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  • We then undertook computational studies that suggest

    2020-02-05

    We then undertook computational studies that suggest the cyanobacterial ALDH (and planctomyces ALDH) represent the evolutionary ancestor of human and other eukaryotic ALDH1/2 given that cfALDH contains signature residues matching both the human proteins throughout the surface of the protein and the core. Additionally, cfALDH is predicted to have an intermediate sized SEC, which allows in all-trans-retinal. Our work also suggests that the size of the SEC is indeed useful in predicting whether an ALDH is able to function on large or small aldehydes [24]. Future work should focus on establishing whether this aldehyde dehydrogenase is responsible for retinoic Metronidazole production in vivo and defining the role of retinoic acid in cyanobacteria. Finally, we note that improved methods for the laboratory synthesis of retinoic acid are in demand, since this molecule is needed for treatment of skin cancers and acne [34]. Bacterial enzymes have been proposed as important in this field, with work underway to produce a metabolically engineered E. coli that can convert glycerol all the way through to retinoic acid [35,36]. The identification of a cyanobacterial enzyme able to catalyse the ultimate step in this biosynthesis may contribute to these developments.
    Materials and methods
    Acknowledgements We thank Dr David Adams at the University of Leeds for providing us with Chlorogloeopsis fritschii PCC 6912. This phylogenetic work was undertaken on MARC1, part of the High Performance Computing and LIDA facilities at the University of Leeds, UK.
    Introduction Steroid hormones, including androgens, estrogens, progestins, glucocorticoids, and mineralocorticoids, play crucial roles in the differentiation, development, growth, and physiological functions of most vertebrates [1]. 3β-Hydroxy-Δ5-steroid dehydrogenase/Δ5,Δ4-isomerase (HSD3B, EC1.1.1.145) catalyzes the oxidative conversion of Δ5-3β-hydroxy steroids into a Δ4-3-oxo steroids. HSD3B is an enzyme responsible for intermediate steroidogenic reaction for the synthesis of androgens, estrogens, progestins, glucocorticoids, and mineralocorticoids in the adrenal cortex, gonads, placenta, and a variety of peripheral target tissues [1]. Here, we primarily discuss the testicular isoform of HSD3B. Many endocrine disruptors, such as industrial materials (phthalates, bisphenols, and perfluoroalkyl substances), insecticides and fungicides (organochloride insecticides and organotins), plant active components (polyphenols, and flavones and isoflavones), as well as drugs (etomidate, troglitazone, and medroxyprogesterone acetate) may cause testosterone deficiency via directly inhibiting testicular HSD3B activity [2]. Since many inhibitory data are obtained from human and rat enzymes, the present review focuses on these two species.
    Testicular HSD3B isoforms
    HSD3B-inhibitory endocrine disruptors Many endocrine disruptors could be anti-androgens. One of their mechanisms is direct inhibition of testicular HSD3B activity [2,24]. These environmental endocrine disruptors are derived from food, environment and other consumer products. After suppression of HSD3B activity, the androgen synthesis is significantly suppressed, leading to developmental and reproductive toxicity, including abnormal reproductive tract, diminished fertility, and hypogonadism [25]. These environmental pollutants include industrial materials (phthalates, bisphenols, and perfluoroalkyl substances), insecticides/fungicides (organochloride insecticides and organotins), food additives (butylated hydroxyanisole), plant active components (polyphenols, and flavones and isoflavones) and drugs. Several environmental endocrine disruptors targeting on testicular HSD3B isoforms are discussed here and their structure-activity-relationship (SAR) is compared (Table 1).
    Summary and conclusion Many environmental endocrine disruptors interfere with steroid biosynthesis and metabolism via inhibiting testicular HSD3B in rats and humans. These endocrine disruptors fall in different groups, in which some chemicals have a clear SAR. These chemicals can inhibit testicular HSD3B, thus lowering androgen production (Fig. 3).