Revisiting the methionine salvage pathway and its paralogues

Sekowska, Agnieszka; Ashida, Hiroshi; Danchin, Antoine

doi:10.1111/1751-7915.13324

Cited by 44 publications

(38 citation statements)

References 193 publications

(226 reference statements)

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“…As a consequence, methionine sparing required also the emergence of an important cycle involving the AdoMet‐related activities producing the methylthioadenosine metabolite. This resulted in omnipresent methionine salvage pathways (Sekowska et al , 2019). In point of fact, AdoMet synthesis and turnover makes use of approximately three to four times the free methionine pool in steady‐state unsupplemented conditions (Thomas et al , 1988; Shlomi et al , 2014).…”

Section: Methionine As the First Amino Acid In Translationmentioning

confidence: 99%

One‐carbon metabolism, folate, zinc and translation

Danchin

Sekowska

You

2020

Microbial Biotechnology

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The translation process, central to life, is tightly connected to the one-carbon (1-C) metabolism via a plethora of macromolecule modifications and specific effectors. Using manual genome annotations and putting together a variety of experimental studies, we explore here the possible reasons of this critical interaction, likely to have originated during the earliest steps of the birth of the first cells.Methionine, S-adenosylmethionine and tetrahydrofolate dominate this interaction. Yet, 1-C metabolism is unlikely to be a simple frozen accident of primaeval conditions. Reactive 1-C species (ROCS) are buffered by the translation machinery in a way tightly associated with the metabolism of iron-sulfur clusters, zinc and potassium availability, possibly coupling carbon metabolism to nitrogen metabolism. In this process, the highly modified position 34 of tRNA molecules plays a critical role. Overall, this metabolic integration may serve both as a protection against the deleterious formation of excess carbon under various growth transitions or environmental unbalanced conditions and as a regulator of zinc homeostasis, while regulating input of prosthetic groups into nascent proteins. This knowledge should be taken into account in metabolic engineering.

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Section: Methionine As the First Amino Acid In Translationmentioning

confidence: 99%

One‐carbon metabolism, folate, zinc and translation

Danchin

Sekowska

You

2020

Microbial Biotechnology

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“…Putative MTA salvage genes were first identified in a 1999 France neonatal meningitis ExPEC isolate (S88) as putative mtnK (ECS88_4901), mtnA (ECS88_4901) and mtnB (ECS88_4903) orthologues of the universal MSP (Touchon et al, ). However, the appearance of an incomplete MSP was perplexing, and the potential functionality speculative (Sekowska, Ashida, & Danchin, ). The E. coli studies presented here (Figure ) demonstrate that this gene cluster, present in 42% of all ExPEC isolates but nearly absent in intestinal pathogenic E. coli isolates (Figure b,c), is a functional DHAP shunt for carbon salvage as DHAP from MTA and 5ʹdAdo and acetaldehyde from 5ʹdAdo.…”

Section: Discussionmentioning

confidence: 99%

A bifunctional salvage pathway for two distinct S‐adenosylmethionine by‐products that is widespread in bacteria, including pathogenic Escherichia coli

North

Wildenthal

Erb

et al. 2020

Molecular Microbiology

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S‐adenosyl‐l‐methionine (SAM) is a necessary cosubstrate for numerous essential enzymatic reactions including protein and nucleotide methylations, secondary metabolite synthesis and radical‐mediated processes. Radical SAM enzymes produce 5ʹ‐deoxyadenosine, and SAM‐dependent enzymes for polyamine, neurotransmitter and quorum sensing compound synthesis produce 5ʹ‐methylthioadenosine as by‐products. Both are inhibitory and must be addressed by all cells. This work establishes a bifunctional oxygen‐independent salvage pathway for 5ʹ‐deoxyadenosine and 5ʹ‐methylthioadenosine in both Rhodospirillum rubrum and Extraintestinal Pathogenic Escherichia coli. Homologous genes for this pathway are widespread in bacteria, notably pathogenic strains within several families. A phosphorylase (Rhodospirillum rubrum) or separate nucleoside and kinase (Escherichia coli) followed by an isomerase and aldolase sequentially function to salvage these two wasteful and inhibitory compounds into adenine, dihydroxyacetone phosphate and acetaldehyde or (2‐methylthio)acetaldehyde during both aerobic and anaerobic growth. Both SAM by‐products are metabolized with equal affinity during aerobic and anaerobic growth conditions, suggesting that the dual‐purpose salvage pathway plays a central role in numerous environments, notably the human body during infection. Our newly discovered bifunctional oxygen‐independent pathway, widespread in bacteria, salvages at least two by‐products of SAM‐dependent enzymes for carbon and sulfur salvage, contributing to cell growth.

