4-Hydroxybenzoic acid serves as an endogenous ring precursor for antroquinonol biosynthesis in Antrodia cinnamomea. (May 2019)

• Record Type: Journal Article
• Authors: Chou, Kevin Chi-Chung; Wu, Hsiang-Lin; Lin, Pei-Yin; Yang, Shang-Han; Chang, Tsu-Liang; Sheu, Fuu; Chen, Kai-Hsien; Chiang, Been-Huang
• Is Part Of: Phytochemistry. Volume 161(2019)
• Page Start: 97
• Page End: 106
• Publication Date: 2019-05
• Subjects: Antrodia cinnamomea -- Antroquinonol -- 4-Acetylantroquinonol B -- Shikimate pathway -- 4-Hydroxybenzoic acid; Botanical chemistry -- Periodicals; Biochemistry -- Periodicals; Botany -- Periodicals; Chimie végétale -- Périodiques; 572.2
• DOI: 10.1016/j.phytochem.2019.02.011
• Languages: English
• ISSNs: 0031-9422

Abstract

Abstract: Antrodia cinnamomea, an endemic fungus species of Taiwan, has long been used as a luxurious dietary supplement to enhance liver functions and as a remedy for various cancers. Antroquinonol (AQ), identified from the mycelium of A. cinnamomea, is currently in phase II clinical trials in the USA and Taiwan for the treatment of non-small-cell lung cancer. In the previous studies, we have demonstrated that AQ and 4-acetylantroquinonol B (4-AAQB) utilize orsellinic acid, via polyketide pathway, as the ring precursor, and their biosynthetic sequences are similar to those of coenzyme Q. In order to test 4-hydroxybenzoic acid (4-HBA), synthesized via shikimate pathway, is the ring precursor of AQ analogs, the strategy of metabolic labeling with stable isotopes was applied in this study. Here we have confirmed that 4-HBA serves as the ring precursor for AQ but not a precursor of 4-AAQB. Experimental results indicated that A. cinnamomea preferentially utilizes endogenous 4-HBA via shikimate pathway for AQ biosynthesis. Exogenous tyrosine and phenylalanine can be utilized for AQ biosynthesis when shikimate pathway is blocked by glyphosate. The benzoquinone ring of 4-AAQB is synthesized only via polyketide pathway, but that of AQ is synthesized via both polyketide pathway and shikimate pathway. The precursor-products relationships diagram of AQ and 4-AAQB in A. cinnamomea are proposed based on the experimental findings. Graphical abstract: Image 1 Highlights: 4-Hydroxybenzoic acid (4-HBA) is a precursor of antroquinonol in Antrodia cinnamomea. Exogenous tyrosine and phenylalanine can be utilized for antroquinonol biosynthesis only when shikimate pathway is blocked. Ring of antroquinonol is synthesized via both shikimate pathway and polyketide pathway. Ring of 4-acetylantroquinonol B is synthesized via polyketide pathway, which may be due to the structural-selectivity of aromatic farnesyltransferase.