Diet and Headache: Part 1 Martin, Vincent T.; Vij, Brinder
Headache,
10/2016, Volume:
56, Issue:
9
Journal Article
Peer reviewed
Background
The role of diet in the management of the headache patient is a controversial topic in the headache field.
Objectives
To review the evidence supporting the hypothesis that specific foods ...or ingredients within foods and beverages trigger attacks of headache and/or migraine and to discuss the use of elimination diets in the prevention of headache disorders
Methods
This represents part 1 of a narrative review of the role of diet in the prevention of migraine and other headache disorders. A PubMed search was performed with the following search terms: “monosodium glutamate,” “caffeine,” “aspartame,” “sucralose,” “histamine intolerance syndrome,” “tyramine,” “alcohol,” “chocolate,” “nitrites,” “IgG elimination diets,” and “gluten.” Each of these search terms was then cross‐referenced with “headache” and “migraine” to identify relevant studies. Only studies that were written in English were included in this review.
Results
Caffeine withdrawal and administration of MSG (dissolved in liquid) has the strongest evidence for triggering attacks of headache as evidenced by multiple positive provocation studies. Aspartame has conflicting evidence with two positive and two negative provocation studies. Observational studies provide modest evidence that gluten‐ and histamine‐containing foods as well as alcohol may precipitate headaches in subgroups of patients. Two of three randomized controlled trials reported that an elimination diet of IgG positive foods significantly decreased frequency of headache/migraine during the treatment as compared to baseline time period.
Conclusions
Certain foods, beverages, and ingredients within foods may trigger attacks of headache and/or migraine in susceptible individuals. Elimination diets can prevent headaches in subgroups of persons with headache disorders.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Muconic acid (MA) is a chemical building block and precursor to adipic and terephthalic acids used in the production of nylon and polyethylene terephthalate polymer families. Global demand for these ...important materials, coupled to their dependence on petrochemical resources, provides substantial motivation for the microbial synthesis of MA and its derivatives. In this context, the
yeast shikimate pathway can be sourced as a precursor for the formation of MA. Here we report a novel strategy to balance MA pathway performance with aromatic amino acid prototrophy by destabilizing Aro1 through C-terminal degron tagging. Coupling of a composite MA production pathway to degron-tagged Aro1 in an
Δ
Δ mutant background led to the accumulation of 5.6 g/liter protocatechuic acid (PCA). However, metabolites downstream of PCA were not detected, despite the inclusion of genes mediating their biosynthesis. Because CEN.PK family strains of
lack the activity of Pad1, a key enzyme supporting PCA decarboxylase activity, chromosomal expression of intact
alleviated this bottleneck, resulting in nearly stoichiometric conversion (95%) of PCA to downstream products. In a fed-batch bioreactor, the resulting strain produced 1.2 g/liter MA under prototrophic conditions and 5.1 g/liter MA when supplemented with amino acids, corresponding to a yield of 58 mg/g sugar.
Previous efforts to engineer a heterologous MA pathway in
have been hindered by a bottleneck at the PCA decarboxylation step and the creation of aromatic amino acid auxotrophy through deleterious manipulation of the pentafunctional Aro1 protein. In light of these studies, this work was undertaken with the central objective of preserving amino acid prototrophy, which we achieved by employing an Aro1 degradation strategy. Moreover, resolution of the key PCA decarboxylase bottleneck, as detailed herein, advances our understanding of yeast MA biosynthesis and will guide future strain engineering efforts. These strategies resulted in the highest titer reported to date for muconic acid produced in yeast. Overall, our study showcases the effectiveness of careful tuning of yeast Aro1 activity and the importance of host-pathway dynamics.
Endogenous tags have become invaluable tools to visualize and study native proteins in live cells. However, generating human cell lines carrying endogenous tags is difficult due to the low efficiency ...of homology-directed repair. Recently, an engineered split mNeonGreen protein was used to generate a large-scale endogenous tag library in HEK293 cells. Using split mNeonGreen for large-scale endogenous tagging in human iPSCs would open the door to studying protein function in healthy cells and across differentiated cell types. We engineered an iPS cell line to express the large fragment of the split mNeonGreen protein (mNG2
) and showed that it enables fast and efficient endogenous tagging of proteins with the short fragment (mNG2
). We also demonstrate that neural network-based image restoration enables live imaging studies of highly dynamic cellular processes such as cytokinesis in iPSCs. This work represents the first step towards a genome-wide endogenous tag library in human stem cells.
