Synthesis and Siderophore Activity of Vibrioferrin and One of Its Diastereomeric Isomers.

Takeuchi, Yasuo; Nagao, Yutaka; Toma, Kyoko; Yoshikawa, Yumiko; Akiyama, Toshihiko; Nishioka, Hiromi; Abe, Hitoshi; Harayama, Takashi; Yamamoto, Satoshi

doi:10.1248/cpb.47.1284

Cited by 15 publications

(16 citation statements)

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“…The methods for synthesis of ␣-ketoglutarate esters were adopted from previous work (6,27). The octyl-␣-ketoglutarate ester was prepared using the following method: octyl-chloroformate was added drop by drop to a solution of ␣-ketoglutaric acid (10 mmol) and triethylamine (1.0 eq) in dichloromethane (50 ml) at ambient temperature.…”

mentioning

confidence: 99%

Cell-Permeating α-Ketoglutarate Derivatives Alleviate Pseudohypoxia in Succinate Dehydrogenase-Deficient Cells

MacKenzie

Selak

Tennant

et al. 2007

Molecular and Cellular Biology

334

294

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Succinate dehydrogenase (SDH) and fumarate hydratase (FH) are components of the tricarboxylic acid (TCA) cycle and tumor suppressors. Loss of SDH or FH induces pseudohypoxia, a major tumor-supporting event, which is the activation of hypoxia-inducible factor (HIF) under normoxia. In SDH-or FHdeficient cells, HIF activation is due to HIF1␣ stabilization by succinate or fumarate, respectively, either of which, when in excess, inhibits HIF␣ prolyl hydroxylase (PHD). To reactivate PHD, we focused on its substrate, ␣-ketoglutarate. We designed and synthesized cell-permeating ␣-ketoglutarate derivatives, which build up rapidly and preferentially in cells with a dysfunctional TCA cycle. This study shows that succinate-or fumarate-mediated inhibition of PHD is competitive and is reversed by pharmacologically elevating intracellular ␣-ketoglutarate. Introduction of ␣-ketoglutarate derivatives restores normal PHD activity and HIF1␣ levels to SDH-suppressed cells, indicating new therapy possibilities for the cancers associated with TCA cycle dysfunction.Under normal oxygenation conditions (normoxia), hypoxiainducible factor alpha (HIF␣) proteins (HIF1␣ and/or HIF2␣), which are the formation-limiting units of the HIF transcription factor heteromer, are constantly both synthesized and degraded, a process that maintains them in high availability but at a very low steady state (4, 25). The high turnover of HIF␣ is mediated by HIF␣ prolyl hydroxylases (PHD1 to -3, also known as EglN1 to -3 and HPH1 to -3). PHDs hydroxylate proline residues on the oxygen-dependent degradation (ODD) domain of HIF␣, generating docking sites for pVHL-part of an E3 ubiquitin ligase complex that targets HIF␣ for degradation (21,22). To catalyze proline hydroxylation, PHDs convert molecular oxygen and ␣-ketoglutarate to carbon dioxide and succinate (22). Although PHDs depend on oxygen for activity, their affinity for oxygen is low (K m ϭ 230 to 250 M), making them good oxygen sensors (11). Under hypoxia, prolyl hydroxylation of HIF␣ and its consequent interaction with pVHL are prevented, and HIF␣ proteins are stabilized (21). Stabilized HIF␣ units bind to the HIF␤ unit, setting off HIF transcription activity. Thus, HIF is physiologically activated by hypoxia, and its downstream targets respond accordingly by increasing angiogenesis and glycolysis.The aberrant stabilization of HIF␣ under normoxic conditions is termed pseudohypoxia. Pseudohypoxia is probably a major cause of tumors associated with VHL mutations (15). Pseudohypoxia was also shown recently in tumor cells with mutations in fumarate hydratase (FH) or in any of three of the four subunits of succinate dehydrogenase (SDH), SDHB, SDHC, or SDHD (5,8,9,19,20,28). Both FH and SDH are mitochondrial proteins; SDH forms complex II of the electron transport chain, and both SDH and FH are enzymes of the tricarboxylic acid (TCA) cycle. In addition, SDH and FH are also bona fide tumor suppressors. Dysfunction of either of these TCA cycle enzymes causes pseudohypoxia, leading to the enhanced neovasculari...

