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  • br Concluding remarks A crucial step

    2020-03-25


    Concluding remarks A crucial step in the microbial degradation of steroids is the 1(2)-dehydrogenation of the steroid nucleus by FAD-dependent Δ1-KSTDs. This step is required to initiate the opening of the steroid nucleus under both aerobic and anaerobic conditions. A large variety of steroid-degrading microorganisms can carry out this biotransformation or harbor gene(s) encoding (putative) Δ1-KSTD(s), attesting the enzyme’s physiological importance and role. Many microorganisms, particularly from the phylum Actinobacteria, may even express multiple Δ1-KSTD isoenzymes. In line with their widespread distribution, Δ1-KSTDs have quite diverse amino Anastrozole sequences. Yet, even the most deviating sequences appear to be compatible with the R. erythropolis SQ1 Δ1-KSTD1 fold, suggesting that Δ1-KSTDs share a common overall fold. Biochemical, structural, and mutational studies substantiated that Δ1-KSTDs catalyze a direct 1(2)-dehydrogenation of 3-ketosteroid substrates. The enzymes make use of a Tyr residue to abstract the axial β-hydrogen from the C2 atom of the substrate as a proton and use FAD to accept the axial α-hydrogen from the C1 atom as a hydride ion. To complete the catalytic cycle, the reduced FAD should be re-oxidized by an electron acceptor. However, the nature of the electron acceptor and mechanism of the re-oxidation are currently incompletely understood and need further investigation. Finally, although AD is a common substrate for Δ1-KSTDs, most biochemically-characterized enzymes are able to accept a wide range of naturally occurring and chemically modified 3-ketosteroids as substrates. How the Δ1-KSTDs fine-tune their substrate specificity is an intriguing subject for further investigation, which may be of interest for future biotechnological development and production of specialty steroids.
    Competing interests
    Acknowledgments This work was partly supported by Universitas Airlangga to AR (Hibah Riset Mandat No. 624/UN3.14/LT/2017). AR was a recipient of a scholarship from the Directorate General of Higher Education, the Ministry of Research, Technology, and Higher Education, Republic of Indonesia.
    Introduction All-trans-Retinoic acid (RA)3 is the major bioactive form of vitamin A that influences a broad spectrum of physiological processes during embryogenesis and adulthood [1], [2], [3]. Through interactions with nuclear transcription factors, retinoic acid receptors (RARs), RA regulates the expression of over 500 genes [4]. RA is synthesized from the alcohol form of vitamin A (all-trans-retinol) via a two-step process. First, all-trans-retinol is oxidized to all-trans-retinaldehyde by retinol dehydrogenases, and then all-trans-retinaldehyde is oxidized to RA by at least three different retinaldehyde dehydrogenases (RALDH 1-3) [reviewed in Ref. [5]]. Studies from several laboratories demonstrated that retinol dehydrogenase 10 (RDH10) is indispensable for RA biosynthesis during mouse embryogenesis [6], [7], [8], [9], [10]. Disruption of retinol oxidation through inactivation of RDH10 results in forelimb, craniofacial, neural, and heart defects, which cumulatively lead to mid-gestational lethality [6], [8]. While this phenotype indicates that RDH10 serves as the major retinol dehydrogenase during mid-embryogenesis, RDH10-null mice also provide evidence for the existence of additional sources of retinol dehydrogenase activity. Most notably, RA synthesis persists in the neural tube of these embryos at E9.5 and E10.5 [7], [10]. Furthermore, RDH10-null embryos can be rescued by supplementation of maternal diets with retinaldehyde when embryos are between developmental stages E7.5 and E9.5 [8]. In adulthood, Rdh10 in Sertoli and/or germ cells appears to be dispensable for spermatogenesis [11]. These observations suggest that other retinol dehydrogenases besides RDH10 contribute to the oxidation of retinol to retinaldehyde for RA biosynthesis during later stages of development as well as in certain adult tissues. However, the molecular identities of these additional retinol dehydrogenases remain elusive.