Rhodoquinone biosynthesis in C. elegans requires precursors generated by the kynurenine pathway

Borrello, Samantha Del; Lautens, Margot; Dolan, Kathleen; Jh, Tan; Davie, Taylor; Schertzberg, Michael R; Spensley, Mark; Caudy, Amy A.; Fraser, Andrew G.

doi:10.7554/elife.48165

Cited by 32 publications

(86 citation statements)

References 67 publications

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“…Within the Caenorhabditis genus, some species, like C. elegans , encode an alanine at COI position 153, while others, including C. afra , encode serine at the same position (Table S6). Several nematodes, including Caenorhabditis worms, can synthesize either ubiquinone, associated with aerobic environments, or rhodoquinone, associated with anaerobic metabolism ( Takamiya et al 1999 ; Del Borrello et al 2019 ; Tan et al 2020 ). These findings suggest that these organisms also encounter fluctuating oxygen concentrations, prompting further speculation that changes to position 153 are linked to oxygen availability or consumption.…”

Section: Resultsmentioning

confidence: 99%

An Unusual Amino Acid Substitution Within Hummingbird CytochromecOxidase Alters a Key Proton-Conducting Channel

Dunn

Akpınar

Sharma

2020

G3 Genes|Genomes|Genetics

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Hummingbirds in flight exhibit the highest mass-specific metabolic rate of all vertebrates. The bioenergetic requirements associated with sustained hovering flight raise the possibility of unique amino acid substitutions that would enhance aerobic metabolism. Here, we have identified a non-conservative substitution within the mitochondria-encoded cytochrome c oxidase subunit I (COI) that is fixed within hummingbirds, but not among other vertebrates. This unusual change is also rare among metazoans, but can be identified in several clades with diverse life histories. We performed atomistic molecular dynamics simulations using bovine and hummingbird COI models, thereby bypassing experimental limitations imposed by the inability to modify mtDNA in a site-specific manner. Intriguingly, our findings suggest that COI amino acid position 153 (bovine numbering convention) provides control over the hydration and activity of a key proton channel in COX. We discuss potential phenotypic outcomes linked to this alteration encoded by hummingbird mitochondrial genomes.

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Section: Resultsmentioning

confidence: 99%

An Unusual Amino Acid Substitution Within Hummingbird CytochromecOxidase Alters a Key Proton-Conducting Channel

Dunn

Akpınar

Sharma

2020

G3 Genes|Genomes|Genetics

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“…A high quality compartmentalized metabolic model allows us to study the metabolic processes of the cell in detail, including pathways that have been poorly studied in the past; in particular, the anaerobic metabolic pathways used by parasitic nematodes are unlike those studied in most other eukaryotes ( Del Borrello et al, 2019 ). Our model is the first to incorporate this pathway and is therefore likely to yield accurate predictions as low oxygen environments are biologically relevant for parasitic nematodes.…”

Section: Discussionmentioning

confidence: 99%

Modeling the metabolic interplay between a parasitic worm and its bacterial endosymbiont allows the identification of novel drug targets

Curran

Grote

Nursimulu

et al. 2020

eLife

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The filarial nematode Brugia malayi represents a leading cause of disability in the developing world, causing lymphatic filariasis in nearly 40 million people. Currently available drugs are not well-suited to mass drug administration efforts, so new treatments are urgently required. One potential vulnerability is the endosymbiotic bacteria Wolbachia—present in many filariae—which is vital to the worm. Genome scale metabolic networks have been used to study prokaryotes and protists and have proven valuable in identifying therapeutic targets, but have only been applied to multicellular eukaryotic organisms more recently. Here, we present iDC625, the first compartmentalized metabolic model of a parasitic worm. We used this model to show how metabolic pathway usage allows the worm to adapt to different environments, and predict a set of 102 reactions essential to the survival of B. malayi. We validated three of those reactions with drug tests and demonstrated novel antifilarial properties for all three compounds.

