Peptide synthesis at the origin of life

doi:10.1126/science.abf1698

GSTDTAP > 气候变化

DOI	10.1126/science.abf1698
	Peptide synthesis at the origin of life
	Kamila B. Muchowska; Joseph Moran
	2020-11-13
发表期刊	Science
出版年	2020
英文摘要	The chemical origin of life is full of chicken-and-egg conundrums. Among these is the origin of protein synthesis. Nature's protein-based enzyme catalysts are built from the polymerization of amino acids, yet this process itself requires enzymes, adenosine triphosphate (ATP), and, most often, a ribosome. How were the first proteins formed on the path from chemistry to life? Despite more than 65 years of research into the chemical origins of life, there is still no clear answer ([ 1 ][1]). On page 865 of this issue, Foden et al. ([ 2 ][2]) tackle the protein-synthesis conundrum from a new angle. Researchers who study prebiotic chemistry have largely pursued two general approaches to make amino acids polymerize in the absence of biological polymers and ATP. Because the direct polymerization of amino acids requires the loss of water, the simplest strategy is to drive the process with wet-dry cycles ([ 3 ][3]). Although drying processes are plausible on a lifeless Earth, they are incompatible with other chemistries in a system containing more than just amino acids. To make matters worse, polymerization under wet-dry cycles might be partially reversible, thus scrambling information contained in the specific peptide sequences ([ 4 ][4]). Retaining intact information would have been essential to life's further complexification. A second major approach uses chemical condensing agents to drive amino acid polymerization. Some of these condensing agents are known from synthetic chemistry but have no clear prebiotic source. Others are plausible in the early Earth environment, but it is difficult to envision them being produced continuously in the needed quantities ([ 1 ][1]). It is unsurprising, however, that nature provides a guide to its own beginnings ([ 5 ][5]). In biochemistry, most amino acid polymerization occurs by translation, which requires ribosomes—a massive assembly of proteins and RNA. Building a primordial ribosome under the conditions of a lifeless planet is a hefty and, as of now, unmet challenge. However, microorganisms use biological nonribosomal peptide synthesis for the production of peptide-based natural products. The nonribosomal peptide synthetases that perform this reaction are chemically much simpler than ribosomes. Nonribosomal peptide synthesis begins with the activation of an amino acid's carboxy terminus by ATP-driven adenylation (see the figure). This is followed by nucleophilic attack on the adenylated amino acid by the thiol moiety of the phosphopantetheine prosthetic group of a peptidyl carrier protein (PCP). The resulting PCP-bound amino acid thioesters undergo peptide bond–forming reactions with one another, leading to amino-to-carboxyl-terminal peptide chain growth. The thiol moiety of phosphopanthetheine is supplied by cysteine, which is also the prevalent organic source of sulfide in biochemistry ([ 6 ][6]). However, most scientists do not believe that cysteine commonly participated in prebiotic chemistry at its earliest stages. Cysteine is often regarded as a late evolutionary addition to the proteinogenic amino acid pool ([ 7 ][7], [ 8 ][8]). ![Figure][9] Building proteins in a prebiotic world Two nonribosomal peptide synthesis reactions highlight the pivotal roles that small-molecule organocatalysis and thiols might have played in the emergence of biochemistry. AMP, adenosine monophosphate; R and R1, amino acid side chain. GRAPHIC: A. KITTERMAN/ SCIENCE Devising a plausible prebiotic route to cysteine has proven to be challenging ([ 9 ][10], [ 10 ][11]). In biology, cysteine synthesis starts from serine and proceeds through a pyridoxal phosphate cofactor-bound dehydroalanine, an intermediate that has a markedly short lifetime in the absence of the cofactor ([ 6 ][6]). Foden et al. proposed how this inherent instability might be overcome by beginning the prebiotic synthesis of cysteine from a nonbiological nitrile analog of the amino acid serine. Proceeding through a doubly acylated dehydroalanine, the acetylated cysteinyl nitrile was obtained in near-neutral water. Given the centrality of cysteine in sulfur biochemistry, the authors wondered if a simpler prebiotic version of nonribosomal peptide synthesis could have relied on this amino acid instead of its more complex biosynthetic successor, phosphopantetheine. Methods that use cysteine moieties in peptide synthesis include cysteinyl thioester–based native chemical ligation ([ 11 ][12]). Although popular, these methods start with a carboxy-terminal amino acid thioester. To make use of this strategy in a prebiotic context, a robust route to amino acid thioesters would be needed—one that could operate without the full toolkit of modern synthetic chemistry ([ 12 ][13]). A previously reported alternative approach demonstrated sulfide-mediated oligomerization of amino nitriles to yield peptides in water. The process began with amino nitriles, but under conditions of alternating reducing and oxidizing environments and excess quantities of sulfide ([ 13 ][14]). Such step-changes in reaction conditions pose a problem for a realistic early Earth scenario. However, by exploiting the fact that thiols reversibly add to α-amidonitriles, Foden et al. proposed a strategy for catalytic and redox-neutral oligopeptide synthesis proceeding via a thioimidate intermediate in neutral water (see the figure). The authors subjected acetylated glycinyl nitrile and free glycine to acetylated cysteine (a hypothetical phosphopantetheine precursor) at 60°C in neutral water. Within 24 hours, an acetylated Gly-Gly peptidyl amidine had formed, at a 60% yield, without the need for synthetic activating agents. This reactivity occurred with a variety of thiols and amino acids. Only amino-terminal serine, threonine, and cysteine could be coupled to α-amidonitriles stereoselectively, which might have implications for the origins of biological homochirality. Foden et al. highlight the potential of small-molecule organocatalysis and the pivotal role that thiols might have played in the emergence of biochemistry. Could nature have made peptides this way before the advent of enzymes or the ribosome? This exciting question reveals how much we do not know about the rationale behind the shaping of life's biochemical pathways and the chemical structures used as cofactors and metabolites ([ 6 ][6]). If life did once use nitrile-based chemistry, it is unclear why it would have shifted to a biochemistry where nitriles are rare. Also, why does life—seemingly so wastefully—use the phosphopantetheine moiety in nonribosomal peptide synthesis, when it might have used a much simpler thiol, such as cysteine? 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领域	气候变化 ; 资源环境
URL	查看原文
引用统计
文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/304121
专题	气候变化资源环境科学
推荐引用方式 GB/T 7714	Kamila B. Muchowska,Joseph Moran. Peptide synthesis at the origin of life[J]. Science,2020.
APA	Kamila B. Muchowska,&Joseph Moran.(2020).Peptide synthesis at the origin of life.Science.
MLA	Kamila B. Muchowska,et al."Peptide synthesis at the origin of life".Science (2020).