The Remarkable Pliability and Promiscuity of Specialized Metabolism

Weng, Jing-Ke; Noel, Joseph P.

doi:10.1101/sqb.2012.77.014787

Cited by 86 publications

(69 citation statements)

References 116 publications

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“…In addition to sharing common mechanisms, DG pathways likely share a common purpose: generating metabolites aimed externally at other organisms rather than at the producing organisms themselves (38)(39)(40). The ability to diversify chemistry enables the producer to adapt as predators, prey, and competitors change.…”

Section: Discussionmentioning

confidence: 99%

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Metabolic model for diversity-generating biosynthesis

Tianero

Pierce

Raghuraman

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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A conventional metabolic pathway leads to a specific product. In stark contrast, there are diversity-generating metabolic pathways that naturally produce different chemicals, sometimes of great diversity. We demonstrate that for one such pathway, tru, each ensuing metabolic step is slower, in parallel with the increasing potential chemical divergence generated as the pathway proceeds. Intermediates are long lived and accumulate progressively, in contrast with conventional metabolic pathways, in which the first step is rate-limiting and metabolic intermediates are shortlived. Understanding these fundamental differences enables several different practical applications, such as combinatorial biosynthesis, some of which we demonstrate here. We propose that these principles may provide a unifying framework underlying diversity-generating metabolism in many different biosynthetic pathways.natural products | secondary metabolism | biosynthesis | RiPP | cyanobactin T here are two fundamentally different types of metabolic pathways in living systems. The first are aimed to generate one or a few discrete chemicals; these comprise the majority of pathways. The second have evolved to produce large numbers of different metabolites (1, 2). Although perhaps fewer in number, this second class, which we will call "diversity generating" (DG), may be responsible for the majority of small molecules in living systems. A key difference is that the compounds produced in the latter generally have a more limited phylogenetic distribution.The metabolic pathways first elucidated were for the synthesis of essential metabolites found in all cells, such as amino acids, purines, or pyrimidines. These conventional metabolic pathways typically comprise multiple metabolic steps, with the intermediates generated in each step converted only to the final product of the pathway. DG pathways, however, do not yield a single final product. Each enzyme in a DG pathway has relaxed substrate specificity and is able to handle a variety of compounds, carrying out the same chemical transformation on different substrates.Previously, an evolutionary framework was developed to explain why some biosynthetic pathways produce many compounds (3-5). In this study we provide the first integrated overview, to our knowledge, of the multiple metabolic steps that comprise a DG biosynthetic pathway. We have uncovered striking differences in how this pathway differs from the canonical features of conventional pathways. Our results provide an initial framework for understanding how DG pathways are designed and how key features of such pathways diverge from the textbook model.We specifically examine the tru and related pat cyanobactin pathways (1, 6). These ribosomally synthesized and posttranslationally modified (RiPP) secondary metabolite pathways were identified in cyanobacterial symbionts of coral reef animals. Their expression required transfer to a model host, Escherichia coli (Fig.

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Section: Discussionmentioning

confidence: 99%

“…The advantage of using the tru pathway is not that it is unique but rather that its wide substrate tolerance has been established experimentally in both laboratory and natural conditions. However, many pathways are believed to exhibit relaxed substrate tolerance (38)(39)(40) and may share unifying features of DG metabolism.…”

Section: Discussionmentioning

confidence: 99%

Metabolic model for diversity-generating biosynthesis

Tianero

Pierce

Raghuraman

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Aromatic structures can be formed either by the polyketide or the shikimic acid pathway, the latter also being a prerequisite to synthetize aromatic amino acids. More information is available in the literature (Rohmer, 1999;Romeo et al, 2000;Hadacek, 2002;Buchanan et al, 2009;Weng and Noel, 2012;Anarat-Cappillino and Sattely, 2014).…”

Section: Lmwms In Living Organisms Definition Biosynthesis and Orgamentioning

confidence: 99%

“…In heterotrophic organisms, aromatic structures are formed via the polyketide pathway. Combinatorial synthesis that utilizes precursors from various of the mentioned pathways together with variable modification of the base skeletons, which is caused by the low substrate specificity of the involved enzymes, yields the huge structural diversity (Gräfe, 1992;Seigler, 1998;Romeo et al, 2000;Hadacek, 2002;Weng and Noel, 2012). Figure 4 presents an overview of structures that are mentioned in the ongoing text.…”

Section: Secondary Lmwmsmentioning

confidence: 99%

Low-molecular-weight metabolite systems chemistry

Hadaček

Bachmann

2015

Front. Environ. Sci.

