Structural and Functional Analysis of Tetracenomycin F2 Cyclase from Streptomyces glaucescens

Thompson, Thomas B.; Katayama, Kinya; Watanabe, Kenji; Hutchinson, C. Richard; Rayment, Ivan

doi:10.1074/jbc.m406144200

Cited by 55 publications

(60 citation statements)

References 30 publications

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“…2). The TcmN-like cyclase participates in first-and second-ring cyclizations (27)(28)(29), whereas TcmI-, OxyN-, and TcmJ-like cyclases are thought to direct subsequent ring closures (5,30). All four of these categories share an evolutionary history with their clustered KS (Fig.…”

Section: Resultsmentioning

confidence: 99%

Evolution of chemical diversity by coordinated gene swaps in type II polyketide gene clusters

Hillenmeyer

Vandova

Berlew

et al. 2015

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

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Natural product biosynthetic pathways generate molecules of enormous structural complexity and exquisitely tuned biological activities. Studies of natural products have led to the discovery of many pharmaceutical agents, particularly antibiotics. Attempts to harness the catalytic prowess of biosynthetic enzyme systems, for both compound discovery and engineering, have been limited by a poor understanding of the evolution of the underlying gene clusters. We developed an approach to study the evolution of biosynthetic genes on a cluster-wide scale, integrating pairwise gene coevolution information with large-scale phylogenetic analysis. We used this method to infer the evolution of type II polyketide gene clusters, tracing the path of evolution from the single ancestor to those gene clusters surviving today. We identified 10 key gene types in these clusters, most of which were swapped in from existing cellular processes and subsequently specialized. The ancestral type II polyketide gene cluster likely comprised a core set of five genes, a roster that expanded and contracted throughout evolution. A key C24 ancestor diversified into major classes of longer and shorter chain length systems, from which a C20 ancestor gave rise to the majority of characterized type II polyketide antibiotics. Our findings reveal that (i) type II polyketide structure is predictable from its gene roster, (ii) only certain gene combinations are compatible, and (iii) gene swaps were likely a key to evolution of chemical diversity. The lessons learned about how natural selection drives polyketide chemical innovation can be applied to the rational design and guided discovery of chemicals with desired structures and properties.evolution | polyketide | natural products | gene cluster

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Section: Resultsmentioning

confidence: 99%

Evolution of chemical diversity by coordinated gene swaps in type II polyketide gene clusters

Hillenmeyer

Vandova

Berlew

et al. 2015

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

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“…The second candidate was a member of the dimeric α+β barrel (DABB) protein superfamily with similarity to stress-responsive proteins from plants (18)(19)(20). The presence of this protein was intriguing because DABB proteins act as polyketide cyclases (e.g., TcmI cyclase) in Streptomyces species (21), although the bacterial cyclases show low sequence similarity to plant DABB proteins. The third candidate was a Betv1-like protein in the same protein family as the Streptomyces TcmN ARO/CYC polyketide cyclase (22).…”

Section: Resultsmentioning

confidence: 99%

“…The structures of three plant stress-responsive DABB proteins are known [Arabidopsis heat stable 1 (AtHS1), the Arabidopsis At5g22580 gene product, and poplar stable protein 1 (SP1)] (27-29). The catalytic mechanisms of the bacterial DABB proteins TcmI cyclase, ActVA-Orf6 monooxygenase, and 4-methylmuconolactone methylisomerase (MLMI) have been investigated by using structural and biochemical approaches (21,30,31). These proteins possess a ferredoxin-like fold with an intermolecular β-barrel and a deep hydrophobic cleft in each monomer where the α 2 -and α 3 -helices arch over the β-sheets.…”

Section: Aromatic Prenyltransferasementioning

confidence: 99%

Identification of olivetolic acid cyclase from Cannabis sativa reveals a unique catalytic route to plant polyketides