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“…A high quality compartmentalized metabolic model allows us to study the metabolic 535 processes of the cell in detail, including pathways that have been poorly studied in the 536 past; in particular, the anaerobic metabolic pathways used by parasitic nematodes are 537 unlike those studied in most other eukaryotes (Del Borrello et al, 2019). Our model is 538 the first to incorporate this pathway and is therefore likely to yield accurate predictions 539 as low oxygen environments are biologically relevant for parasitic nematodes.…”

Section: Hypotheses 534mentioning

confidence: 99%

Modeling the metabolic interplay between a parasitic worm and its bacterial endosymbiont allows the identification of novel drug targets

Curran

Grote

Nursimulu

et al. 2019

Preprint

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24The filarial nematode Brugia malayi represents a leading cause of disability in the 25 developing world, causing lymphatic filariasis in nearly 40 million people. Currently 26 available drugs are not well-suited to mass drug administration efforts, so new 27 treatments are urgently required. One potential vulnerability is the endosymbiotic 28 bacteria Wolbachia-present in many filariae-which is vital to the worm. 29Genome scale metabolic networks have been used to study prokaryotes and protists 30 and have proven valuable in identifying therapeutic targets, but only recently have been 31 applied to eukaryotic organisms. Here, we present iDC625, the first compartmentalized 32 metabolic model of a parasitic worm. We used this model to show how metabolic 33 pathway usage allows the worm to adapt to different environments, and predict a set of 34 99 reactions essential to the survival of B. malayi. We validated three of those reactions 35 with drug tests and demonstrated novel antifilarial properties for all three compounds. 36 37 resistance in these species against diethylcarbamazine (Eberhard et al., 1991), 60ivermectin (Awadzi et al., 2004; Eng et al., 2006), and albendazole (Schwab et al., 61 2005) has been reported for many years. 62An alternative strategy for treatment has been the use of traditional antibiotics to target 63 the endosymbiotic bacteria that live within most filarial nematodes. These bacteria are 64 from the genus Wolbachia, specific to each helminth, and found to be essential for adult 65 worm fitness and reproduction (Taylor et al., 2013). Targeting these bacteria with the 66 antibiotic doxycycline was shown to reduce numbers of Wolbachia present in the 67 worms, sterilize adult females, and reduce symptoms of lymphatic filariasis (Debrah et 68 al., 2009; Rao et al., 2012; Ghedin et al., 2009; Taylor et al., 2010). While antibiotic 69 treatment remains a viable option for individual patients, long treatment times and 70 contraindications for children and pregnant women limit its suitability for mass-drug 71 administration efforts (Taylor et al., 2010). This strategy is ongoing, as recent evidence 72 suggests that the commonly used antibiotic rifampicin may also possess filaricidal 73 activity, but these data are preliminary and have not yet been tested in humans 74 (Aljayyoussi et al., 2017). A more recent study proposes faster-acting antibiotics that 75 belong to the tetracycline class of drugs (Taylor et al., 2019). 76Considering the limitations of current treatment regimes, there is an urgent need to 77 identify new drug targets against filarial nematodes that directly impact adult worm 78 survival and, if possible, are specific enough to avoid the potential complications that 79 arise in regions co-endemic for O. volvulus or L. loa. Genome scale metabolic 80 reconstruction and constraint-based modelling have emerged as effective strategies to 81 identify critical metabolic enzymes and pathways (Oberhardt et al., 2008; Chavali et al., 82 2008; Lee et al., 2009; Song et al., 2013),...

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Rhodoquinone biosynthesis in C. elegans requires precursors generated by the kynurenine pathway

Cited by 32 publications

References 67 publications

An Unusual Amino Acid Substitution Within Hummingbird CytochromecOxidase Alters a Key Proton-Conducting Channel

An Unusual Amino Acid Substitution Within Hummingbird CytochromecOxidase Alters a Key Proton-Conducting Channel

Modeling the metabolic interplay between a parasitic worm and its bacterial endosymbiont allows the identification of novel drug targets

Modeling the metabolic interplay between a parasitic worm and its bacterial endosymbiont allows the identification of novel drug targets

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