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mentioning

confidence: 99%

Cell-Permeating α-Ketoglutarate Derivatives Alleviate Pseudohypoxia in Succinate Dehydrogenase-Deficient Cells

MacKenzie

Selak

Tennant

et al. 2007

Molecular and Cellular Biology

334

294

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“…The 13 C NMR data of 3 ( Table 1 ) assigned with the assistance of the HSQC experiment ( Figure S4 ) confirmed the 11 carbon signals, which corresponded to three carboxyl carbons ( δ C 170.3, 170.5, and 175.3), two oxygenated carbons ( δ C 64.2 and 72.9), four sets of methylene groups ( δ C 18.6, 30.2, 42.7, and 42.7), one methoxy-oriented carbon ( δ C 50.7), and one methyl carbon ( δ C 12.5). Based on this evidence, it was predicted that compound 3 was a citric acid derivative, since the characteristic NMR data of 3 was similar to that of the citric acid derivatives [ 21 , 22 ]. The gross structure of 3 was determined by 2D NMR experiments ( 1 H- 1 H COSY; Figure S3 and HMBC; Figure S5 ).…”

Section: Resultsmentioning

confidence: 99%

“…The structures of the known compounds ( Figure 1 ) were determined to be ( S )-dimethyl malate ( 1 ) [ 26 ], ( S )-5,1′-dimethyl citrate ( 2 ) [ 21 ], 1′-butyl-1,5-dimethyl citrate ( 5 ) [ 22 ], and butyl quinate ( 7 ) [ 27 ] by spectroscopic methods, including 1 H and 13 C NMR spectra, by comparing their spectroscopic data with those previously reported in the literature and MS data obtained from LC/MS analysis. To the best of our knowledge, compounds 2 , 5 , and 7 are reported from H. rhamnoides for the first time in this study.…”

Section: Resultsmentioning

confidence: 99%

Phytochemical Analysis of the Fruits of Sea Buckthorn (Hippophae rhamnoides): Identification of Organic Acid Derivatives

Lee

Jang

Park

et al. 2021

Plants

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Hippophae rhamnoides L. (Elaeagnaceae), commonly known as “Sea buckthorn” and “Vitamin tree”, is a spiny deciduous shrub whose fruit is known for its nutritional composition, such as vitamin C, and is consumed as a dietary supplement worldwide. As part of our ongoing efforts to identify structurally new and bioactive constituents from natural resources, the phytochemical investigation of the extract of H. rhamnoides fruits led to the isolation of one malate derivative (1), five citrate derivatives (2–6), and one quinate derivative (7). The structures of the isolated compounds were elucidated by analysis of 1D and 2D nuclear magnetic resonance (NMR) spectroscopic data and high-resolution electrospray ionization (HR-ESI) liquid chromatography–mass spectrometry (LC/MS) data. Three of the citrate derivatives were identified as new compounds: (S)-1-butyl-5-methyl citrate (3), (S)-1-butyl-1′-methyl citrate (4), and (S)-1-methyl-1′-butyl citrate (6), which turned out to be isolation artifacts. The absolute configurations of the new compounds were established by quantum chemical electronic circular dichroism (ECD) calculation, which is an informative tool for verifying the absolute configuration of organic acid derivatives. The isolated compounds 1–7 were evaluated for their stimulatory effects on osteogenesis. Compounds 1, 3, 4, 6, and 7 stimulated osteogenic differentiation up to 1.4 fold, compared to the negative control. These findings provide experimental evidence that active compounds 1, 3, 4, 6, and 7 induce the osteogenesis of mesenchymal stem cells and activate bone formation.

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“…Iron uptake was studied with 55 Fe 3+ proving that vibrioferrin acts as a siderophore despite the fact that it has only five ligand sites, the two a-hydroxy acids and the free citric acid carboxyl group. Possibly a solvent molecule satisfies the eighth octahedral position (393,411 3+ -to-ligand ratio, and NMR studies of the Ga 3+ complex confirm the participation of the two a-hydroxy-and of the a-amino acid functions in complex formation. Uptake studies with 55 Fe 3+ showed that staphyloferrin B acts as a siderophore, but it is less efficient than staphyloferrin A.…”

Section: Siderophores With 2-oxoglutaric Acid Unitsmentioning

confidence: 89%

“…16) was isolated from Vibrio parahaemolyticus. The stereochemistry of the central citric acid C-atom is R, that of the alanine part is S as shown by stereospecific synthesis (411). Iron uptake was studied with 55 Fe 3+ proving that vibrioferrin acts as a siderophore despite the fact that it has only five ligand sites, the two a-hydroxy acids and the free citric acid carboxyl group.…”

Section: Siderophores With 2-oxoglutaric Acid Unitsmentioning

confidence: 94%

Microbial Siderophores

Budzikiewicz

2010

Fortschritte Der Chemie Organischer Naturstoffe / Progress in the Chemistry of Organic Natural Products, Vol. 92

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Synthesis and Siderophore Activity of Vibrioferrin and One of Its Diastereomeric Isomers.

Cited by 15 publications

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Cell-Permeating α-Ketoglutarate Derivatives Alleviate Pseudohypoxia in Succinate Dehydrogenase-Deficient Cells

Cell-Permeating α-Ketoglutarate Derivatives Alleviate Pseudohypoxia in Succinate Dehydrogenase-Deficient Cells

Phytochemical Analysis of the Fruits of Sea Buckthorn (Hippophae rhamnoides): Identification of Organic Acid Derivatives

Microbial Siderophores

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