Catalyst: On Organic Systems Chemistry and Origins Research
2017; Elsevier BV; Volume: 2; Issue: 4 Linguagem: Inglês
10.1016/j.chempr.2017.03.018
ISSN2451-9308
Autores Tópico(s)Photoreceptor and optogenetics research
ResumoYitzhak Tor is a professor of chemistry and biochemistry and the George W. and Carol A. Lattimer Professor at the University of California, San Diego. He earned his doctorate degree at the Weizmann Institute of Science (1990) and was a postdoctoral fellow at the California Institute of Technology (1990–1993). His research focuses on the chemistry and biology of nucleosides, nucleotides, and nucleic acids as well as the development of cellular delivery agents and fluorescent nucleoside analogs. He is the editor-in-chief of Perspectives in Medicinal Chemistry and Organic Chemistry Insights. Yitzhak Tor is a professor of chemistry and biochemistry and the George W. and Carol A. Lattimer Professor at the University of California, San Diego. He earned his doctorate degree at the Weizmann Institute of Science (1990) and was a postdoctoral fellow at the California Institute of Technology (1990–1993). His research focuses on the chemistry and biology of nucleosides, nucleotides, and nucleic acids as well as the development of cellular delivery agents and fluorescent nucleoside analogs. He is the editor-in-chief of Perspectives in Medicinal Chemistry and Organic Chemistry Insights. As stated by the late Robert Shapiro in his captivating monograph, “The question of our origin is a glorious one.”1Shapiro R. Origins: A Skeptic’s Guide to the Creation of Life on Earth. Summit Books, 1986Google Scholar How did we arrive at our contemporary biology, which appears extremely diverse but utilizes almost universally the same fundamental processes and building blocks? Such a loaded question has obviously yielded numerous theories (some better defined, a la Shapiro, as myths because they do not adhere to any scientific scrutiny). Perhaps more importantly, though, distinct disciplines have naturally been concerned with different facets of the problem. Although biologists might have been fascinated by the emergence of functional cells or transitioning into multicellular-based living forms, chemists have had to contend with prebiotic chemistry and its associated mysteries and challenges. So, when and how does inanimate chemistry become biology? One cannot do justice to this interdisciplinary, fascinating, and controversial subject and its major players and colorful hypotheses in such a short opinion piece, and as such, it will have to be rather focused. In particular, emphasis will be given to a chemist’s point of view and specifically to the pertinent challenges that organic chemistry has faced. After all, the origin of life is an organic-chemistry-centric query. So, what is life? From a chemist’s perspective, living systems are characterized by non-equilibrium intricate systems of complex and networked reactions capable of self-sustaining and self-replicating (e.g., reproducing) while being adaptive and responsive (hence capable of open-ended evolution). Life thus requires the capability to store and propagate information (i.e., “genetic” material) and a continuous supply of essential reagents and building blocks (i.e., “metabolic” processes). Compartmentalization is clearly essential, because it ultimately sustains such processes, defines entities (i.e., “self” versus “non-self”), and facilitates their adaptation and evolution. This segregation from the environment could also signify a transition from “chemical evolution” (or aptness) to true Darwinian evolution, where beneficial traits and enhanced fitness are gained through accumulated mutations or modifications in the genetic blueprint. Although the definition above conceptually catalogs key traits and functions, it does not identify the specific players, namely the molecules involved. Yet again, our extant biology tells us that we have arrived at a rather specific set of fundamental building blocks that facilitate all of these multifaceted processes, including α-l-amino acids as the fundamental unit of contemporary proteins and selected few pyrimidine and purine heterocyclic nucleobases that, together (and exclusively) with d-ribose and phosphate, constitute our β-nucleotides, the building blocks of our genetic material (and of many cofactors and second messengers). Indeed, their source is where the organic chemistry conundrum lies. What was then the prebiotic origin of the basic building blocks of life? Challenges mount because the conditions and locations are debatable. Compounding the task of identifying viable pathways is the presumed necessity to operate with limited inventory of mostly low-molecular-weight gaseous reagents (e.g., ammonia, hydrogen cyanide, etc.) and transformations employing only a handful of functional groups (e.g., nitriles, aldehydes, unsaturated hydrocarbons, etc.). Significant efforts have been invested in such explorations, however, since the breakthrough 1953 Miller-Urey experiment.2Bada J.L. Lazcano A. Science. 