Diet and Headache: Part 2 Martin, Vincent T.; Vij, Brinder
Headache,
10/2016, Volume:
56, Issue:
9
Journal Article
Peer reviewed
Background
Comprehensive diets do not require the exclusion of a specific provocative food or ingredient, but regulate the quantities of core components of foods such as vitamins, ions, proteins, ...carbohydrates, and fats.
Objectives
To review the evidence supporting the use of comprehensive diets in the prevention of migraine and other headache disorders and to discuss the mechanisms through which food, and ingredients within foods and beverages might trigger attacks of headache
Methods
This represents Part 2 of a narrative review of the role of diet in the prevention of migraine and other headache disorders. A PubMed search was performed with the following search terms: “folate,” “vitamin D,” “low fat diet,” “omega‐3 and omega‐6 fatty acid diet,” “ketogenic diet,” “Atkins diet,” and “sodium.” Each of these search terms was then crossreferenced with “headache” and “migraine” to identify relevant studies. Only studies that were written in English were included in this review.
Results
Low fat and high omega‐3/low omega‐6 fatty diets decrease the frequency of attacks of migraine and/or other headache disorders as demonstrated in two separate randomized controlled trials. A ketogenic diet was more effective than a standard diet in reducing the frequency of migraine in a single nonrandomized clinical study. An observation study found that dietary consumption of folate was inversely associated with the frequency of migraine attacks in persons with migraine with aura that have the C variant of the methylene tetrahydrofolate reductase gene. The mechanisms though which diets may precipitate headache include their effects on neuropeptides, neuro‐receptors and ion channels, inflammation, sympathetic nervous system, release of nitric oxide, vasodilation, and cerebral glucose metabolism.
Conclusions
Evidence exists to support the use of comprehensive diets in the prevention of migraine and other headache disorders. However, the results of these studies should be considered preliminary until replicated in larger randomized controlled clinical trials.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
•Developed data-mining framework to study plant specialized metabolism.•Compared two next-generation sequencing technologies.•Assigned functional information to >800,000 transcripts from 20 plant ...species.•Described selection of gene candidates associated with six metabolic pathways.
Plants produce a vast array of specialized metabolites, many of which are used as pharmaceuticals, flavors, fragrances, and other high-value fine chemicals. However, most of these compounds occur in non-model plants for which genomic sequence information is not yet available. The production of a large amount of nucleotide sequence data using next-generation technologies is now relatively fast and cost-effective, especially when using the latest Roche-454 and Illumina sequencers with enhanced base-calling accuracy. To investigate specialized metabolite biosynthesis in non-model plants we have established a data-mining framework, employing next-generation sequencing and computational algorithms, to construct and analyze the transcriptomes of 75 non-model plants that produce compounds of interest for biotechnological applications. After sequence assembly an extensive annotation approach was applied to assign functional information to over 800,000 putative transcripts. The annotation is based on direct searches against public databases, including RefSeq and InterPro. Gene Ontology (GO), Enzyme Commission (EC) annotations and associated Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway maps are also collected. As a proof-of-concept, the selection of biosynthetic gene candidates associated with six specialized metabolic pathways is described. A web-based BLAST server has been established to allow public access to assembled transcriptome databases for all 75 plant species of the PhytoMetaSyn Project (www.phytometasyn.ca).
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
L-tyrosine is a common precursor for a wide range of valuable secondary metabolites, including benzylisoquinoline alkaloids (BIAs) and many polyketides. An industrially tractable yeast strain ...optimized for production of L-tyrosine could serve as a platform for the development of BIA and polyketide cell factories. This study applied a targeted metabolomics approach to evaluate metabolic engineering strategies to increase the availability of intracellular L-tyrosine in the yeast Saccharomyces cerevisiae CEN.PK. Our engineering strategies combined localized pathway engineering with global engineering of central metabolism, facilitated by genome-scale steady-state modelling.
