Abstract
In the presence of CoA, cell-free extracts prepared from porcine liver was found to convert 7,8-dihydroxyflavone (DHF) to a pantetheine conjugate, which was a novel flavonoid. We purified a 7,8-DHF-converting enzyme from the extracts, and identified it as hemoglobin (Hb). The purified Hb showed the following two activities: (i) degradation of CoA into pantetheine through hydrolytic cleavage to yield pantetheine and 3′-phospho-adenosine-5′-diphosphate (ADP) independently of heme, and (ii) addition of a thiol (e.g., pantetheine, glutathione and cysteine) to 7,8-DHF through C-S bond formation. Human Hb also exhibited the above flavonoid-converting activity. In addition, heme-containing enzymes such as peroxidase and catalase added each of pantetheine, glutathione and cysteine to the flavonoid, although no pantetheine conjugates were synthesized when CoA was used as a substrate. These findings indicated that the thiol-conjugating activity is widely observed in heme-containing proteins. On the other hand, only Hb catalyzed the hydrolysis of CoA, followed by the thiol conjugation to synthesize the pantetheine conjugate. To the best of our knowledge, this is the first report showing that Hb has the catalytic ability to convert naturally occurring bioactive compounds, such as dietary flavonoids, to the corresponding conjugates in the presence of thiol donors or CoA.
Highlights
For many years, natural products have been recognized as a rich source of compounds for drug discovery
We have studied the metabolism of biologically active natural compounds, such as curcumin[12], sesamin[13], and piperonal[14]
After incubation for 7 h at 37 °C, the products that could be derived from 7,8-DHF were formed when CoA was added to the reaction mixture (Fig. S1)
Summary
Natural products have been recognized as a rich source of compounds for drug discovery. Flavonoids absorbed by the small intestine are exclusively converted into conjugates in the liver, and the resultant conjugates enter the circulatory system[6]. Glucuronidated and sulfated flavonoids showed protective activity against endothelial dysfunction in vivo[11] These unique activities of metabolized flavonoids are a part of the bioactivity of ingested flavonoids. We proposed a new biocatalyst concept; actinorhodin, a natural low-molecular mass organic compound, acts as a biocatalyst under physiological conditions[15]. This finding opens the door to a new field of organocatalysts in living organisms.
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