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“…As a consequence, natural selection retained a variety of enzymes meant to scavenge adenine wastes, so that any downwards trend in the ever critical ATP supply would be easily overcome-see e.g. (51,52 (57). These enzymes share a common descent, showing that life has easily evolved a panoply of related activities.…”

Section: An Unexpected Secret Of Life: Cytosine Metabolism Provides Bmentioning

confidence: 99%

A path towards SARS-CoV-2 attenuation: metabolic pressure on CTP synthesis rules the virus evolution

Ouzounis

Wang

et al. 2020

Preprint

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Fighting the COVID-19 epidemic summons deep understanding of the way SARS-CoV-2 taps into its host cell metabolic resources. We describe here the singular metabolic background that creates a bottleneck constraining coronaviruses to evolve towards likely attenuation in the long term. Cytidine triphosphate (CTP) is at the crossroad of the biosynthetic processes that allow the virus to multiply. This is because CTP is in demand for three essential steps. It is a building block of the virus genome, it is required for synthesis of the cytosine-based liponucleotide precursors of the viral envelope and, finally, it is a critical building block of the host transfer RNAs synthesis. The CCA 3'-end of all the transfer RNAs required to translate the RNA genome and further transcripts into the proteins used to build active virus copies is not coded in the human genome. It must be synthesized de novo from CTP and ATP. Furthermore, intermediary metabolism is built on compulsory steps of synthesis and salvage of cytosine-based metabolites via uridine triphosphate (UTP) that keep limiting CTP availability. As a consequence, accidental replication errors tend to replace cytosine by uracil in the genome, unless recombination events allow the sequence to return to its ancestral sequences. We document some of the consequences of this situation in the function of viral proteins. We also highlight and provide a raison d'être to viperin, an enzyme of innate antiviral immunity, which synthesizes 3ʹ-deoxy-3′,4ʹ-didehydro-CTP (ddhCTP) as an extremely efficient antiviral nucleotide.We thank all the authors who shared genomic data in public database, and an acknowledgment table for sequences retrieved from GISAID (110) is provided (Supplementary Table S2). CONTRIBUTIONSAD designed the study and wrote the bulk of the manuscript. ZO, JL and WC developed the in silico analyses of cytosine evolution, codon usage biases and phylogeny. ZO, DW and WS performed the analysis and ZO wrote the corresponding part of the manuscript. CO designed and performed phylogenetic studies based on indels. PM identified the importance of several key steps in CTP synthesis. All authors read, wrote some sections and contributed to the final version of the manuscript.AD is a founder of Stellate Therapeutics, a company developing applications of metabolism for prevention and cure of neurodegenerative diseases and a founder of Virtexx, a company developing antiviral molecules. ZO and authors from Shenzhen are employed by the BGI, a company developing applications of genome studies. PM is a founder of Theraxen, a company developing synthetic biology approaches for drug development. The other authors declare no conflict of interest.

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Revisiting the methionine salvage pathway and its paralogues

Cited by 44 publications

References 193 publications

One‐carbon metabolism, folate, zinc and translation

One‐carbon metabolism, folate, zinc and translation

A bifunctional salvage pathway for two distinct S‐adenosylmethionine by‐products that is widespread in bacteria, including pathogenic Escherichia coli

A path towards SARS-CoV-2 attenuation: metabolic pressure on CTP synthesis rules the virus evolution

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