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Low-molecular-weight metabolites (LMWMs) comprise primary or central and a plethora of intermediary or secondary metabolites, all of which are characterized by a molecular weight below 900 Dalton. The latter are especially prominent in sessile higher organisms, such as plants, corals, sponges and fungi, but are produced by all types of microbial organisms too. Common to all of these carbon molecules are oxygen, nitrogen and, to a lesser extent, sulfur, as heteroatoms. The latter can contribute as electron donators or acceptors to cellular redox chemistry and define the potential of the molecule to enter charge-transfer complexes. Furthermore, they allow LMWMs to serve as organic ligands in coordination complexes with various inorganic metals as central atoms. Especially the transition metals Fe, Cu, and Mn can catalyze one electron reduction of molecular oxygen, which results in formation of free radical species and reactive follow-up reaction products. As antioxidants LMWMs can scavenge free radicals. Depending on the chemical environment, the same LMWMs can act as pro-oxidants by reducing molecular oxygen. The cellular regulation of redox homeostasis, a balance between oxidation and reduction, is still far from being understood. Charge-transfer and coordination complex formation with metals shapes LMWMs into gel-like matrices in the cytosol. The quasi-polymer structure is lost usually during the isolation procedure. In the gel state, LMWMs possess semiconductor properties. Also proteins and membranes are semiconductors. Together they can represent biotransistor components that can be part of a chemoelectrical signaling system that coordinates systems chemistry by initiating cell differentiation or tissue homeostasis, the activated and the resting cell state, when it is required. This concept is not new and dates back to Albert Szent-Györgyi.

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“…The evolution of new metabolic pathways is, to a large extent, driven by two processes-gene duplication and enzyme multifunctionality, the latter arising due to low substrate specificity and/ or promiscuity (Khersonsky and Tawfik, 2010;Weng and Noel, 2012) (Fig. 1B).…”

Section: Characterizing Plant Metabolic Pathways and Their Evolutionmentioning

confidence: 99%

The study of plant specialized metabolism: Challenges and prospects in the genomics era

Moghe

Kruse

2018

American J of Botany

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Plants produce a diverse array of compounds through an extensive, evolutionarily malleable network of metabolic pathways. These metabolites are typically classified into two types-primary and specialized-with most of the diversity occurring among specialized metabolites (Fig. 1A). Metabolite presence-absence and types vary dynamically in an individual plant (within/between tissues/organs, developmental stages, across the circadian cycle), between populations, and also between species. Conservatively, it was estimated that each species harbors ~4.7 unique metabolites, and over a million metabolites were predicted to exist across the plant kingdom (Afendi et al., 2012).The scale of metabolite diversity raises multiple challenges for the study of plant specialized metabolism. First, it creates the challenge of identifying these compounds. While genomic and transcriptomic technologies have advanced significantly in the last decade, the complexity of metabolite structures and their chemical properties hinders adoption of standardized protocols for their detection. Second, the lineage-specific nature of specialized metabolism (Fig. 1A) creates the challenge of identifying biosynthetic enzymes and studying their evolution in non-reference species. Finally, there is still much to be understood about the ecological importance of chemical structural diversity in a single plant and across populations. In this article, we discuss these challenges and potential opportunities in more detail. CHARACTERIZING THE VAST DIVERSITY OF PLANT METABOLITESPlant metabolites are typically detected using gas or liquid chromatography, coupled with mass spectrometry (GC-MS or LC-MS). GC-MS is appropriate for compounds that can be readily converted to gas phase, such as some terpenoids, sterols, fatty acids, and aromatic volatiles. It is typically used for low molecular weight compounds that are stable at high temperatures, either in their native form or after some chemical derivatization. LC-MS, on the other hand, is applicable for a much broader array of compounds and generally does not require any derivatization.Despite significant advances in MS technologies, several challenges remain for characterizing plant metabolite diversity. First, because of the large diversity of chemical structures, a variety of different protocols must be used to characterize the true "metabolome", i.e., the entire metabolite repertoire, of a plant, unlike the relative uniformity of experimental designs in transcriptomics or genomics. Various factors at the sample preparation, liquid chromatography, mass spectrometry (MS), and data analysis steps can influence which and how well metabolite peaks are detected. The second challenge involves identifying the thousands of metabolites observed in MS data from highly sensitive MS instruments. A recent study found evidence for >300 compounds of a single metabolite class (acylsugars) in a single leaf surface extract (Moghe et al., 2017).

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The Remarkable Pliability and Promiscuity of Specialized Metabolism

Cited by 86 publications

References 116 publications

Metabolic model for diversity-generating biosynthesis

Metabolic model for diversity-generating biosynthesis

Low-molecular-weight metabolite systems chemistry

The study of plant specialized metabolism: Challenges and prospects in the genomics era

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