Keyword(s):

Quantum Mechanics ◽

Natural Selection ◽

Rna World ◽

Biological Evolution ◽

Variable Theory ◽

Cosmological Natural Selection ◽

Einstein Podolsky Rosen ◽

World Hypothesis ◽

Rna World Hypothesis

Chapter 7 describes the fundamental role of randomness in quantum mechanics, in generating the first biomolecules, and in biological evolution. Experiments testing the Einstein–Podolsky–Rosen paradox have demonstrated, via Bell’s inequalities, that no local hidden variable theory can provide a viable alternative to quantum mechanics, with its fundamental randomness built in. Randomness presumably plays an equally important role in the chemical assembly of a wide array of polymer molecules to be sampled for their ability to store genetic information and self-replicate, fueling the sort of abiogenesis assumed in the RNA world hypothesis of life’s beginnings. Evidence for random mutations in biological evolution, microevolution of both bacteria and antibodies and macroevolution of the species, is briefly reviewed. The importance of natural selection in guiding the adaptation of species to changing environments is emphasized. A speculative role of cosmological natural selection for black-hole fecundity in the evolution of universes is discussed.

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Sensory Transduction

10.1093/oso/9780198835028.001.0001 ◽

2019 ◽

Cited By ~ 2

Author(s):

Gordon L. Fain

Keyword(s):

Ion Channels ◽

Receptor Cell ◽

Electrical Response ◽

Second Messengers ◽

Sensory Transduction ◽

Sensory Receptor ◽

Signal Pathways ◽

Sense Organs ◽

Sensory Physiology ◽

Effector Molecules

Sensory Transduction provides a thorough and easily accessible introduction to the mechanisms that each of the different kinds of sensory receptor cell uses to convert a sensory stimulus into an electrical response. Beginning with an introduction to methods of experimentation, sensory specializations, ion channels, and G-protein cascades, it provides up-to-date reviews of all of the major senses, including touch, hearing, olfaction, taste, photoreception, and the “extra” senses of thermoreception, electroreception, and magnetoreception. By bringing mechanisms of all of the senses together into a coherent treatment, it facilitates comparison of ion channels, metabotropic effector molecules, second messengers, and other components of signal pathways that are common themes in the physiology of the different sense organs. With its many clear illustrations and easily assimilated exposition, it provides an ideal introduction to current research for the professional in neuroscience, as well as a text for an advanced undergraduate or graduate-level course on sensory physiology.

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Endothelin stimulates chloride secretion across canine tracheal epithelium

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.1991.261.2.l188 ◽

1991 ◽

Vol 261 (2) ◽

pp. L188-L194 ◽

Cited By ~ 2

Author(s):

P. I. Plews ◽

Z. A. Abdel-Malek ◽

C. A. Doupnik ◽

G. D. Leikauf

Keyword(s):

Epithelial Cells ◽

Short Circuit ◽

Second Messengers ◽

Short Circuit Current ◽

Chloride Secretion ◽

Tracheal Epithelium ◽

Membrane Phospholipids ◽

Cl Secretion ◽

Tracheal Epithelial Cells ◽

Tracheal Epithelial

The endothelins (ET) are a group of isopeptides produced by a number of cells, including canine tracheal epithelial cells. Because these compounds are endogenous peptides that may activate eicosanoid metabolism, we investigated the effects of ET on Cl secretion in canine tracheal epithelium. Endothelin 1 (ET-1) was found to produce a dose-dependent change in short-circuit current (Isc) that increased slowly and reached a maximal value within 10-15 min. When isopeptides of ET were compared, 300 nM ET-1 and ET-2 produced comparable maximal increases in Isc, whereas ET-3 produced smaller changes in Isc (half-maximal concentrations of 2.2, 7.2, and 10.4 nM, respectively). Ionic substitution of Cl with nontransported anions, iodide and gluconate, reduced ET-1-induced changes in Isc. Furthermore, the response was inhibited by the NaCl cotransport inhibitor, furosemide. In paired tissues, ET-1 significantly increased mucosal net 36Cl flux without significant effect on 22Na flux. The increase in Isc induced by ET was diminished by pretreatment with indomethacin. The second messengers mediating the increase in Isc were investigated in cultured canine tracheal epithelial cells. ET-1 stimulated the release of [3H]arachidonate from membrane phospholipids, increased intracellular Ca2+ (occasionally producing oscillations), and increased adenosine 3',5'-cyclic monophosphate accumulation. The latter was diminished by indomethacin. Thus ET is a potent agonist of Cl secretion (with the isopeptides having the following potency: ET-1 greater than or equal to ET-2 greater than ET-3) and acts, in part, through a cyclooxygenase-dependent mechanism.

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Are Scientific Models of Life Testable? A Lesson from Simpson’s Paradox

Sci ◽

10.3390/sci2030073 ◽

2020 ◽

Vol 2 (3) ◽

pp. 73

Author(s):

Prasanta S. Bandyopadhyay ◽

Nolan Grunska ◽

Don Dcruz ◽

Mark C. Greenwood

Keyword(s):

Origin Of Life ◽

Rna World ◽

Scientific Models ◽

Scientific Model ◽

Simpson’S Paradox ◽

World Theory ◽

Life Issues ◽

The Origin Of Life ◽

Logical Sense ◽

Simpson's Paradox

We address the need for a model by considering two competing theories regarding the origin of life: (i) the Metabolism First theory and (ii) the RNA World theory. We discuss two inter-related points. (I) Models are valuable tools in understanding both the processes and intricacies of the origin of life issues. (II) Insights from models also help us to evaluate the core objection to origin of life theories called “the inefficiency objection” commonly raised by proponents of both the Metabolism First theory and the RNA World theory against each other. We use Simpson’s paradox as a tool for challenging this objection. We will use models in various senses ranging from taking them as representations of reality to treating them as theories/accounts that provide heuristics for probing reality. In this paper, we will frequently use models and theories interchangeably. Additionally, we investigate Conway’s Game of Life and contrast it with our Simpson’s Paradox (SP)-based approach to emergence of life issues. Finally, we discuss some of the consequences of our view. A scientific model is testable in three senses: (i) a logical sense, (ii) a nomological sense, and (iii) a current technological sense. The SP-based model is testable in the logical sense. It is also testable nomologically. However, it is not currently feasible to test it.

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