Gagne

Stout²,

Liu³

et al. 2012

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

262

236

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Δ 9 -Tetrahydrocannabinol (THC) and other cannabinoids are responsible for the psychoactive and medicinal properties of Cannabis sativa L. (marijuana). The first intermediate in the cannabinoid biosynthetic pathway is proposed to be olivetolic acid (OA), an alkylresorcinolic acid that forms the polyketide nucleus of the cannabinoids. OA has been postulated to be synthesized by a type III polyketide synthase (PKS) enzyme, but so far type III PKSs from cannabis have been shown to produce catalytic byproducts instead of OA. We analyzed the transcriptome of glandular trichomes from female cannabis flowers, which are the primary site of cannabinoid biosynthesis, and searched for polyketide cyclase-like enzymes that could assist in OA cyclization. Here, we show that a type III PKS (tetraketide synthase) from cannabis trichomes requires the presence of a polyketide cyclase enzyme, olivetolic acid cyclase (OAC), which catalyzes a C2-C7 intramolecular aldol condensation with carboxylate retention to form OA. OAC is a dimeric α+β barrel (DABB) protein that is structurally similar to polyketide cyclases from Streptomyces species. OAC transcript is present at high levels in glandular trichomes, an expression profile that parallels other cannabinoid pathway enzymes. Our identification of OAC both clarifies the cannabinoid pathway and demonstrates unexpected evolutionary parallels between polyketide biosynthesis in plants and bacteria. In addition, the widespread occurrence of DABB proteins in plants suggests that polyketide cyclases may play an overlooked role in generating plant chemical diversity.natural products | phytocannabinoid | terpenophenolic | aldolase | ferredoxin-like

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“…Ferredoxin-like fold proteins are widely distributed in all domains of life and are associated with diverse biochemical functions, ranging from monooxygenases in actinorhodin biosynthesis in Streptomyces coelicolor (Sciara et al 2003) to noncatalytic ribosomal L30 proteins (Mao and Williamson 1999). Interestingly, tetracenomycin F2 cyclase, a polyketide cyclase in the biosynthetic pathway of the antibiotic tetracenomycin C that is produced by various Streptomyces species, also belongs to the ferredoxin-like fold (Thompson et al 2004), although sequence analysis suggests that the two ferredoxin-like fold polyketide cyclases arose independently in plants and bacteria (Gagne et al 2012).…”

Section: Emergence Of Reconfigured Catalytic Mechanismsmentioning

confidence: 99%

The Remarkable Pliability and Promiscuity of Specialized Metabolism

Weng

Noel

2012

Cold Spring Harbor Symposia on Quantitative Biology

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Metabolic pathways are often considered "perfected" or at least predictable as substrates efficiently rearrange into products through the intervention of an optimized enzyme. Moreover, single catalytic steps link up, forming a myriad of metabolic circuits that are often modeled with a high degree of certainty. However, on closer examination, most enzymes are not precise with respect to their activity, using not just one substrate but often a variety and producing not just one product but a diversity. Hence, the metabolic systems assembled from enzymes possessing varying degrees of what can be termed catalytic promiscuity are not clear-cut and restrictive; rather, they may at times operate stochastically in the intracellular milieu. This "messiness" complicates our understanding of normal and aberrant cellular behavior, while paradoxically sowing the seeds for future advantageous metabolic adaptations for host organisms. Catalytic promiscuity is intrinsically associated with the dynamic nature of enzyme structures and their chemical mechanisms, both key to enzyme and metabolic evolvability. In addition to primary (core) metabolism, which is essential for survival, organisms also possess highly elaborated secondary (specialized) metabolic systems. These specialized enzymes and pathways often provide unique adaptive strategies for a myriad of organisms and their populations in challenging and changing ecosystems. Generally, enzymes of specialized metabolism show attenuated kinetic activities and expanded catalytic promiscuity compared with their phylogenetic relatives rooted in primary metabolism. We propose that evolvability may be a selected trait in many specialized metabolic systems spread across populations of organisms exposed to continually fluctuating biotic and abiotic environmental pressures. As minor metabolites arising from catalytic messiness provided enhanced population fitness, specificity relaxed, and catalytic efficiency was attenuated. This updated view provides a mechanistic basis for reaching a deeper understanding of the evolutionary underpinnings of the explosion of chemodiversity in nature.Fundamentally, metabolism is a chemical property of living organisms, defined as the collection of enzymecatalyzed chemical reactions that synthesize or deconstruct metabolic chemicals necessary to sustain life and contribute to the reproductive success of host populations in the face of ever-changing environmental pressures. Similarly to other catalysts, enzymes do not alter the equilibrium of the chemical reactions but enhance the rate of the reactions by lowering their activation energies (Cook and Cleland 2007). Reactions catalyzed by enzymes are generally precise and efficient, involving specific metabolic substrates transformed into predictable metabolic products using defined catalytic mechanisms. This ordered view of one enzyme -one mechanism -one product comes from seminal discoveries made by many investigators during the last century, focused for excellent practical reasons on the phylogenetically...

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Structural and Functional Analysis of Tetracenomycin F2 Cyclase from Streptomyces glaucescens

Cited by 55 publications

References 30 publications

Evolution of chemical diversity by coordinated gene swaps in type II polyketide gene clusters

Evolution of chemical diversity by coordinated gene swaps in type II polyketide gene clusters

Identification of olivetolic acid cyclase from Cannabis sativa reveals a unique catalytic route to plant polyketides

The Remarkable Pliability and Promiscuity of Specialized Metabolism

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