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  • br Conclusions The PQQ dependent CcPDH is the first

    2019-10-11


    Conclusions The PQQ-dependent CcPDH is the first PQQ-dependent enzyme identified in eukaryotes. The PQQ cofactor binds the enzyme with high affinity, reflected in a Kd of 1.1 nM, and the enzyme oxidizes 2KG, l-fucose, and rare sugars such as d-arabinose and l-galactose. The AA8 cytochrome b domain exhibits spectral and electrochemical features that are almost identical to those observed for the AA8 domains of CDHs, suggesting that CcPDH can activate LPMOs, as was indeed observed. The amino CTPB and sequence of the AA12 domain in CcPDH is clearly distinct from those of known PQQ-dependent enzymes, underpinning the novelty of this family of PQQ-dependent enzymes. The fungal PQQ-dependent enzymes provide an expanded perspective on the enzymatic degradation of plant polysaccharides, especially due to their ability to activate LPMOs. However, the physiological role of this enzyme remains unclear. Further studies on AA12 enzymes have a potential to generate new concepts in plant biomass degradation and may even shed light on symbiotic interplay between fungi and bacteria.
    Conflict of interest statement
    References and recommended reading Papers of particular interest, published within the period of review, have been highlighted as:
    Acknowledgements This work was supported by a Grant-in-Aid for Young Scientific Research (B), JSPS KAKENHI Grant Number 17K17703 to KT, and Grant-in-Aid for Scientific Research (B), JSPS KAKENHI Grant Number 18H02252 to MY, and by a Grant-in-Aid for Innovative Areas18H05484 and 18H05494 from the Japanese Ministry of Education, Culture, Sports, and Technology (MEXT) to KI. AV & VGHE were supported by the Research Council of Norway through the BioMim project, grant number 243663.
    Introduction Dihydrotestosterone (DHT) is a potent androgen [1]. DHT can promote prostate cancer cell growth [2]. Androgen ablation therapy, including castration or use of luteinizing hormone-releasing hormone agonists, is the main treatment of prostate cancer. Although androgen ablation is very effective for the early treatment of prostate cancer, the cancer may recur in some patients, becoming the androgen-independent prostate cancer [2]. Recent studies have demonstrated that the rates of prostate cancer recurrence are high, suggesting that the ablation may not completely inhibit the production of androgens. DHT production has been reported in androgen-independent prostate cancer cells, where testosterone is used as a substrate [3]. The homeostasis of DHT depends on its biosynthesis and metabolism, including 5α-reductase 1 (SRD5A1, EC 1.3.99.5), 3α-hydroxysteroid dehydrogenase (AKR1C14, EC 1.1.1.225), and retinol dehydrogenase type II (RDH2, EC 1.1.1.105) [4]. Blocking DHT production could have benefits to treat prostate cancer. Gossypol (GOS) is a polyphenol isolated from cotton seeds. It exists as (+) or (−) enantiomer and was used as a male contraceptive [5,6]. GOS is also being tested to treat various types of cancer, including prostate cancer [7,8], lung cancer [9], colon cancer [10], breast cancer [11], bladder cancer [12], and glioblastoma [13]. Interestingly, it was found that (−) GOS was a potent BCL-2 inhibitor [7,8,13], being effective for the androgen-independent prostate cancer [7]. The suppression of DHT by GOS, if it can, may also have the benefits for its treatment of the androgen-independent prostate cancer. DHT is generated from testosterone by SRD5A1 [14]. Rat immature Leydig cells are a good model for investigating the effects of GOS on DHT production. Rat immature Leydig cells contain DHT synthetic enzyme SRD5A1 (encoded by Srd5a1) [15,16] and metabolizing enzymes 3α-hydroxysteroid dehydrogenase (encoded by Akr1c14) [15], and RDH2 (encoded by Rdh2) [16,17] and can secrete androstanediol after the catalysis of SRD5A1 and AKR1C14 (Fig. 1). We hypothesized that GOS inhibited SRD5A1, AKR1C14, and RDH2 and controlled the intracellular level of DHT. In the present study, rat SRD5A1, AKR1C14, and RDH2 were expressed in COS-1 cells. The potency and mode of action of GOS to inhibit these enzymes in both expressed enzyme preparations and rat immature Leydig cells were examined. Molecular docking study of GOS on the crystal structure of AKR1C14 was performed.