The stereochemistry of α-oxidation of fatty acids in plants: the configuration of biosynthetic long-chain 2-hydroxy acids

Hitchcock, C. H. S.; Rose, Adam J.

doi:10.1042/bj1251155

Cited by 21 publications

(8 citation statements)

References 4 publications

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“…2-OHFAs are constituents of sphingolipids and membrane lipids in plants [46,47] and animals and are abundant in microorganisms [48], animal wool waxes, skin lipids and some specialized tissues ( e.g. brain) [13].…”

Section: Discussionmentioning

confidence: 99%

Fatty acid 2-hydroxylation inhibits tumor growth and increases sensitivity to cisplatin in gastric cancer

et al. 2019

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Background Most gastric cancers are diagnosed at an advanced or metastatic stage with poor prognosis and survival rate. Fatty acid 2-hydroxylase (FA2H) with high expression in stomach generates chiral ( R )-2-hydroxy FAs (( R )-2-OHFAs) and regulates glucose utilization which is important for cell proliferation and invasiveness. We hypothesized that FA2H impacts gastric tumor growth and could represent a novel target to improve gastric cancer therapy. Methods FA2H level in 117 human gastric tumors and its association with tumor growth, metastasis and overall survival were examined. Its roles and potential mechanisms in regulating tumor growth were studied by genetic and pharmacological manipulation of gastric cancer cells in vitro and in vivo . Findings FA2H level was lower in gastric tumor tissues as compared to surrounding tissues and associated with clinicopathologic status of patients, which were confirmed by analyses of multiple published datasets. FA2H depletion decreased tumor chemosensitivity, partially due to inhibition of AMPK and activation of the mTOR/S6K1/Gli1 pathway. Conversely, FA2H overexpression or treatment with ( R )-2-OHFAs had the opposite effects. In line with these in vitro observations, FA2H knockdown promoted tumor growth with increased level of tumor Gli1 in vivo . Moreover, ( R )-2-OHFA treatment significantly decreased Gli1 level in gastric tumors and enhanced tumor chemosensitivity to cisplatin, while alleviating the chemotherapy-induced weight loss in mice. Interpretation Our results demonstrate that FA2H plays an important role in regulating Hh signaling and gastric tumor growth and suggest that ( R )-2-OHFAs could be effective as nontoxic wide-spectrum drugs to promote chemosensitivity. Fund Grants of NSF, NIH, and PAPD.

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Section: Discussionmentioning

confidence: 99%

Fatty acid 2-hydroxylation inhibits tumor growth and increases sensitivity to cisplatin in gastric cancer

et al. 2019

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“…Mechanistically, the reaction might be similar to the hydroxylation step during a-oxidation of fatty acids (Hitchcock and Rose, 1971). Opposite to the hydroxylation step in fatty acid b-oxidation, a-oxidation-associated hydroxylation occurs on a single bond rather than a double bond.…”

Section: Discussionmentioning

confidence: 99%

Different Routes for Conifer- and Sinapaldehyde and Higher Saccharification upon Deficiency in the Dehydrogenase CAD1

Déjardin²,

et al. 2017

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In the search for renewable energy sources, genetic engineering is a promising strategy to improve plant cell wall composition for biofuel and bioproducts generation. Lignin is a major factor determining saccharification efficiency and, therefore, is a prime target to engineer. Here, lignin content and composition were modified in poplar (Populus tremula 3 Populus alba) by specifically down-regulating CINNAMYL ALCOHOL DEHYDROGENASE1 (CAD1) by a hairpin-RNA-mediated silencing approach, which resulted in only 5% residual CAD1 transcript abundance. These transgenic lines showed no biomass penalty despite a 10% reduction in Klason lignin content and severe shifts in lignin composition. Nuclear magnetic resonance spectroscopy and thioacidolysis revealed a strong increase (up to 20-fold) in sinapaldehyde incorporation into lignin, whereas coniferaldehyde was not increased markedly. Accordingly, ultra-high-performance liquid chromatography-mass spectrometry-based phenolic profiling revealed a more than 24,000-fold accumulation of a newly identified compound made from 8-8 coupling of two sinapaldehyde radicals. However, no additional cinnamaldehyde coupling products could be detected in the CAD1-deficient poplars. Instead, the transgenic lines accumulated a range of hydroxycinnamate-derived metabolites, of which the most prominent accumulation (over 8,500-fold) was observed for a compound that was identified by purification and nuclear magnetic resonance as syringyl lactic acid hexoside. Our data suggest that, upon down-regulation of CAD1, coniferaldehyde is converted into ferulic acid and derivatives, whereas sinapaldehyde is either oxidatively coupled into S9(8-8)S9 and lignin or converted to sinapic acid and derivatives. The most prominent sink of the increased flux to hydroxycinnamates is syringyl lactic acid hexoside. Furthermore, low-extent saccharification assays, under different pretreatment conditions, showed strongly increased glucose (up to +81%) and xylose (up to +153%) release, suggesting that down-regulating CAD1 is a promising strategy for improving lignocellulosic biomass for the sugar platform industry.

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“…Hydroxy fatty acids are widely found in plants (Hitchcock & Rose 1971;Bohannon & Kleiman 1975, Keinanen et al 2003) and various fungi (Van Dyk et al 1994). Some hydroxy fatty acids have been shown to inhibit the growth of plant pathogenic fungi (Hou & Foreman 2000) and 3-hydroxy acid fatty acids are antifungal in general (Sj€ ogren et al 2003).…”

Section: Discussionmentioning

confidence: 99%

The effects of hydroxy fatty acids on the hyphal branching of germinated spores of AM fungi

Nagahashi

Douds

2011

Fungal Biology

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The stereochemistry of α-oxidation of fatty acids in plants: the configuration of biosynthetic long-chain 2-hydroxy acids

Cited by 21 publications

References 4 publications

Fatty acid 2-hydroxylation inhibits tumor growth and increases sensitivity to cisplatin in gastric cancer

Fatty acid 2-hydroxylation inhibits tumor growth and increases sensitivity to cisplatin in gastric cancer

Different Routes for Conifer- and Sinapaldehyde and Higher Saccharification upon Deficiency in the Dehydrogenase CAD1

The effects of hydroxy fatty acids on the hyphal branching of germinated spores of AM fungi

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