Addition of a tyrosine feedback resistant version of 3-deoxy-D-arabino-heptulosonate-7-phosphate synthase Aro4 from S. cerevisiae was combined with overexpression of either a tyrosine feedback resistant yeast chorismate mutase Aro7, the native pentafunctional arom protein Aro1, native prephenate dehydrogenase Tyr1 or cyclohexadienyl dehydrogenase TyrC from Zymomonas mobilis. Loss of aromatic carbon was limited by eliminating phenylpyruvate decarboxylase Aro10. The TAL gene from Rhodobacter sphaeroides was used to produce coumarate as a simple test case of a heterologous by-product of tyrosine. Additionally, multiple strategies for engineering global metabolism to promote tyrosine production were evaluated using metabolic modelling. The T21E mutant of pyruvate kinase Cdc19 was hypothesized to slow the conversion of phosphoenolpyruvate to pyruvate and accumulate the former as precursor to the shikimate pathway. The ZWF1 gene coding for glucose-6-phosphate dehydrogenase was deleted to create an NADPH deficiency designed to force the cell to couple its growth to tyrosine production via overexpressed NADP(+)-dependent prephenate dehydrogenase Tyr1. Our engineered Zwf1(-) strain expressing TYRC ARO4(FBR) and grown in the presence of methionine achieved an intracellular L-tyrosine accumulation up to 520 μmol/g DCW or 192 mM in the cytosol, but sustained flux through this pathway was found to depend on the complete elimination of feedback inhibition and degradation pathways.
Our targeted metabolomics approach confirmed a likely regulatory site at DAHP synthase and identified another possible cofactor limitation at prephenate dehydrogenase. Additionally, the genome-scale metabolic model identified design strategies that have the potential to improve availability of erythrose 4-phosphate for DAHP synthase and cofactor availability for prephenate dehydrogenase. We evaluated these strategies and provide recommendations for further improvement of aromatic amino acid biosynthesis in S. cerevisiae.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The yeast Saccharomyces cerevisiae is powerful for studying human G protein-coupled receptors as they can be coupled to its mating pathway. However, some receptors, including the mu opioid receptor, ...are non-functional, which may be due to the presence of the fungal sterol ergosterol instead of cholesterol. Here we engineer yeast to produce cholesterol and introduce diverse mu, delta, and kappa opioid receptors to create sensitive opioid biosensors that recapitulate agonist binding profiles and antagonist inhibition. Additionally, human mu opioid receptor variants, including those with clinical relevance, largely display expected phenotypes. By testing mu opioid receptor-based biosensors with systematically adjusted cholesterol biosynthetic intermediates, we relate sterol profiles to biosensor sensitivity. Finally, we apply sterol-modified backgrounds to other human receptors revealing sterol influence in SSTR5, 5-HTR4, FPR1, and NPY1R signaling. This work provides a platform for generating human G protein-coupled receptor-based biosensors, facilitating receptor deorphanization and high-throughput screening of receptors and effectors.
Abstract
Reprogramming cellular behaviour is one of the hallmarks of synthetic biology. To this end, prokaryotic allosteric transcription factors (aTF) have been repurposed as versatile tools for ...processing small molecule signals into cellular responses. Expanding the toolbox of aTFs that recognize new inducer molecules is of considerable interest in many applications. Here, we first establish a resorcinol responsive aTF-based biosensor in Escherichia coli using the TetR-family repressor RolR from Corynebacterium glutamicum. We then perform an iterative walk along the fitness landscape of RolR to identify new inducer specificities, namely catechol, methyl catechol, caffeic acid, protocatechuate, L-DOPA, and the tumour biomarker homovanillic acid. Finally, we demonstrate the versatility of these engineered aTFs by transplanting them into the model eukaryote Saccharomyces cerevisiae. This work provides a framework for efficient aTF engineering to expand ligand specificity towards novel molecules on laboratory timescales, which, more broadly, is invaluable across a wide range of applications such as protein and metabolic engineering, as well as point-of-care diagnostics.
Graphical Abstract
Graphical Abstract
Benzylisoquinoline alkaloids (BIAs) represent a large class of plant secondary metabolites, including pharmaceuticals such as morphine, codeine and their derivatives. Large-scale production of ...BIA-based pharmaceuticals is limited to extraction and derivatization of alkaloids that accumulate in planta. Synthesis of BIAs in microbial hosts could bypass such limitations and transform both industrial production of BIAs with recognized value and research into uncharacterized BIAs. Here we reconstitute a 10-gene plant pathway in Saccharomyces cerevisiae that allows for the production of dihydrosanguinarine and its oxidized derivative sanguinarine from (R,S)-norlaudanosoline. Synthesis of dihydrosanguinarine also yields the side-products N-methylscoulerine and N-methylcheilanthifoline, the latter of which has not been detected in plants. This work represents the longest reconstituted alkaloid pathway ever assembled in yeast and demonstrates the feasibility of the production of high-value alkaloids in microbial systems.
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