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• W2748597739 abstract "17beta-hydroxysteroid dehydrogenase (17beta-HSD) type 1 and type 3 function as estrogen and androgen activity regulators, respectively, thereby playing key roles in sexual differentiation, pregnancy and sex-steroid associated types of cancers in mammals. Although in non-mammalian vertebrates similar functions of the respective sex-steroids have been reported, there is still only little information available on enzymes which metabolize and regulate these substances. In this work the identification and characterization of the zebrafish homologs of 17beta-HSD type 1 and type 3 is described. In silico screens of available EST and genomic databases yielded a set of candidate sequences, which were successively complemented to give rise to the full-length coding sequences. For 17beta-HSD type 1 and type 3 three putative zebrafish homologs each were obtained. To the respective human and mouse homologs they displayed a highly similar exon architecture and shared about 50-60% identical amino acids. Thorough subsequent analyses on DNA, RNA and protein level were carried out to identify the true homolog among the candidate sequences. In this way, zebrafish 17beta-HSD type 1 (zfHSD 1) and two closely related, paralogous photoreceptor-associated retinol dehydrogenases (zfprRDH 1 and zfprRDH 2) were identified. Expression analyses during embryogenesis and in tissues of adult male and female fish revealed specific expression patterns for each zebrafish gene. In this respect, zfHSD 1 was highly similar to the mammalian 17beta-HSDs type 1 whereas from the two zfprRDHs only type 1 resembled an expression profile similar to its mammalian homolog and type 2 displayed widespread expression. Phylogenetic analyses supported the affiliation of the zebrafish proteins to the respective enzyme groups and suggested the duplicated zfprRDH to be fish-specific and absent in other vertebrates. These analyses identified a close evolutionary connection between 17beta-HSDs type 1 and retinol dehydrogenases, which was further highlighted by dissection of 17beta-HSDs type 1 and prRDHs on protein level. Sequence analyses revealed residues and conserved elements typical for each enzyme group. Furthermore, presence and integrity of structural and functional motifs of the short-chain dehydrogenase/reductase family suggested all three zebrafish enzymes to be functional and similar to their mammalian homologs. This aspect was more closely investigated by homology modeling, based on the crystal structure of the human enzyme. Several amino acids important in recognition and binding of cofactor and substrate, and essential for the catalytic mechanism were identified. Structural differences to the closely related zfprRDHs especially affecting the substrate binding part were outlined and one highly conserved amino acid close to the catalytic center suggested to function in retinoid-steroid discrimination. Activity measurements on recombinant zebrafish wild type zfHSD 1, zfprRDH 1 and zfprRDH 2 supported the notion that, in spite of their close relation, only the first of these enzymes was capable of catalyzing the reduction of estrone to estradiol, characteristic for all so far analyzed 17beta-HSDs type 1. Furthermore, mutation of the aforementioned amino acid hypothesized to be involved in substrate discrimination in all three enzymes did reduce catalytic activity in zfHSD 1 whereas the two zfprRDHs did not show an increased affinity towards steroids. Concerning the 17beta-HSD type 3 candidates, extensive analyses revealed the zebrafish homolog (zfHSD 3) and two closely related paralogous forms of 17beta-HSD type 12. Phylogenetic analyses highlighted the close and complex evolution of both groups identifying 17beta-HSD type 12 as the ancient, fatty acid metabolising progenitor of vertebrate 17beta-HSDs type 3. Unlike in case of zfHSD 1, zfHSD 3 had an expression profile different to that of its mammalian homolog. It is discussed that this may be a leftover of its fatty acid synthesizing ancestor or might be caused by involvement of zfHSD 3 in several related functions that in mammals are taken over by additional enzymes." @default.
• W2748597739 created "2017-08-31" @default.
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• W2748597739 date "2004-01-01" @default.
• W2748597739 modified "2023-09-27" @default.
• W2748597739 title "Identification and Characterization of Zebrafish 17beta-HSD Type 1 and Type 3" @default.
• W2748597739 hasPublicationYear "2004" @default.
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