2003; 300: 745-746Crossref PubMed Scopus (95) Google Scholar, 3McCollom T.M. Annu. Rev. Earth Planet. Sci. 2013; 41: 207-229Crossref Scopus (84) Google Scholar This well-known process had demonstrated the formation of amino acids by exposing a mixture of CH4, NH3, H2O, and H2 to spark discharge. Although an incredible milestone, such processes have been questioned as the actual pathway to proteinaceous amino acids because relatively low yields, racemic mixtures, and numerous “by-products” (e.g., urea) are obtained. Formulating prebiotically viable pathways to the contemporary nucleosides and nucleotides has proven even more trying. Beyond the formation of the heterocyclic nucleobases themselves, initially thought to be independently generated through oligomerization of HCN, it has been challenging to replicate their exclusive regio- and stereo-specific attachment to d-ribose in the lab. Furthermore, even the formation of d-ribose as the dominant monosaccharide core, potentially available for glycosylation reactions with nucleobases en route to nucleosides, has been puzzling. Classical views suggesting monosaccharide formation via the formose reaction are problematic mostly because of the difficulties controlling such aldol-like reactions with formaldehyde as the key player. This has been one of the most contentious issues for the reasons discussed next. The sheer complexity of extant living systems and the chicken-and-egg paradoxes inflicted by contemporary biology—our genetic material encodes proteins, which facilitate its replication and the biosynthesis of the necessary nucleoside building blocks—have mystified researchers. In an attempt to reconcile such predicaments, the RNA world hypothesis was formulated.4Robertson M.P. Joyce G.F. Cold Spring Harb. Perspect. Biol. 2012; 4: a003608Crossref Scopus (293) Google Scholar This identifies RNA as a key ancestral molecule capable of both storing information and displaying catalytic abilities (thus combining genetic and metabolic traits). Although not without flaws, it is currently the most reasonable hypothesis at our disposal.5Benner S.A. Kim H.-J. Carrigan M.A. Acc. Chem. Res. 2012; 45: 2025-2034Crossref PubMed Scopus (174) Google Scholar Its challengers, however, have justifiably emphasized the lack of prebiotically viable pathways to nucleotides, the necessary basic components. This has seemingly provided the intellectual freedom to propagate a myriad of alternatives, including “proto-RNA” or other RNA-like (“XNA”) polymers, thus avoiding the elephant in the room: any alternative information-carrying polymer(s) will ultimately have to “evolve” into our contemporary nucleic acids. The chemical community thus has had to either delineate chemically viable pathways to ultimately advance such primitive substitutes into RNA or, alternatively, approach the problem head on and come up with prebiotically viable routes to our contemporary pyrimidine and purine nucleosides and nucleotides. This conundrum has placed prebiotic chemists in dire straits. There is hope, however. The emergence of prebiotic systems chemistry could dramatically change this landscape, as discussed at length by Islam and Powner in this issue of Chem. Its essence, although perhaps counterintuitive at first, posits that the use of complex multi-component reactions, which in certain cases include catalytic additives, photochemical stimulation, and physical separations, can propagate cleaner and more selective reactions, leading to the molecules of life. Early discoveries in this developing field have illustrated that some notoriously non-selective processes can be tamed, affording key building blocks in respectable yields and “correct” stereochemistry while minimizing the formation of undesirable side products. Coupling such reactions to physical processes (e.g., crystallization) has also been illustrated to put uncontrolled and unproductive processes back on track. Effective pathways for long-sought-after prebiotic building blocks have been revealed. Maybe even more exciting is the possibility that common or similar prebiotically accessible ancestor molecules (such as functionalized five-membered heterocycles) could have held central and even global functions in such chemistry, either as reagents or as catalysts. To emphasize the early successes and potential of such approaches, it is worthwhile to recognize the demonstrations that have so far had a rather dramatic impact on the field of prebiotic chemistry. Particularly significant are the following observations, made primarily by Powner and Sutherland:6Powner M.W. Gerland B. Sutherland J.D. Nature. 