Amino acid concentrations in serum and aqueous humor from subjects with extreme myopia or senile cataract.

Wuu, Jia-An; Wen, Liang-Yen; Chuang, T.-J.; Chang, Gu-Gang

doi:10.1093/clinchem/34.8.1610

Cited by 20 publications

(9 citation statements)

References 9 publications

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“…Additionally, some of the amino acids profiled (phenylalanine, leucine, isoleucine, valine, alanine and threonine) were previously reported as important markers of extreme myopia and senile cateract in AH, measured using an amino acid analyzer [17].…”

Section: Characterization Of the Profilementioning

confidence: 99%

Looking into aqueous humor through metabolomics spectacles − exploring its metabolic characteristics in relation to myopia

Barbas-Bernardos

Armitage

Garcı́a

et al. 2016

Journal of Pharmaceutical and Biomedical Analysis

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Aqueous humor is the transparent fluid found in the anterior chamber of the eye that provides the metabolic requirements to the avascular tissues surrounding it. Despite the fact that metabolomics could be a powerful tool in the characterization of this biofluid and in revealing metabolic signatures of common ocular diseases such as myopia, it has never to our knowledge previously been applied in humans. In this research a novel method for the analysis of aqueous humor is presented to show its application in the characterization of this biofluid using CE-MS. The method was extended to a dual platform method (CE-MS and LC-MS) in order to compare samples from patients with different severities of myopia in order to explore the disease from the metabolic phenotype point of view. With this method, a profound knowledge of the metabolites present in human aqueous humor has been obtained: over 40 metabolites were reproducibly and simultaneously identified from a low volume of sample by CE-MS, including among others, a vast number of amino acids and derivatives. When this method was extended to study groups of patients with high or low myopia in both CE-MS and LC-MS, it has been possible to identify over 20 significantly different metabolite and lipid signatures that distinguish patients based on the severity of myopia. Among these, the most notable higher abundant metabolites in high myopia were aminooctanoic acid, arginine, citrulline and sphinganine while features of low myopia were aminoundecanoic acid, dihydro-retinoic acid and cysteinylglycine disulfide. This dual platform approach offered complementarity such that different metabolites were detected in each technique. Together the experiments presented provide a whelm of valuable information about human aqueous humor and myopia, proving the utility of non-targeted metabolomics for the first time in analyzing this type of sample and the metabolic phenotype of this disease.

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Section: Characterization Of the Profilementioning

confidence: 99%

Looking into aqueous humor through metabolomics spectacles − exploring its metabolic characteristics in relation to myopia

Barbas-Bernardos

Armitage

Garcı́a

et al. 2016

Journal of Pharmaceutical and Biomedical Analysis

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“…Because blood aspartate levels (0-15 uM) 16,17 do not allow adequate aspartate import in most cell types, aspartate availability and aspartate-derived nucleotide synthesis depend on mitochondrial respiration and TCA cycle flux. We and others 1,[18][19][20] have shown that ETC impairment leads to inhibition of mTORC1 activity.…”

Section: Discussionmentioning

confidence: 99%

Asparagine signals mitochondrial respiration and can be targeted to impair tumour growth

