Oncogenic K-Ras decouples glucose and glutamine metabolism to support cancer cell growth

A systems approach using 13C metabolic flux analysis (MFA), non-targeted tracer fate detection (NTFD), and transcriptional profiling was applied to investigate the role of oncogenic K-Ras in metabolic transformation.K-Ras transformed cells exhibit an increased glycolytic rate and lower flux through the oxidative tricarboxylic acid (TCA) cycle.K-Ras transformed cells show a relative increase in glutamine anaplerosis and reductive TCA metabolism.Transcriptional changes driven by oncogenic K-Ras suggest control nodes associated with the metabolic reprogramming of cancer cells

Divergent amino acid and sphingolipid metabolism in patients with inherited neuro-retinal disease

OBJECTIVES: The non-essential amino acids serine, glycine, and alanine, as well as diverse sphingolipid species, are implicated in inherited neuro-retinal disorders and are metabolically linked by serine palmitoyltransferase (SPT), a key enzyme in membrane lipid biogenesis. To gain insight into the pathophysiological mechanisms linking these pathways to neuro-retinal diseases we compared patients diagnosed with two metabolically intertwined diseases: macular telangiectasia type II (MacTel), hereditary sensory autonomic neuropathy type 1 (HSAN1), or both. METHODS: We performed targeted metabolomic analyses of amino acids and broad sphingolipids in sera from a cohort of MacTel (205), HSAN1 (25) and Control (151) participants. RESULTS: MacTel patients exhibited broad alterations of amino acids, including changes in serine, glycine, alanine, glutamate, and branched-chain amino acids reminiscent of diabetes. MacTel patients had elevated 1-deoxysphingolipids but reduced levels of complex sphingolipids in circulation. A mouse model of retinopathy indicates dietary serine and glycine restriction can drive this depletion in complex sphingolipids. HSAN1 patients exhibited elevated serine, lower alanine, and a reduction in canonical ceramides and sphingomyelins compared to controls. Those patients diagnosed with both HSAN1 and MacTel showed the most significant decrease in circulating sphingomyelins. CONCLUSIONS: These results highlight metabolic distinctions between MacTel and HSAN1, emphasize the importance of membrane lipids in the progression of MacTel, and suggest distinct therapeutic approaches for these two neurodegenerative diseases

Mesaconate is synthesized from itaconate and exerts immunomodulatory effects in macrophages.

peer reviewedSince its discovery in inflammatory macrophages, itaconate has attracted much attention due to its antimicrobial and immunomodulatory activity1-3. However, instead of investigating itaconate itself, most studies used derivatized forms of itaconate and thus the role of non-derivatized itaconate needs to be scrutinized. Mesaconate, a metabolite structurally very close to itaconate, has never been implicated in mammalian cells. Here we show that mesaconate is synthesized in inflammatory macrophages from itaconate. We find that both, non-derivatized itaconate and mesaconate dampen the glycolytic activity to a similar extent, whereas only itaconate is able to repress tricarboxylic acid cycle activity and cellular respiration. In contrast to itaconate, mesaconate does not inhibit succinate dehydrogenase. Despite their distinct impact on metabolism, both metabolites exert similar immunomodulatory effects in pro-inflammatory macrophages, specifically a reduction of interleukin (IL)-6 and IL-12 secretion and an increase of CXCL10 production in a manner that is independent of NRF2 and ATF3. We show that a treatment with neither mesaconate nor itaconate impairs IL-1β secretion and inflammasome activation. In summary, our results identify mesaconate as an immunomodulatory metabolite in macrophages, which interferes to a lesser extent with cellular metabolism than itaconate

Phosphoglycerate dehydrogenase diverts glycolytic flux and contributes to oncogenesis

Most tumors exhibit increased glucose metabolism to lactate, however, the extent to which glucose-derived metabolic fluxes are used for alternative processes is poorly understood [1, 2]. Using a metabolomics approach with isotope labeling, we found that in some cancer cells a relatively large amount of glycolytic carbon is diverted into serine and glycine metabolism through phosphoglycerate dehydrogenase (PHGDH). An analysis of human cancers showed that PHGDH is recurrently amplified in a genomic region of focal copy number gain most commonly found in melanoma. Decreasing PHGDH expression impaired proliferation in amplified cell lines. Increased expression was also associated with breast cancer subtypes, and ectopic expression of PHGDH in mammary epithelial cells disrupted acinar morphogenesis and induced other phenotypic alterations that may predispose cells to transformation. Our findings show that the diversion of glycolytic flux into a specific alternate pathway can be selected during tumor development and may contribute to the pathogenesis of human cancer.National Institutes of Health (U.S.)National Cancer Institute (U.S.)Smith Family FoundationDamon Runyon Cancer Research FoundationBurroughs Wellcome Fun

Tracing insights into human metabolism using chemical engineering approaches.

Metabolism coordinates the conversion of available nutrients toward energy, biosynthetic intermediates, and signaling molecules to mediate virtually all biological functions. Dysregulation of metabolic pathways contributes to many diseases, so a detailed understanding of human metabolism has significant therapeutic implications. Over the last decade major technological advances in the areas of analytical chemistry, computational estimation of intracellular fluxes, and biological engineering have improved our ability to observe and engineer metabolic pathways. These approaches are reminiscent of the design, operation, and control of industrial chemical plants. Immune cells have emerged as an intriguing system in which metabolism influences diverse biological functions. Application of metabolic flux analysis and related approaches to macrophages and T cells offers great therapeutic opportunities to biochemical engineers