2009; 459: 239-242Crossref PubMed Scopus (842) Google Scholar, 7Sutherland J.D. Angew. Chem. Int. Ed. 2016; 55: 104-121Crossref PubMed Scopus (254) Google Scholar (1) systems-chemistry-inspired reactions have successfully been shown to generate simple sugars that are essential for ribonucleoside and ribonucleotide synthesis while providing entry into more than half of the proteinogenic amino acids, as well as glycerol (the core triol unit of lipids) and key components of extant metabolic pathways (e.g., phosphoenol moieties); (2) new approaches, opening pathways into the extant nucleosides while circumventing the notoriously challenging N-glycosylation reactions, have been formulated for the pyrimidine nucleosides—related pathways could provide entry into the purine landscape; and (3) additional elements, including sulfur, phosphorous, and transition-metal ions (e.g., CuI/II), as well as physical processes (irradiation, physical separation, etc.), seem to have profound influence on critical reactions either by taming undesired processes or by facilitating hitherto inaccessible ones. It is important to note, of course, that other approaches have been and are being investigated. Although some are at more advanced stages than others, such explorations could ultimately find their place under the expanding umbrella of prebiotic systems chemistry. My personal favorites include (1) Schreiner’s gas-phase formation of hydroxycarbene, which can be viewed as the fundamental unit of monosaccharides and thus be exploited to open new pathways into simple sugars;8Ley D. Gerbig D. Schreiner P.R. Org. Biomol. Chem. 2012; 10: 3781-3790Crossref PubMed Scopus (136) Google Scholar (2) Benner’s pursuit of the profound effects of borates on monosaccharides and their reactivity;5Benner S.A. Kim H.-J. Carrigan M.A. Acc. Chem. Res. 2012; 45: 2025-2034Crossref PubMed Scopus (174) Google Scholar and (3) Carell’s elegant entry into the purine nucleoside manifold through the condensation of formamidopyrimidines with monosaccharides.9Becker S. Thoma I. Deutsch A. Gehrke T. Mayer P. Zipse H. Carell T. Science. 2016; 352: 833-836Crossref PubMed Scopus (135) Google Scholar Together with the pioneering work of Sutherland and Powner discussed above, I see their significance in stirring the field and promoting a departure from old dogmas that might have been fairly debilitating and detrimental to progress. Perhaps more significantly, though, we are experiencing a “head on” tackle of the most challenging aspects of prebiotic chemistry with true scholarship and “good old-fashioned” physical organic chemistry insight. Such a mechanistic-driven approach embraces thermodynamic and/or kinetic hurdles, suggesting the implausibility of certain pathways, and uses them as guiding rules to look elsewhere, beyond the simple disconnections that might be abundant in modern synthetic chemistry. Anecdotally, it is also satisfying to see young investigators entering and revitalizing this demanding field.10Wagner A.J. Blackmond D.G. ACS Cent Sci. 2016; 2: 775-777Crossref PubMed Scopus (14) Google Scholar In days where more and more budding scientists choose to engage in practical “solution-oriented” research (a direction I would define more as a “chemical engineering” tactic than as basic research), it is refreshing to see young organic chemists attacking intellectually loaded fundamental problems. So what are the lessons learned? Systems chemistry approaches seem to have stirred this field onto a new trajectory. Pushing away from the classical pathways relying on spark-discharge-based syntheses, formose-based pathways, and standard glycosylations has proven prudent in formulating fresh approaches to the building blocks of life. It is clear that challenges still exist. One worthy of mentioning is, of course, nature’s “homochirality.” Systems chemistry approaches could ultimately provide deeper insight into this intriguing challenge as well. Beyond origins research, systems chemistry is gaining grounds in related fields (as extensively discussed by Miljanić in this issue of Chem), and perhaps such explorations will ultimately converge into coherent