Krall

Mullen

Surjono

et al. 2020

Preprint

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Mitochondrial respiration is critical for cell proliferation. In addition to producing ATP via the electron transport chain (ETC), respiration is required for the generation of TCA cycle-derived biosynthetic precursors, such as aspartate, an essential substrate for nucleotide synthesis.Because mTORC1 coordinates availability of biosynthetic precursors with anabolic metabolism, including nucleotide synthesis, a link between respiration and mTORC1 is fitting. Here we show that in addition to depleting intracellular aspartate, ETC inhibition depletes aspartate-derived asparagine and impairs mTORC1 activity. Providing exogenous asparagine restores mTORC1 activity, nucleotide synthesis, and proliferation in the context of ETC inhibition without restoring intracellular aspartate in a panel of cancer cell lines. As a therapeutic strategy, the combination of ETC inhibitor metformin, which limits tumour asparagine synthesis, and either asparaginase or dietary asparagine restriction, which limit tumour asparagine consumption, effectively impairs tumour growth in several mouse models of cancer. Because environmental asparagine is sufficient to restore proliferation with respiration impairment, both in vitro and in vivo, our findings suggest that asparagine synthesis is a fundamental purpose of mitochondrial respiration. Moreover, the results suggest that asparagine signals active respiration to mTORC1 to communicate biosynthetic precursor sufficiency and promote anabolism. IntroductionRecent literature has demonstrated that asparagine is important for amino acid homeostasis, maintenance of mTORC1 activity, and tumour progression 1-3 . Asparagine regulation of mTORC1 activity and downstream anabolism may explain the clinical efficacy of extracellularacting asparaginase in the treatment of leukaemias that obtain most of their asparagine from the environment. Most solid tumours, however, are capable of synthesizing asparagine via asparagine synthetase (ASNS), making them less responsive to asparaginase 4 . In addition, elevated ASNS expression, and presumably increased de novo asparagine synthesis, accompanies asparaginase resistance in leukaemia 5 . Because cells can obtain asparagine from the environment or synthesize asparagine de novo, targeting both sources may be required to effectively exploit tumour asparagine dependence.Cellular respiration couples nutrient oxidation to ATP production through oxidative phosphorylation. Although most cancer cells convert the majority of consumed glucose to lactate, concurrent respiration is essential: suppressing respiration through ETC inhibition impairs proliferation [6][7][8][9] . Recent literature has shown that ATP synthesis via the ETC is dispensable for cancer cell proliferation. Rather, aspartate synthesis requirements explain the reliance of proliferating cells on respiration 6,7 . Electron acceptors are limiting upon ETC inhibition, resulting in compromised NAD+ recycling, impaired flux through the TCA cycle, and depletion of TCA cycle-derived aspartate. Supplementing cell cu...

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“…Aspartate is required for both purine and pyrimidine de novo synthesis. As Blood aspartate level in human is very low [48] and uptake of aspartate may be not sufficient for cell proliferation, a primary function of respiration in proliferating cell was found to support aspartate biosynthesis, ensuring cancer cell survival and proliferation [49, 50].…”

Section: Metabolic Co-dependency Shaped By Environmentmentioning

confidence: 99%

Targeting cancer's metabolic co-dependencies: A landscape shaped by genotype and tissue context

Bi¹,

Wu²,

Zhang³

et al. 2018

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

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Tumors cells reprogram their metabolism to fuel rapid growth. The ability to trace nutrient fluxes in the context of specific alterations has provided new mechanistic insight into the process of oncogenic transformation. A broad array of complementary genetic, epigenetic, transcriptional and translational mechanisms has been identified, revealing a metabolic landscape of cancer. However, cancer metabolism is not a static or uniform process, including within a single tumor. Tumor cells adapt to changing environmental conditions, profoundly shaping the enzymatic dependencies of individual cells. The underlying molecular mechanisms of adaptation, and the specific interactions between tumor genotype, oncogenic signaling, and tissue/biochemical context, remain incompletely understood. In this review, we examine dynamic aspects of how metabolic dependencies develop in cancer, shaped both by genotype and biochemical environment, and review how these interlaced processes generate targetable metabolic vulnerabilities. This article is part of a Special Issue entitled: Cancer Metabolism edited by Dr. Chi Van Dang.

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Amino acid concentrations in serum and aqueous humor from subjects with extreme myopia or senile cataract.

Cited by 20 publications

References 9 publications

Looking into aqueous humor through metabolomics spectacles − exploring its metabolic characteristics in relation to myopia

Looking into aqueous humor through metabolomics spectacles − exploring its metabolic characteristics in relation to myopia

Asparagine signals mitochondrial respiration and can be targeted to impair tumour growth

Targeting cancer's metabolic co-dependencies: A landscape shaped by genotype and tissue context

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