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Metals promote sequences of the reverse Krebs cycle.

ABSTRACT: The reverse tricarboxylic acid (rTCA) cycle (also known as the reverse Krebs cycle) is a central anabolic biochemical pathway whose origins are proposed to trace back to geochemistry, long before the advent of enzymes, RNA or cells, and whose imprint remains intimately embedded in the structure of core metabolism. If it existed, a primordial version of the rTCA cycle would necessarily have been catalysed by naturally occurring minerals at the earliest stage of the transition from geochemistry to biochemistry. Here, we report non-enzymatic promotion of multiple reactions of the rTCA cycle in consecutive sequence, whereby 6 of its 11 reactions were promoted by Zn2+, Cr3+ and Fe0 in an acidic aqueous solution. Two distinct three-reaction sequences were achieved under a common set of conditions. Selectivity was observed for reduction reactions producing rTCA cycle intermediates compared with those leading off-cycle. Reductive amination of ketoacids to furnish amino acids was observed under similar conditions. The emerging reaction network supports the feasibility of primitive anabolism in an acidic, metal-rich reducing environment.

SUBMITTER: Muchowska KB

PROVIDER: S-EPMC5659384 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Metals promote sequences of the reverse Krebs cycle.

Muchowska Kamila B KB Varma Sreejith J SJ Chevallot-Beroux Elodie E Lethuillier-Karl Lucas L Li Guang G Moran Joseph J

Nature ecology & evolution 20171002 11

The reverse tricarboxylic acid (rTCA) cycle (also known as the reverse Krebs cycle) is a central anabolic biochemical pathway whose origins are proposed to trace back to geochemistry, long before the advent of enzymes, RNA or cells, and whose imprint remains intimately embedded in the structure of core metabolism. If it existed, a primordial version of the rTCA cycle would necessarily have been catalysed by naturally occurring minerals at the earliest stage of the transition from geochemistry to ...[more]

PMID: 28970480

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Project description:BackgroundAlternol is a natural compound isolated from fermentation products of a mutant fungus. Our previous studies demonstrated that Alternol specifically kills cancer cells but spares benign cells.MethodsTo investigate the mechanism underlying alternol-induced cancer cell-specific killing effect, we took a comprehensive strategy to identify Alternol's protein targets in prostate cancer cells, including PC-3, C4-2, and 22RV1, plus benign BPH1 cell lines. Major experimental techniques included biotin-streptavidin pulldown assay coupled with mass-spectrometry, in vitro enzyme activity assay for Krebs cycle enzymes and gas chromatography-mass spectrometry (GC-MS) for metabolomic analysis.ResultsAmong 14 verified protein targets, four were Krebs cycle enzymes, fumarate hydratase (FH), malate dehydrogenase-2 (MDH2), dihydrolipoamide acetyltransferase (DLAT) in pyruvate dehydrogenase complex (PDHC) and dihydrolipoamide S-succinyltransferase (DLST) in a-ketoglutarate dehydrogenase complex (KGDHC). Functional assays revealed that PDHC and KGDHC activities at the basal level were significantly higher in prostate cancer cells compared to benign prostate BPH1 cells, while alternol treatment reduced their activities in cancer cells close to the levels in BPH1 cells. Although FH and MDH2 activities were comparable among prostate cancer and benign cell lines at the basal level, Alternol treatment largely increased their activities in cancer cells. Metabolomic analysis revealed that Alternol treatment remarkably reduced the levels of malic acid, fumaric acid, and isocitric acid and mitochondrial respiration in prostate cancer cells. Alternol also drastically reduced mitochondrial respiration and ATP production in PC-3 cells in vitro or in xenograft tissues but not in BPH1 cells or host liver tissues.ConclusionsAlternol interacts with multiple Krebs cycle enzymes, resulting in reduced mitochondrial respiration and ATP production in prostate cancer cells and xenograft tissues, providing a novel therapeutic strategy for prostate cancer treatment.

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Metals promote sequences of the reverse Krebs cycle.

Publications

Metals promote sequences of the reverse Krebs cycle.

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