unifying models. My personal ulterior motive in writing this opinion piece is to further inspire young investigators to get involved in this fertile research endeavor and bring their own unbiased thinking into this fascinating field. It is apparent that departing from old dogmas has broken the Gordian knot that has, in many respects, slowed progress in this field. Fresh scholarly analyses have yet again demonstrated their power in tackling challenges previously viewed as insurmountable. However, in times where “alternative facts” are thriving and scientific observations are being questioned, the community engaged in prebiotic chemistry and origins research has to be particularly resilient. It is worthwhile citing Orgel, who, while addressing a particular debate in this field, pointedly stated, “Theories of the origin of life based on metabolic cycles cannot be justified by the inadequacy of competing theories: they must stand on their own.”11Orgel L.E. PLoS Biol. 2008; 6: e18Crossref PubMed Scopus (163) Google Scholar Indeed, the burden on organic chemists is still overwhelming.12Pross A. What is Life? How Chemistry Becomes Biology. Oxford University Press, 2016Google Scholar But, attacking one of the biggest scientific challenges in full force will ultimately teach us why living entities are more than the sum of their chemical components and how chemistry ultimately becomes biology! Reaction: Systematic Hope for Life’s OriginsNiles LehmanChemMay 11, 2017In BriefNiles Lehman received his BS in chemistry from the University of California, Berkeley, in 1984 and his PhD in evolutionary biology from the University of California, Los Angeles, in 1990. He is currently a professor of chemistry at Portland State University and is the editor-in-chief of the Journal of Molecular Evolution. His research focuses on the evolutionary processes leading from chemistry to biology, especially the ability of informational polymers such as RNA to create cooperative networks. Full-Text PDF Open ArchivePrebiotic Systems Chemistry: Complexity Overcoming ClutterIslam et al.ChemApril 13, 2017In BriefPrebiotic systems chemistry is providing unprecedented scope for exploring the origins of life and an exciting new perspective on a four-billion-year-old problem. At the heart of this new systems approach is an understanding that individual classes of metabolites cannot be considered in isolation if the chemical origin of life on Earth is to be successfully elucidated. This review aims to highlight several recent advances that suggest that canonical nucleotides and proteinogenic amino acids are predisposed chemical structures. Full-Text PDF Open ArchiveSmall-Molecule Systems ChemistryOgnjen Š. MiljanićChemApril 13, 2017In BriefSystems chemistry embraces the inherent complexity of chemical phenomena rather than seeking to limit it. Complex chemical systems can operate under kinetic or thermodynamic control and give rise to emergent properties that are impossible to observe in individual components of the system. This review highlights examples of the systems approach to dynamic combinatorial libraries, autocatalytic processes, and chemical reactions at the origins of life, as well as the use of systems chemistry in reaction discovery and synthesis of complex functional molecules. Full-Text PDF Open ArchiveReaction: Life, Origins, and the SystemTerence P. KeeChemMay 11, 2017In BriefTerry Kee is an associate professor of chemistry at the University of Leeds. After earning his doctorate degree at the University of Durham (1989), he spent time as a SERC-NATO postdoctoral fellow at the Massachusetts Institute of Technology (1989–1990) with the now Nobel Laureate Richard R. Schrock. His most recent research in the fields of astrobiology and abiogenesis aims to combine aspects of chemistry, physics, and philosophy to formulate a general theory of living. He served as president of the Astrobiology Society of Britain from 2010 to 2016. Full-Text PDF Open ArchiveReaction: A New Genesis for Origins Research?Leroy CroninChemMay 11, 2017In BriefLeroy Cronin is the Regius Professor of Chemistry at the University of Glasgow. He earned his DPhil at the University of York (1997) and was a postdoctoral fellow in Edinburgh (1998) and an Alexander von Humboldt Research Fellow at the University of Bielefeld (1999). His research focuses on complex chemical systems, artificial intelligence in chemistry, supramolecular chemistry, self-assembly, self-organization, chemical robotics, metal oxides, and redox-active molecules. Full-Text PDF Open Archive
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